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23.06.2016 | Axel Heidenreich
PSA Screening and Diagnosis
Seite 2 23.06.2016 | Axel Heidenreich
The Problem……..
Seite 2RKI 2012
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The Problem……..
Seite 3RKI 2012
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Was sagen die Leitlinien?
Seite 4Heidenreich A et al., Eur Urol 2014; 65: 124 - 137
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• Dutch, retrospective, primary care database analysis; N: >60,000 PCa pts• Continuous increase of PSA testing incidence rate in men ≥45 yr:
– 2002: 15.5 per 1,000 person-yrs 2011: 54.3 per 1,000 person-yrs
– Higher increase in incidence rates as from 2005 than before 2005
• Estimation of relative risk on having a PSA test for men with different comorbidities:
Hamoen EHJ. Eur Urol Suppl 2013:12(1):e12(abs.12)
A rising incidence rate of PSA testing is seen from 2002 to 2011 despite recommendations to restrict PSA testing in several guidelines
PSA testing: discrepancies between guidelines and clinical practice
Data from poster
± 4-fold increase
Comorbidity Relative riskOverweight 1.50 (95% CI 1.39-1.62)
Psychiatric disease 1.31Joint disorders 1.30
Diabetes mellitus 1.29Respiratory disease 1.28
Cardiovascular diseases 1.27
What is the clinical reality?
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Screening: USA versus Europe
Seite 6
AUA Recommendation1 EAU Recommendation2
No PSA for men < 40 years Baseline PSA at age 40-45 years
No PSA for men 40-54 years
Shared decision and consent for men 55-69 years
Screening intervall ≥ 2 years adaptation of early detection dependen on 1rst PSA
No PSA for men > 70 years orr life expectancy < 15 years
PSA if life expectancy > 10 years
1Carter AB et al., J Urol 2013; 2Heidenreich A et al., Eur Urol 2013
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1. Early detection of PCA reduces mortality2. Early detetion reduces frequency of locally advanced
and metastatic PCA3. Early detection in men > 10 years life expectancy4. Baseline PSA at age 405. Individualized, PSA adapted follow-up6. Risk models including biomarkers are mandatory for
the future
Seite 8 23.06.2016 | Axel Heidenreich Schröder et al. N Engl J Med. 2009
Seite 9 23.06.2016 | Axel Heidenreich Schröder et al. N Engl J Med. 2009
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Follow-up: 13 yearsRisk reduction 27%NO > 70 years
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Follow-up 9 years 11 years 13 years
numbers needed to invite 1410 979 781
numbers needed to detect 48 35 27
Screening only indicated if life expectancy > 10 yearsHigh Rate of overdiagnosis and overtreatment
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Göteborg randomised population-based PCA screening
• 32.298 men, 50-64 years• Biopsy at PSA > 3.4 ng/ml (1995 – 1998), PSA > 2.5
ng/ml since 1999
• PCA – incidence higher(12.7% vs 8.2%)• Rate of ≥ T3 or M1 significantly lower(p=0.0003)• Risk reduction PCA - death 44% (HR 0.56, 95% CI,
0.32-0.82, p = 0.002)
Hugosson J et al., Lancet Oncol 2010
Seite 13 23.06.2016 | Axel HeidenreichHugosson et al. Lancet Oncology Juli 2010
Cumulative Cancer/Specific Mortality
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Göteborg screening trial
• 14 years follow up
• Risk Reduction of PCa mortality 0,56
• NNS (Number needed to be screened)
293
• NNT (Numbers needed to treat) 12
Hugosson et al. Lancet Oncology Juli 2010
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Early Detection reduces metastatic and locally advanced PCA
