Abstract Context Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are ...debated. Objective To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS. Evidence acquisition Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS. Evidence synthesis Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2 – v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion ( TMPRSS2 : ERG ) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up. Conclusions There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future. Patient summary Several PSA–based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way.
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 . . .
Relative increase of grade 4 and presence of invasive cribriform and/or intraductal carcinoma have individually been associated with adverse outcome of Gleason score 7 (GS 7) prostate cancer. The ...objective of this study was to investigate the relation of Gleason grade 4 tumor percentage (%GG4) and invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. We reviewed 1031 prostate cancer biopsies from the European Randomized Study of Screening for Prostate Cancer. In total 370 men had G3+4=7. The relation of invasive cribriform and/or intraductal carcinoma and %GG4 with biochemical recurrence-free survival (BCRFS) after radical prostatectomy (n=146) and radiation therapy (n=195) was analyzed using Cox regression. Invasive cribriform and/or intraductal carcinoma occurred in 7/121 (6%) patients with 1–10% GG4, 29/131 (22%) with 10–25%, and 52/118 (44%) with 25–50% GG4 (P<0.001). In crude analysis, both invasive cribriform and/or intraductal carcinoma (HR 2.72; 95% CI: 1.33–5.95; P=0.006) and 10–50% GG4 (HR 2.43; 95% CI: 1.10–5.37; P=0.03) were associated with BCRFS after prostatectomy. In adjusted analysis, invasive cribriform and/or intraductal carcinoma was an independent predictor for BCRFS (HR 2.40; 95% CI: 1.03–5.60; P=0.04) after prostatectomy, whereas percentage %GG4 (HR 1.00; 95% CI: 0.97–1.03; P=0.80) was not. While invasive cribriform and/or intraductal carcinoma (HR 2.58; 95% CI: 1.59–4.21; P<0.001) performed better than 10–50% GG4 (HR 1.24; 95% CI: 0.67–2.29; P=0.49) for prediction of BCRFS after radiation therapy, both parameters were insignificant in analysis adjusted for prostate-specific antigen (P=0.001), positive biopsies (P<0.001) and tumor volume (P=0.05). In conclusion, increased %GG4 is associated with invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. Invasive cribriform and/or intraductal carcinoma is an independent parameter for BCR after prostatectomy, whereas %GG4 is not. The presence of invasive cribriform and/or intraductal carcinoma has to be included in pathology reports and should act as exclusion criterion for active surveillance.
Grade groups (GGs) are an important parameter for therapeutic decision making in prostate cancer (Pca) patients. Invasive cribriform and/or intraductal carcinoma (CR/IDC) has an independent ...prognostic value for disease outcome, but are not included in the GG limiting their clinical use.
To perform a proof-of-principle study incorporating CR/IDC in the current GG.
All prostate biopsies of 1031 men with screen-detected Pca between 1993 and 2000 were reviewed for the current GG (ranging from 1 to 5) and CR/IDC. The cribriform grade (cGrade) was equal to the GG if CR/IDC was present and GG minus 1 if not. GG1 was cGrade1 if intraductal carcinoma was absent.
Biopsy review for GG and CR/IDC. A total of 406 patients had received radical prostatectomy (RP), 508 radiotherapy (RT), 108 surveillance, and eight hormonal therapy, and the treatment was unknown for one patient.
Outcome measurements and statistical analysis disease-specific survival (DSS), metastasis-free survival (MFS), and biochemical recurrence–free survival (BCRFS) after 15.1 yr (interquartile range 10.9–19.7 yr) follow-up were compared using Harrell’s C-statistic.
The biopsy GGs were 486 GG1, 310 GG2, 104 GG3, 64 GG4, and 67 GG5; cGrade distributions were 738 cGrade1, 102 cGrade2, 91 cGrade3, 58 cGrade4, and 42 cGrade5. The cGrade had a better discriminative value than the GG for DSS (C-index 0.79; 95% confidence interval 0.74–0.83 vs 0.76; 0.71–0.82) and MFS (0.79; 0.74–0.84 vs 0.77; 0.72–0.82). The discriminative value for BCRFS after RP and RT was similar for both models. Different diagnostic, such as use of sextant biopsies, and therapeutic strategies in the 1990s are the limitations of this study.
The cGrade is a simple Pca grade modification with better discriminative values for DSS and MFS than the GG, particularly impacting decision making in men with current GG2 Pca.
Microscopic grading is an important factor for decision making in prostate cancer (Pca) patients. We show that a simple grade modification better predicts Pca outcome and might improve treatment choices.
Pathological grading is an important parameter for decision making in prostate cancer patients. We show that a simple modification of the current International Society of Urologic Pathology/World Health Organization grade groups incorporating cribriform architecture results in a significantly better discriminative value for disease-specific and metastasis-free survival.
