Abstract Objectives To study active surveillance as a management option for the important number of prostate cancer patients who would not have been diagnosed in the absence of screening. Patients ...and methods We analyzed baseline characteristics and outcome parameters of all men on active surveillance who were screen-detected in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Recruitment and surveillance of men were not guided by a protocol but depended on individual decisions of patients and their physicians. Results Active surveillance was applied in 278 men detected by screening from 1993 to 2006. At diagnosis, their median age was 69.8 yr (25–75p; 66.1–72.8); median PSA 3.6 ng/ml (25–75p; 3.1–4.8), and the clinical stage was T1c in 220 (79.1%) and T2 in 58 (20.9%). During the follow-up of median 3.4 yr, 103 men (44.2%) had a PSA doubling time that was negative (ie, half-life) or longer than 10 yr. Men detected at rescreening were significantly more likely to be on active surveillance, and they had more beneficial characteristics. Deferred treatment was elected in 82 cases (29.0%). Overall survival was 89% after 8 yr; the cause-specific survival was 100%. Conclusions This report shows a beneficial, although preliminary, outcome of screen-detected men managed on active surveillance. Men were more likely to be on active surveillance if the disease was detected at repeated screening. The report also shows that an important proportion of men have prolonged PSA doubling times, although the value of this parameter has not been established in untreated men.
Abstract Background The value of digital rectal examination (DRE) as a screening test for prostate cancer (PC) is controversial in the current prostate-specific antigen (PSA) era. Objectives To ...determine (1) the additional value of a suspicious DRE for the detection of PC in men with an elevated PSA level in subsequent screenings and (2) the tumour characteristics of PCs detected in men with a suspicious DRE. Design, setting, participants Within the screening study, from 1997–2006 men aged 55–75 years were invited for an every 4-yr PSA determination. A PSA level ≥3.0 ng/ml prompted a DRE and a transrectal ultrasound (TRUS)–guided, lateralized sextant biopsy. Throughout the three screenings of the ERSPC, Rotterdam, 5040 biopsy sessions were evaluated. Measurements We determined the positive predictive values (PPVs) of a suspicious DRE and normal DRE, which entailed, respectively, the proportion of PCs detected in men with a suspicious DRE or normal DRE divided by, respectively, all biopsied men with a suspicious DRE or normal DRE. Results and limitations At initial screening, the PPV of a suspicious DRE, in conjunction with an elevated PSA level, to detect PC was 48.6% compared to 22.4% for men with a normal DRE. Both PPVs decreased in consecutive screens: respectively, 29.9% versus 17.1% (screen 2) and 21.2% versus 18.2% (screen 3). Respectively, 71.0% ( p < 0.001), 68.8% ( p < 0.001), and 85.7% ( p = 0.002) of all PCs with a Gleason score >7 were detected in men with a suspicious DRE at screens 1, 2, and 3. A limitation is that only biopsied men were evaluated. Conclusions At initial and subsequent screenings, the chance of having cancer at biopsy was higher in men with a suspicious DRE compared to men with a normal DRE (to a lesser extent in subsequent screenings), and the combination of a PSA level ≥3.0 ng/ml with a suspicious DRE resulted in detecting significantly more PCs with Gleason score >7. DRE may be useful in more selective screening procedures to decrease unnecessary biopsies and overdiagnosis.
Abstract Context Androgen-deprivation therapy (ADT) plays a pivotal role in the management of locally advanced and metastatic prostate cancer (PCa). When and for how long to apply ADT have remained ...controversial issues. Objective To review randomised studies of ADT (orchiectomy or luteinising hormone-releasing hormone analogues) in PCa—both immediate and deferred/adjuvant studies—to elucidate a possible interaction between local treatment and ADT. Evidence acquisition Published randomised studies on ADT in various stages of PCa were included in this review. Evidence synthesis Studies of immediate versus deferred ADT without local treatment consistently showed only limited benefit for overall survival (OS; hazard ratio HR: 0.90; 95% confidence interval CI, 0.83–0.97) and cancer-specific survival (CSS; HR: 0.79; 95% CI, 0.71–0.89). In contrast, ADT as an adjuvant to radiation therapy in patients with high-risk localised disease or locally advanced disease was associated with substantial OS and CSS benefits. A similar benefit was seen in patients with proven systemic disease (node-positive patients after radical prostatectomy). Overall, the data suggest a clinically important survival benefit (HR for OS: 0.69; 95% CI, 0.61–0.79) when a local treatment has been applied to the primary tumour. Possible mechanisms of this therapeutic effect are discussed. Conclusions We conclude that an interaction between local treatment and ADT is suggested by this systematic review. In patients with advanced and aggressive disease who are at a high risk to die from PCa and who are treated for their primary tumour with curative intent, immediate and sustained ADT improves OS and CSS significantly. The local therapy in T3 and/or lymph node–positive disease is an essential part of the optimal treatment. However, this intensive treatment is unnecessary in a substantial number of patients with T3 and/or N1 disease with a slow natural history or high competing death risk.
