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Overdetection of prostate cancer
ESMO Brussel 2007
Chris H.Bangma
Erasmus University Medical Centre
Rotterdam, The Netherlands
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Increasing Pca incidence with age
225.000 in Europe annually
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PSA and cancer incidence in men aged 50-75
PSA (ng/ml)
>= 10.0
>= 4.0 - < 10.0
>= 3.0 - < 4.0
>= 2.0 - < 3.0
>= 1.0 - < 2.0
< 1.0
%
40
30
20
10
0 2
11
7
13
31
36
ProportionProstate Cancer
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Clinical incidence over time increases (Netherlands)
0100020003000400050006000700080009000
10000
2000 2001 2002 2003 2004 2005
new Pca
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The diagnosis of low risk prostate cancer is increasing
Cooperberg et al, J Urol 2003Year
‘90 ‘92 ‘94 ‘96 ‘98 ‘00
% ofpatients
20
40
60
80
100
0
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Albertsen tables JAMA ‘97
N=767
Clinical stage ≤ T2
Palliative treatment
Dark grey = PCa †
Light grey = nonPCa †
White = survival
Natural course of Pca
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There is more cancer than we can detect currently
Autopsy data (Gosselaer 2005)
Cystoprostatectomy data (Damiano R, Eur Urol 2007)
010
20
30
40
50
60
70
30-39
40-49
50-59
60-69
70-79
autopsyincidence
screeningincidence
Sakr 1993
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5.12.5
1.6
2.42.6
3.21.1
1.7
Pca detection frequency in screeningERSPC first round
260.000 participants aged 50-75
in 8 EC countries
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Tumor volumes in 550 radical prostatectomy specimens per PSA range detected in round 1 and 2 (ERSPC Rotterdam)minimal tumours: <0.5 ml, Gleason <7
Median, mean tumorvolume in ml (range)
% minimaltumor
Median, mean tumorvolume in ml (range)
%minimaltumor
PSA range(ng/mL)**
Round 1 (n=386) Round 2 (n=164)
< 3.0 0.28, 0.32 (0.00-1.09) 67 0.28, 0.38 (0.00-1.80) 56
3.0 – 3.9 0.58, 0.72 (0.00-3.10) 45 0.43, 0.63 (0.00-2.17) 31
4.0 – 9.9 0.77, 1.08 (0.00-13.48) 27 0.63, 1.06 (0.01-7.93) 46
> 10 1.82, 2.16 (0.00-7.99) 13 1.33, 2.04 (0.00-8.94) 36
Total 0.65, 1.06 (0.00-13.48)* 33 0.45, 0.86 (0.00-8.94)* 43
* Significant, p=0.001** Correlation tumor volume/PSA level. round 1: R
2 = 0.15, round 2: R
2 = 0.12 (p=0.0001)
Overdiagnosis estimated to be 54 % in screening (Draisma 2003)
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Conclusion 1: Big wave of small cancers…big threat of overdiagnosis (and subsequent overtreatment!)
