Abstract Background Evidence from randomized trials on the effects of screening for prostate cancer (PCa) on disease-specific mortality accumulates slowly with increasing follow-up. Objective To ...assess data on PCa-specific mortality in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. Design, setting, and participants A randomized controlled trial with randomization after signed, written informed consent (efficacy trial). In the period 1993–1999, a total of 42 376 men aged 54–74 yr were randomized to a screening arm (S-arm) ( n = 21 210 with screening every 4 yr, applying a total prostate-specific antigen PSA level cut-off ≥3.0 ng/ml as biopsy indication) or a control arm (C-arm) ( n = 21 166; no intervention). Outcome measurements and statistical analysis Number of PCas detected per arm depicted by predefined time periods and prognostic groups. PCa-specific mortality analyses using Poisson regression in age group 55–74 yr at randomization and separately in the predefined age group of 55–69 yr. Results and limitations After a median follow-up of 12.8 yr, 19 765 men (94.2%) were screened at least once and 2674 PCas were detected (of which 561 21.0% were interval PCas). In the C-arm, 1430 PCas were detected, resulting in an excess incidence of 59 PCas per 1000 men randomized (61 PCas per 1000 in age group 55–69 yr). Thirty-two percent of all men randomized have died. PCa-specific mortality relative-risk (RR) reductions of 20.0% overall (age: 55–74 yr; p = 0.042) and 31.6% (age: 55–69 yr; p = 0.004) were found. A 14.1% increase was found in men aged 70–74 yr (not statistically significant). Absolute PCa mortality was 1.8 per 1000 men randomized (2.6 per 1000 men randomized in age group 55–69 yr). The number needed to invite and number needed to manage were 565 and 33, respectively, for age group 55–74 yr, and 392 and 24, respectively, for age group 65–69 yr. Given the slow natural history of the disease, follow-up might be too short. Conclusions Systematic PSA-based screening reduced PCa-specific mortality by 32% in the age range of 55–69 yr. The roughly twofold higher incidence in the S-arm underlines the importance of tools to better identify those men who would benefit from screening.
OBJECTIVE
To evaluate the efficacy and safety of degarelix, a new gonadotrophin‐releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in ...a 1‐year phase III trial involving patients with prostate cancer.
PATIENTS AND METHODS
In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate‐specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen‐deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator’s assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12‐month study. Both the intent‐to‐treat (ITT) and per protocol populations were analysed.
RESULTS
The primary endpoint of the trial was suppression of testosterone to ≤0.5 ng/mL at all monthly measurements from day 28 to day 364, thus defining the treatment response. This was achieved by 97.2%, 98.3% and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were ≤0.5 ng/mL in 96.1% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (P < 0.001). The hormonal side‐effect profiles of the three treatment groups were similar to previously reported effects for androgen‐deprivation therapy. The s.c. degarelix injection was associated with a higher rate of injection‐site reactions than with the i.m. leuprolide injection (40% vs <1%; P < 0.001, respectively). There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3% vs 9%. P < 0.01, respectively), arthralgia (4% vs 9%, P < 0.05, respectively) and chills (4% vs 0%, P < 0.01, respectively). There were no systemic allergic reactions.
CONCLUSIONS
Degarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1‐year treatment period. Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study. Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists. Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide. Furthermore, there is no need for antiandrogen supplements to prevent the possibility of clinical ‘flare’.
A man’s baseline prostate-specific antigen level can guide decisions on the repeat screening interval, as demonstrated using 16-yr follow-up data from the ERSPC trial.
The European Association of ...Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age.
To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2–4 yr).
We evaluated 25589 men aged 55–59 yr, 16898 men aged 60–64 yr, and 12936 men aged 65–69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2–4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU).
We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60–61 yr.
The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2–1.5% for men with PSA <1.0 ng/ml to 13.3–13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60–61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60–61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68–70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76–78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice.
In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55–69 yr is a strong indicator to delay or stop further screening.
In prostate cancer screening, the patient’s baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.
Landmarks in prostate cancer screening Schröder, Fritz H.
BJU international,
October 2012, 2012-Oct, 2012-10-00, 20121001, Letnik:
110, Številka:
s1
Journal Article
Recenzirano
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Prostate‐specific antigen (PSA) has been widely applied to diagnosis and follow‐up of prostate cancer, which led to research on its potential role in the early detection of the disease and its use ...in screening.
