Summary Background The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but ...screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. Methods ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55–69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50–74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years’ follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. Findings With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83–1·99) after 9 years (1·64 1·58–1·69 including France), 1·66 (1·60–1·73) after 11 years, and 1·57 (1·51–1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70–1·03) after 9 years, 0·78 (0·66–0·91) after 11 years, and 0·79 (0·69–0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490–1929) men invited for screening or one per 27 (17–66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61–0·88). Interpretation In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. Funding Each centre had its own funding responsibility.
In this trial, investigators tested the effect of prostate-specific–antigen testing on the death rate from prostate cancer in more than 162,000 men between the ages of 55 and 69 years in seven ...European countries. A significant reduction in prostate-cancer mortality was found after a median follow-up of 9 years. Overdiagnosis and overtreatment were important limitations of the screening program.
Measurement of serum prostate-specific antigen (PSA), a biomarker for prostate cancer,
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is useful for the detection of early prostate cancer.
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Nevertheless, the effect of PSA-based screening on prostate-cancer mortality remains unclear.
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The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in the early 1990s to determine whether a reduction of 25% in prostate-cancer mortality could be achieved by PSA-based screening.
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Preliminary data from this study have been published and can be accessed at www.erspc.org. Another randomized screening trial in the United States, the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial, was initiated around the same . . .
Abstract 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.
Abstract Background The complications of prostate needle biopsy (PNB) are important when considering the benefits and harms of prostate cancer screening. Studies from the United States and Canada ...have recently reported increasing numbers of hospitalizations for infectious complications after PNB. Objective Examine the risk of infectious complications and hospital admissions after PNB in a European screening trial. Design, setting, and participants From 1993 to 2011, 10 474 PNBs were performed in the European Randomized Study of Screening for Prostate Cancer (Rotterdam section). Prophylaxis originally consisted of trimethoprim-sulfamethoxazole. Beginning in 2008, it was changed to ciprofloxacin. Measurements Febrile complications and hospital admissions were assessed by questionnaires 2 wk after PNB. Logistic regression was used to identify risk factors for biopsy-related fever and hospital admission. Results and limitations Fever and hospital admission were reported on 392 of 9241 questionnaires (4.2%) and 78 of 9198 questionnaires (0.8%), respectively. Although most fevers were managed on an outpatient basis, 81% of hospital admissions were for infection. Of the 56 available blood cultures, 34 were positive with Escherichia coli as the predominant organism. On multivariable analysis, prostate enlargement and diabetes were significantly associated with an increased risk of fever after PNB, whereas later year of biopsy was the only factor significantly associated with an increased risk of hospital admission. Conclusions In a European screening trial, <5% PNBs resulted in febrile complications. Significant risk factors included diabetes and prostatic enlargement. Although most fevers were managed on an outpatient basis, infection remained the leading cause of hospital admission after PNB. Consistent with prior international reports, the frequency of hospital admissions after PNB significantly increased over time. Nevertheless, the absolute frequency of hospital admissions related to PNB was low and should not dissuade healthy men who would benefit from early prostate cancer diagnosis from undergoing biopsy when clinically indicated.
The European Randomized Study of Screening for Prostate Cancer continues to show a 21% reduction in prostate-cancer mortality in the screening group, after 11 years of follow-up. The number of ...cancers that would need to be detected to prevent one prostate-cancer death is 37. Screening does not affect all-cause mortality.
Screening for prostate cancer has remained controversial, despite results showing a significant reduction in the rate of death from prostate cancer (relative reduction, 20%) among men offered screening for prostate-specific antigen (PSA).
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The European Randomized Study of Screening for Prostate Cancer (ERSPC) is a multicenter trial initiated in 1991 in the Netherlands and in Belgium, with five more European countries (Sweden, Finland, Italy, Spain, and Switzerland) joining between 1994 and 1998. Recruitment was completed in these centers between 1995 and 2003. Later, France also joined, with enrollment in 2000–2005, but data from the French cohort were not included in the . . .
Abstract 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 ).
Purpose The identification of clinically insignificant prostate cancer could help avoid overtreatment. Current criteria for insignificant prostate cancer use a tumor volume threshold of less than 0.5 ...ml for the index tumor. In this study we reassess this tumor volume threshold for clinically insignificant prostate cancer using an independent data set. Materials and Methods The rate of insignificant prostate cancer was calculated by modeling lifetime risk estimates of prostate cancer diagnosis in screened and nonscreened participants in a randomized prostate cancer screening trial. Using lifetime risk estimates 50.8% of screen detected prostate cancer was calculated to be clinically insignificant and the 49.2% largest tumor volume of 325 prostatectomy specimens was used to determine the threshold tumor volume for insignificant prostate cancer. Because stage and grade represent the strongest determinants of cancer aggressiveness, we also calculated the tumor volume threshold for insignificant cancer after the selection of patients with organ confined prostate cancer without Gleason pattern 4/5. The analyses were performed for total tumor volume and for index tumor volume. Results The minimum threshold tumor volume of the index tumor and total tumor was 0.55 and 0.70 ml, respectively. After accounting for tumor stage and grade we obtained a threshold volume for the index tumor and total tumor of 1.3 and 2.5 ml, respectively. Conclusions We confirmed the original value of the index tumor volume threshold of 0.5 ml for insignificant prostate cancer, and we demonstrated that clinically insignificant prostate cancer may include index Gleason score 6, pT2 tumors with volumes up to at least 1.3 ml. These results suggest a reconsideration of current methods and nomograms used for pretreatment risk assessment.
Abstract Context Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have ...assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk–benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease. Objective Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds. Evidence acquisition A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated. Evidence synthesis Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone–releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality. Conclusions Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk–benefit ratio.
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