Prostate‐specific antigen‐based prostate cancer screening remains a controversial topic. Up to now, there is worldwide consensus on the statement that the harms of population‐based screening, mainly ...as a result of overdiagnosis (the detection of clinically insignificant tumors that would have never caused any symptoms), outweigh the benefits. However, worldwide opportunistic screening takes place on a wide scale. The European Randomized Study of Screening for Prostate Cancer showed a reduction in prostate cancer mortality through prostate‐specific antigen based‐screening. These population‐based data need to be individualized in order to avoid screening in those who cannot benefit and start screening in those who will. For now, lacking a more optimal screening approach, screening should only be started after the process of shared decision‐making. The focus of future research is the reduction of unnecessary testing and overdiagnosis by further research to better biomarkers and the value of the multiparametric magnetic resonance imaging, potentially combined in already existing prostate‐specific antigen‐based multivariate risk prediction models.
Abstract Background Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. Objective To assess the effect of screening for PCa on the incidence of ...metastatic disease in a randomized trial. Design, setting, and participants Data were available for 76 813 men aged 55–69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. Intervention Regular screening based on serum PSA measurements was offered to 36 270 men randomized to the screening arm, while no screening was provided to the 40 543 men in the control arm. Outcome measurements and statistical analysis The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. Results and limitations After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively ( p < 0.001). This finding translated into a relative reduction of 30% (hazard ratio HR: 0.70; 95% confidence interval CI, 0.60–0.82; p = 0.001) in the intention-to-screen analysis and a 42% ( p = 0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41–0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. Conclusions PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.
Background and purpose
Individualized risk-adapted algorithms in prostate cancer (PCa) diagnosis using predictive prebiopsy variables in addition to prostate-specific antigen value may result in a ...considerable reduction of unnecessary systematic biopsies. Multi-parametric magnetic resonance imaging (mpMRI) has emerged as a secondary prediction tool that can further improve the detection of clinically significant prostate cancer (csPCa). This review explores the performance of new MRI risk models for indicating a biopsy for prostate cancer diagnosis.
Results and considerations
The area under the receiver-operating characteristic curve for detecting csPCa varies between 0.64 and 0.91 in biopsy-naïve men, and between 0.78 and 0.93 in men with a previous negative biopsy. The utility of multivariate risk prediction tools including MRI suspicion scores as an extra input parameter has the potential to avoid a notable number of biopsies and detection of clinically insignificant PCa at a low price of missing some csPCa. The trade-off depends on the risk threshold that is chosen. In biopsy-naïve men a net benefit was obtained at a risk threshold of above 10% for csPCa in most MRI risk prediction models. All constructed MRI risk models used (referral) patient cohorts with high prevalence of csPCa. Using more representative cohorts from daily clinical screening, net benefit may attenuate at lower risk thresholds. Strengths and limitations of these models are discussed.
Future directions
To assess their wider applicability, in-depth analysis of mpMRI predictive qualities should be further investigated, in combination with required external validation of these models in a multicenter setting with large prospective datasets.
Objective
To systematically review and meta‐analyse evidence regarding the additional value of magnetic resonance imaging (MRI) and MRI‐targeted biopsies to confirmatory systematic biopsies in ...identifying high‐grade prostate cancer in men with low‐risk disease on transrectal ultrasonography (TRUS) biopsy, as active surveillance (AS) of prostate cancer is recommended for men with Gleason 3 + 3 on standard TRUS‐guided biopsy. Confirmatory assessment can include repeat standard TRUS‐guided biopsy, and/or MRI with targeted biopsy when indicated.
Methods
A systematic review of the Embase, Medline, Web‐of‐science, Google scholar, and Cochrane library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)‐2 criteria. Studies reporting men with Gleason 3 + 3 prostate cancer who had chosen AS based on transrectal systematic biopsy findings and had undergone MRI with systematic ± targeted biopsy at confirmatory assessment were included. The primary outcome was detection of any Gleason pattern ≥4.
Results
Included reports (six) of men on AS (n = 1 159) showed cancer upgrading (Gleason ≥3 + 4) in 27% (95% confidence interval CI 22–34%) using a combined approach of MRI‐targeted biopsies and confirmatory systematic biopsies. MRI‐targeted biopsies alone would have missed cancer upgrading in 10% (95% CI 8–14%) and standard biopsies alone would have missed cancer upgrading in 7% (95% CI 5–10%). No pathway was more favourable than the other (relative risk RR 0.92, 95% CI 0.79–1.06). In all, 35% (95% CI 27–43%) of men with a positive MRI were upgraded, compared to 12% (95% CI 8–18%) of men with a negative MRI being upgraded (RR 2.77, 95% CI 1.76–4.38).
Conclusions
A pre‐biopsy MRI should be performed before confirmatory systematic TRUS‐guided biopsies in men on AS, together with MRI‐targeted biopsies when indicated. A combined approach maximises cancer detection, although other factors within multivariate risk prediction can be used to aid the decision to biopsy in these men.
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