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The value of PSA screening in reducing disease mortality is controversial and several studies have been conducted to determine the actual benefits. One of the early studies, the Tyrol Screening Study conducted in 1993, showed that during 2004 to 2008 there was a significant reduction in prostate cancer mortality in men aged >60 years compared with the mortality rate during 1989 to 1993.
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Two studies that showed no benefit of screening in terms of prostate cancer death were conducted in Sweden in 1987 and 1988.
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The Prostate, Lung, Colorectal, and Ovarian Screening Study conducted in the USA during 1993 to 2001 and involving 76 693 men showed no benefit of screening at 10 years but the trial can be criticised due to excessive contamination of the unscreened group.
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In contrast, the European Randomized Study of Screening for Prostate Cancer (ERSPC), the largest randomised study with 162 388 participants study, showed that at a median follow‐up of 9 years a prostate cancer mortality reduction of 20% resulted (P= 0.04). In an analysis limited to four ERSPC centres with a follow‐up of 12.0 years, screening resulted in an overall reduction of metastatic disease of 31%.
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The arguments against PSA screening include the risks associated with screening tests themselves, e.g. biopsy‐related haematuria, urosepsis, and over diagnosis and overtreatment of prostate cancer. The overall evidence points in favour of PSA screening and steps can be taken to avoid overtreatment by offering patients active surveillance.
Background: Screening for prostate cancer advances the time of diagnosis (lead time) and detects cancers that would not have been diagnosed in the absence of screening (overdetection). Both ...consequences have considerable impact on the net benefits of screening. Methods: We developed simulation models based on results of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which enrolled 42 376 men and in which 1498 cases of prostate cancer were identified, and on baseline prostate cancer incidence and stage distribution data. The models were used to predict mean lead times, overdetection rates, and ranges (corresponding to approximate 95% confidence intervals) associated with different screening programs. Results: Mean lead times and rates of overdetection depended on a man’s age at screening. For a single screening test at age 55, the estimated mean lead time was 12.3 years (range = 11.6–14.1 years) and the overdetection rate was 27% (range = 24%–37%); at age 75, the estimates were 6.0 years (range = 5.8–6.3 years) and 56% (range = 53%–61%), respectively. For a screening program with a 4-year screening interval from age 55 to 67, the estimated mean lead time was 11.2 years (range = 10.8–12.1 years), and the overdetection rate was 48% (range = 44%–55%). This screening program raised the lifetime risk of a prostate cancer diagnosis from 6.4% to 10.6%, a relative increase of 65% (range = 56%–87%). In annual screening from age 55 to 67, the estimated overdetection rate was 50% (range = 46%–57%) and the lifetime prostate cancer risk was increased by 80% (range = 69%–116%). Extending annual or quadrennial screening to the age of 75 would result in at least two cases of overdetection for every clinically relevant cancer detected. Conclusions: These model-based lead-time estimates support a prostate cancer screening interval of more than 1 year.
Abstract Background The performance characteristics of serum prostate-specific antigen (PSA) as a diagnostic test for prostate cancer (PCa) are poor. The performance of the PCa antigen 3 (PCA3) gene ...as a primary diagnostic is unknown. Objective Assess the value of PCA3 as a first-line diagnostic test. Design, setting and participants Participants included men aged 63–75 who were invited for rescreening in the period from September 2007 to February 2009 within the European Randomised Study of Screening for Prostate Cancer, Rotterdam section. Interventions Lateral sextant biopsies were performed if the serum PSA value was ≥3.0 ng/ml and/or the PCA3 score was ≥10. Measurements Measurements included distribution and correlation of PSA value and PCA3 score and their relation to the number of cases and the characteristics of PCa detected. Additional value of PCA3 was included in men with previous negative biopsy and/or PSA <3.0 ng/ml. Results and limitations In 721 men, all biopsied, 122 PCa cases (16.9%) were detected. Correlation between PSA and PCA3 is poor (Spearman rank correlation: ρ = 0.14; p < 0.0001). A PSA ≥3.0 ng/ml misses 64.7% of the total PCa that can be detected with the sextant biopsy technique and 57.9% of serious PCa (T2a or higher and/or Gleason grade ≥4, n = 19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 ≥35 are 32%, 26.3%, and 51.7%. Performance of PCA3 in men with low PSA (area under the curve AUC: 0.63) and/or previous negative biopsy (AUC: 0.68) is unclear but has limited reliability due to small numbers. Conclusions PCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population.