• Risk of metastases at initial diagnosis reduced by– 30% in ERSPC trial
– 48.9% in Göteborg study
• Risk of locally advanced PCA significantly (p < 0.001) reduced– cumulative incidence 0.67% versus 0.86%
– Risk reduction at 12 years 30%
Seite 16 23.06.2016 | Axel HeidenreichEur Urol 2013; 64: 347 - 354
1. Early detection reduces PCA – related mortality2. Early detection reduces frequency of locally advanced
and metastatic PCA3. Early detection in men with life expectancy > 10
years4. Baseline PSA at age 40 years5. Individualized, PSA – adapted early detection6. Multivariable risk models for the furture
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Early detection of life expectancy > 10 years
• n = 1167 men, geb. 1921
• Blood samples 1981/1982 (60 years)
• Comparison with cancer registry 2006 (25 years Follow-up)
• Baseline < 2.0 ng/ml• significantly riské of diagnosis• significantly riské of metastases
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• Baseline < 2.0 ng/ml• risk of death 26timesÝ
if PSA > 2.0 ng/ml
Ø 62% of all PCAØ 80% of all metastasesØ 90% of all death
Early detection of life expectancy > 10 years
• n = 1167 men, geb. 1921
• Blood samples 1981/1982 (60 years)
• Comparison with cancer registry 2006 (25 years Follow-up)
Seite 19 23.06.2016 | Axel HeidenreichEur Urol 2013; 64: 347 - 354
1. Early detection reduces PCA – related mortality2. Early detection reduces frequency of locally advanced
and metastatic PCA3. Early detection in men with life expectancy > 10 years4. Baseline PSA at age 40 years5. Individualized, PSA – adapted early detection6. Multivariable risk models for the furture
Seite 20 23.06.2016 | Axel Heidenreich
Baseline PSA at Age 40
• median PSA in men 30-49 years 0.6 – 0.78 ng/ml
• Loeb et al. (Urology 2006)
– N = 13.943 men < 60 Jahre
– PSA > 1.0 ng/ml => 14.6times elevated risk PCA (41-49J)
=> 7.6times elevated risk PCA (51-59 J)
=> significantly more T3, N1 & M1
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• median PSA in men 30-49 years 0.6 – 0.78 ng/ml
• Västerbotten Intervention Project (BMJ 2009)– Risk of PCA after a mean follow-up of 23 years
• 3.9% PSA < 1.0 ng/ml (reference group)
• OR 9.1Ý PSA 1.0 – 2.0 ng/ml
• OR 23.3Ý PSA 2.0 – 3.0 ng/ml
• OR 43.9Ý PSA 3.0 – 4.0 ng/ml
Baseline PSA at Age 40
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• median PSA in men 30-49 years 0.6 – 0.78 ng/ml
• Malmö Preventive Project (BMJ 2013)– Baseline-PSA correlates with metastases and PCA-related
mortality • Metastases after15 years elevated 3times (45-49J)
• Metastases after 15 years elevated 10times (50-55J)
• PCA-related death after 15 years elevated 2.7times (45-49J)
• PCA-related death after 15 years elevated 5.1times (50-55J)
Baseline PSA at Age 40
Seite 23 23.06.2016 | Axel HeidenreichEur Urol 2013; 64: 347 - 354
1. Early detection reduces PCA – related mortality2. Early detection reduces frequency of locally advanced
and metastatic PCA3. Early detection in men with life expectancy > 10 years4. Baseline PSA at age 40 years5. Individualized, PSA – adapted early detection6. Multivariable risk models for the furture
Seite 24 23.06.2016 | Axel Heidenreich
Risk Adapted Early Detection
• Screening intervalls
– 2-4 years if PSA > 1.0 ng/ml at age 45 – 49 years
– Up to 8 years if PSA < 1.0 ng/ml
Intervall Cancers
Schröder Ito Hugoson Candas
PSA, initial ≤ 1.0 ng/ml ≤ 1.0 ng/ml ≤ 3.0 ng/ml ≤ 3.0 ng/ml
N 1703 4794 5267 5387
Follow-up 4, 8 years annually 2, 4 years anually
PCA 8 (0.4%) 4 (0.1%) 111 (2.1%)* 134 (2.5%)*
Recommendation 8 years 4-5 years 4 years 7 years