Study Type – Diagnosis (validating cohort)
Level of Evidence 1b
What's known on the subject? and What does the study add?
The European Randomized study of Screening for Prostate Cancer (ERSPC) showed ...a reduction in prostate cancer mortality of 21% for PSA‐based screening at a median follow‐up of 11 years. In the ERSPC, men are screened at 4‐year intervals. A prostate biopsy is recommended for men with a PSA level ≥3.0 ng/mL.
The study shows that the positive predictive value (PPV) of a prostate biopsy indicated by PSA‐based screening remains equal throughout consecutive screening rounds in men without a previous biopsy. In men who have previously had a benign biopsy, the PPV drops considerably, but 20% of the cancers detected still show aggressive characteristics.
OBJECTIVE
•
To assess the positive predictive value (PPV) of prostate biopsy, indicated by a prostate‐specific antigen (PSA) threshold of ≥3.0 ng/mL, over time, in the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC).
PATIENTS AND METHODS
•
In the Rotterdam section of the ERSPC, a total of 42 376 participants, aged 55–74 years, identified from population registries were randomly assigned to a screening or control arm.
•
For the ERSPC men undergo PSA screening at 4‐year intervals. A total of three screening rounds were evaluated; therefore, only men aged 55–69 years at the first screening were eligible for the present study.
RESULTS
•
PPVs for men without previous biopsy remained equal throughout the three subsequent screenings (25.5, 22.3 and 24.8% respectively).
•
Conversely, PPVs for men with a previous negative biopsy dropped significantly (12.0 and 15.2% at the second and third screening, respectively).
•
Additionally, in men with and without previous biopsy, the percentage of aggressive prostate cancers (clinical stage >T2b, Gleason score ≥7) decreased after the first round of screening from 44.4 to 23.8% in the second (P < 0.001) and 18.6% in the third round (P < 0.001).
•
Repeat biopsies accounted for 24.6% of all biopsies, but yielded only 8.6% of all aggressive cancers.
CONCLUSIONS
•
In consecutive screening rounds the PPV of PSA‐based screening remains equal in previously unbiopsied men.
•
In men with a previous negative biopsy the PPV drops considerably, but 20% of cancers detected still show aggressive characteristics.
•
Individualized screening algorithms should incorporate previous biopsy status in the decision to perform a repeat biopsy with the aim of further reducing unnecessary biopsies.
Abstract 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.
Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk ...for prostate cancer.
To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer.
Studies identified in PubMed, Web of Science, and CancerLit.
The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate.
Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom.
The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio OR in the highest vs. lowest quintile, 1.38 95% CI, 1.19 to 1.60; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake.
Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies.
High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.
The relationship between prostate-specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy for a ...given PSA level is affected by identifiable characteristics of the cohort under study.
We used data from five European and three U.S. cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally weighted scatterplot smoothing.
The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased the risk of cancer (odds ratio for >6- versus 6-core biopsy, 1.35; 95% confidence interval, 1.18-1.54; P < 0.0005); recent screening led to a smaller increase in risk per unit change in PSA (P = 0.001 for interaction term) and U.S. cohorts had higher risk than the European cohorts (2.14; 95% confidence interval, 1.99-2.30; P < 0.0005).
Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated.
Objective To demonstrate the safety and efficacy of up to 5 years of degarelix treatment and the effects of crossing over from leuprolide to degarelix in the extension phase of a phase III pivotal ...1-year trial. Methods Patients receiving degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression–free survival (secondary end points). Results Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on degarelix or crossed over from leuprolide. The prostate-specific antigen progression–free survival hazard rate was decreased significantly after the crossover in the leuprolide to degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen >20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019). Conclusion Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression–free survival benefit established for degarelix over leuprolide during year 1 remained consistent at 5 years.
PDF