Abstract Context Castration-resistant prostate cancer (CRPC) refers to patients who no longer respond to surgical or medical castration. Standard treatment options are limited. Objective To review ...the concepts and rationale behind targeted agents currently in late-stage clinical testing for patients with CRPC. Evidence acquisition Novel targeted therapies in clinical trials were identified from registries. The MEDLINE database was searched for all relevant reports published from 1996 to October 2009. Bibliographies of the retrieved articles and major international meeting abstracts were hand-searched to identify additional studies. Evidence synthesis Advances in our understanding of the molecular mechanisms underlying prostate cancer (PCa) progression has translated into a variety of treatment approaches. Agents targeting androgen receptor (AR) activation and local steroidogenesis, angiogenesis, immunotherapy, apoptosis, chaperone proteins, the insulin-like growth factor (IGF) pathway, RANK-ligand, endothelin receptors, and the Src family kinases are entering or have recently completed accrual to phase 3 trials for patients with CRPC. Conclusions A number of new agents targeting mechanisms of PCa progression with early promising results are in clinical trials and have the potential to provide novel treatment options for CRPC in the near future.
Quality-of-Life Effects of PSA Screening
PSA screening of men between the ages of 55 and 69 years resulted in a reduction in deaths from prostate cancer. However, when overdiagnosis and treatment ...sequelae were considered, the number of quality-adjusted life-years gained through screening was also reduced.
After a median follow-up of 9 years, the initial results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed a significant relative reduction of 20% in prostate-cancer mortality among men undergoing prostate-specific antigen (PSA) screening, with a reduction of 27% after adjustment for selection bias.
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In recently updated results at 11 years, the relative reduction in prostate-cancer mortality in the screening group was 29% after adjustment for selection bias.
2
At the Gothenburg center in the ERSPC, there was a reduction of 44% in prostate-cancer mortality after a median follow-up of 14 years among all men (including those . . .
Abstract 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.
In prostate cancer genomic rearrangements involving genes encoding ETS transcription factors are commonly present, with androgen-regulated transmembrane protease, serine 2 (TMPRSS2)-v-ets ...erythroblastosis virus E26 oncogen homologue (ERG) gene fusion occurring in 40-70%. Studies on the predictive value of ERG rearrangement as detected by in-situ hybridization or polymerase chain reaction have resulted in varying outcomes. The objective of this study was to correlate immunohistochemical ERG protein expression with clinico-pathological parameters at radical prostatectomy specimens, and to determine its predictive value for postoperative disease recurrence and progression in a prostate cancer screening cohort. Since androgen receptor is downregulated by ERG in cell lines, we also compared the expression of respective proteins. We selected 481 participants from the European Randomized Study of Screening for Prostate Cancer treated by radical prostatectomy for prostate adenocarcinoma. A tissue microarray was constructed containing representative cores of all prostate cancer specimens as well as 22 xenografts and seven cell lines. Immunohistochemical expression of ERG and androgen receptor was correlated with prostate-specific antigen (PSA), Gleason sum, pT-stage, surgical margins, biochemical recurrence, local recurrence, overall death and disease-specific death. ERG expression was detected in 284 patients (65%). Expression occurred significantly more frequent in patients with PSA ≤10 ng/ml (P=0.024). There was no significant association between ERG and Gleason sum, pT-stage or surgical margin status. PSA (P=0.011), Gleason sum (P=0.003), pT-stage (P=0.001) and surgical margin status (P<0.001) all had independent value for postoperative biochemical recurrence, while positive surgical margin (P=0.021) was the only independent predictor for local recurrence. ERG protein expression did not have prognostic value for the clinical end points in uni- and multivariate analyses. A positive correlation existed between ERG and androgen receptor expression in single tissue cores (P<0.001). In conclusion, immunohistochemical ERG expression has no predictive value for prostate cancer recurrence or progression after radical prostatectomy. Increasing ERG levels are associated with the upregulation of androgen receptor expression in clinical specimens.
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