* 3 (0.04%) if initial PSA < 1.5 ng/ml0, if initial PSA < 1.0 ng/ml
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Diagnosis
• Diagnosis of Prostate Cancer needs histopathological validation despite modern imaging studies
• Prostate Biopsy:
• guideline recommendation: TRUS – guided 10 - 12-core Biopsy
è TRUS-guided, transrectalè TRUS-guided, transperinealè MRI – TP – Fusion Biopsy
Seite 27 23.06.2016 | Axel HeidenreichSeite 27
Risk Calculators
Vergleich der Risikokalkulatoren und PSA, PSA Quotient
0 20 40 60 80 1000
20
40
60
80
100
100-Spezifität
Sen
sitiv
ität
ERSPC-3ERSPC-4PCPTSRCPSA bei BiopsiePSA Quotient
Risk Calculators topredict a positive biopsyand the presence of high risk PCA
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PCA – primary diagnosis
17
8
9
10
11
2
3
4
5
12 6
• Low detection rate 30-35%• Overdiagnosis• Complications & infection 5-8%• Urosepsis 0.5 – 3%
» N=7,216 men who underwent initial prostate biopsy (Bx) (1993-2011)
Multivariate analysis: positive predictor – negative predictor
Van Den Heuvel S. Eur Urol Suppl 2012:11(1):abs.825
These data are useful to counsel pts prior to initial Bx on the complication risk
Complications of initial prostate biopsy and predictors for complications: results from ERSPC Rotterdam
Complication N (% of pts) Independent predictors OR 95% CI PHaematospermia 3,545 (54.7%) Age (continuous) 0.91 0.90-0.92 <0.001
Year (>2001 vs ≤2001) 1.25 1.11-1.40 <0.001Comorbidities (yes vs no) 0.82 0.74-0.91 <0.001
Prostate volume (continuous) 0.99 0.99-0.99 0.046Haematuria 1,577 (25.0%) Comorbidities (yes vs no) 1.2 1.1-1.3 0.005
Prostate volume (continuous) 1.01 1.01-1.01 <0.001Pain 306 (5.0%) Age (continuous) 0.97 0.95-0.99 0.02
Year (>2001 vs ≤2001) 0.66 0.49-0.88 0.005Fever 261 (4.2%) No significant predictors
Hospitalisation 44 (0.7%) No significant predictors
Complications of Biopsy Techniques
Complications Transrectal1 Transperineal2
Pain at Biopsy 43,6% 0%UTI & fever 17,5% 0%Prostatitis 4.5% 0.4%Urosepsis 0.7% 0%Hematuria 65,8% 41,8%Hemospermia 92,6% N/AHematochezia 36,8% 0%Acute urinary retention n.k. 13,4%
1 DJ. Rosario et al.BMJ 2012;344 2 own data
Biopsy PCA-Detection Rates
PCA-DetectionTRUS – guided biopsy1 30% – 43%
Transperineal Biopsy 62.5%
MRT-Fusion Biopsy(biopsienaiv)3 66%
1 EAU Guidelines on PCA2 own data3 CM. Moore et al. Eur Urol 63 (2013), 125-140
Dorsal: 76%
Anterioventral: 83,3%
Transitional: 55,5%
Perineal Prostate Biopsy
Perineale Prostatabiopsie –eigene Erfahrungen
Einteilung nach Gleason Score:Gleason 6 37,5% Gleason 7 25% Gleason 8-10 37,5%
mpMRT
Figure 3 shows the basal sectors that were added to thebiopsy plan when prostate volume was greater than 50 cc.Automatic needle placement for systematic cores was notavailable at that time. The median number of targetedcores was 4. Depending on lesion size, 2 to 6 targeted coreswere taken.
In the first 10 men the whole procedure, includingplanning and navigation, took around 60 minutes. Laterthe intervention time decreased to 30 minutes per patient,including larynx mask anesthesia. General anesthesia
helps minimize motion artifact and is the most appreci-ated biopsy analgesia for German men.12 Antibiotic pro-phylaxis consisted of fluoroquinolone treatment for3 days.
A 20-item purposely designed questionnaire was sentto all patients to document post-biopsy morbidity (erectilefunction, infections complications, hematuria and hema-toma) and disease specific followup (PSA, further prostatebiopsies, actual treatment regimen and, if available, his-topathology reports).
Statistical analysis was performed using SPSS!,version 20 with p <0.05 considered statistically signifi-cant. We calculated k to compare targeted vs systematicapproaches. PC risk groups were defined according toNCCN guidelines.13 PSA cutoffs and biopsy criteria wereused. Low risk and very low risk were combined into asingle risk level, including lowdGleason score 2 to 6 andPSA less than 10 ng/ml, intermediatedGleason score 7 orPSA 10 to 20 ng/ml and highdGleason score 8-10 or PSAgreater than 20 ng/ml.
RESULTSIn 200 of 347 patients (58%) with suspicion of PCbiopsy samples revealed PC (table 1). In 147 of the200 men (73.5%) biopsy proven PC was intermedi-ate or high risk according to NCCN criteria.13 Of177 men undergoing primary biopsy cancer wasdiagnosed in 114 (64%), including low risk tumors in23 (20%). Of 170 patients without a previous cancerdiagnosis re-biopsy was positive in 86 (51%),revealing clinically relevant tumors in 56 (65%). Atotal of 100 patients had 1 previous negative biopsyand 70 had 2 or more previously negative trans-rectal biopsies (detection rate 51 of 100 or 51% and35 of 70 or 50%, respectively).
On multiparametric 3 Tesla MRI without anendorectal coil 104, 149 and 94 cases were diag-nosed as highly, questionably and not suspicious forPC, respectively. We did not use the Prostate Im-aging Reporting and Data System (PI-RADS) scoredescribed in the 2012 European Society of Urogen-ital Radiology (ESUR) guidelines14 because thepublication was not available when the study pro-tocol was initiated. Of 104 men with MRI lesionsconsidered highly suspicious tumor was detected in86 (82.6%), including 62 with a Gleason score of 7 orgreater. In 149 patients with questionable MRIlesions tumor was detected in 100 (67%). Of 94 cases80 (85.1%) described as not suspicious for PC onMRI were also negative on biopsy.
Table 2 shows a detailed evaluation of targetedvs template biopsies. Biopsies from 1 trajectory wereonly taken once. If this trajectory was located in asuspicious area, it was considered targeted andsystematic since no additional systematic biopsieswere taken from this region. Moreover, routinehistopathological evaluation at our center did not
Figure 2. Three Tesla mp-MRI without endorectal coil ques-tionably suspicious for PC. T2 images with diffuse low intensesignal in peripheral zone (A), type 2 enhancement curve (C ) anddecreased ADC (D) without correlate in high b values (B).
Figure 1. Three Tesla mp-MRI without endorectal coil highlysuspicious for PC. T2 image with homogeneous low signalarea (A), focal area with hyperintense signal on long b800b-value images (B), type 3 contrast enhancement curve intypical localization (C ) and focal area with decreased ADC (D).
1382 MAGNETIC RESONANCE IMAGING TARGETED BIOPSY FOR DETECTION OF PROSTATE CANCER
How to Perform Image-guided Prostate Biopsy: In-bore and Fusion 3 Approaches.Kuru T, Herden J, Zugor V, Akbarov I, Pfister D, Porres D, Heidenreich AEur Urol Focus 2016; article in press
MRI – TRUS Fusion – 4 Steps1. mpMRI done, suspicious areas identified and marked
=> ESUR score
MRI – TRUS Fusion – 4 Schritte1. mpMRI done, suspicious areas identified and marked
=> ESUR score2. Surface reconstruction in MRI, caculation prostate
volume
MRI – TRUS Fusion – 4 Schritte1. mpMRI done, suspicious areas identified and marked
=> ESUR score2. Surface reconstruction in MRI, caculation prostate
volume3. Reconstruction of prostatic area via 3D-TRUS
MRI – TRUS Fusion – 4 Schritte1. mpMRI done, suspicious areas identified and marked
=> ESUR score2. Surface reconstruction in MRI, caculation prostate
volume3. Reconstruction of prostatic area via 3D-TRUS4. Elastic surface reconstruction, marking of the MRI –
suspicious areas
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mpMRI of the Prostate
Heidenreich A et al., Eur Urol 2014; 65: 467-479
Indication
§ Re-Biopsie following negative 1rst-line
Bx
§ identification of PCA in the anterior zone
(TP - biopsy)
§ local staging in selected cases with
intermediate/high risk PCA