Hokusai 1830
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Can we recognise indolent tumours upfront? (Steyerberg, Kattan, Roobol, et al. J Urol 2007)
247 patients Pca T1-2 >> radical prostatectomy>> step section histology
121 (48 % !) indolent disease (<0.5 ml, no Gleason 4)
Statistic analysis identifies relevant prognostic factors
Age
PSA
Prostate volume
Micturition complaints
Stage
Grade
Cancer volume in biopsies
Number of positive cancer biopsies
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Score chart for the prediction of indolent prostate cancer (Steyerberg et al 2007)
Variable Values Score Variable Values Score Sum Serum PSA (ng/mL) 20 0 Biopsy Gleason 3+3 0 13 2 Scores 1 and 2 2+3 1 9.0 4 2+2 4 6.0 6 5.0 7 mm cancerous 20 0 4.0 8 tissue (total 10 2 3.3 9 over biopsy cores) 8 3 2.2 11 4 5 1.0 15 2 7 Ultrasound volume (cc) 20 0 1 9
40 2 mm non-cancerous 40 0 60 4 tissue (total over 60 2 80 6 biopsy cores) 80 4 Score (sum all
scores) 24
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9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Score
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%P
roba
bilit
y of
indo
lent
can
cer
11 8 12 13 16 24 27 27 28 28 21 16 15 7 7 9 913% 16% 19% 23% 28% 33% 39% 45% 52% 58% 64% 69% 74% 79% 83% 86% 89%
<=
Prediction
>=
N
Predicted probability of indolent cancer according to sum of scores
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Active surveillance: strategy to deminish overtreatment of minimal cancers
Active surveillance: regular monitoring, and delayed invasive treatment
on signs of tumour progression
Watchful Waiting Watchful Waiting Watchful Waiting Watchful Waiting Watchful Waiting Active Surveillance
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PRIAS: free access www.prias-project.org
PRIAS means Prostate cancer Research International:
Active Surveillance
It is a web-based tool used to include and follow-up patients
considered to have indolent disease
International observational study based on experience in watchful
waiting and guided by experts to optimise active surveillance
http://www.urosource.com/congress-television/berlin-2007/
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PRIAS inclusion: conservative approach
Criteria for inclusion in PRIAS:1. Histologically proven adenocarcinoma of the prostate2. Men should be fit for curative treatment3. PSA-level at diagnosis ≤ 10 ng/mL4. PSA density (PSA D) less than 0,25. Clinical stage T1C or T2 6. Adequate biopsy sampling (see 'biopsy protocol')7. Gleason score 3+3=68. One or 2 biopsy cores invaded with prostate cancer9. Participants must be willing to attend the follow-up visits
Exclusion-criteria:1. Men who can not or do not want to be irradiated or operated2. A former therapy for prostate cancer
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Year 1 Year 2 Year 3 - ~
PSA 4 times 4 times 2 times a year
DRE 2 times 1 time 1 time a year
Repeat biopsy 1 timeAt 4, 7 and 10 years, thereafter every 5
years
Visit 2 times 1 time 1 time
Schedule active surveillance study
Analysing biologic tumour behavior
Correcting for sampling errors
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Flowchart for follow-up
Metastases on bone scan?
No
Yes
Yes
Yes
Yes
Yes
Yes
Active Surveillance
PSA < 20 ng/ml
Clinical stage < cT 3
PSA DT > 3 years
Repeat biopsy indicated by time path?
PSA DT > 10 years
Continue Active Surveillance
Repeat biopsy:Maximal 2 cores with PCAND Gleason score 3+3
Yes
Yes
No
No
No No
End of Study
Definitive therapy
No
No
PSA kinetics can indicate a biopsy or treatment shift
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Unique protected individualised entry
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Modification of follow-up data feasible: curves
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Is active surveillance safe?
Natural course of disease of Gleason 6 cancer after 20 years 85-96 %
Lead time of 12 years in screening setting
D’Amico: low risk population (PSA<10, Bx Gleason <7 and T1-2): 5 year cancer specific survival after therapy of 98%
Klotz 2005: PSADT< 2 years as an indication for active therapy after active surveillance misses few progressive tumours over 8 years (1 % metas)
ERSPC: 100% tumour specific survival in 61 patients over 4 years of active surveillance (Roemeling 2006)
Delayed radical prostatectomy does not increase tumor stages (Carter 2003, Roemeling 2007)
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350300250200150100500
LastFUMnthSinceRP
1,0
0,8
0,6
0,4
0,2
0,0
Cu
m S
urv
iva
l
Onbekend-censored
Nee-censoredJa-censoredOnbekendNeeJa
Indolent
Survival Functions
Overall and cancer specific survivalminimal (cGleason 6, PSA 10, T1c) versus relevant cancers (> Gleason 6, cT2)
350300250200150100500
LastFUMnthSinceRP
1,0
0,8
0,6
0,4
0,2
0,0
Cu
m S
urv
iva
l
Onbekend-censored
Nee-censoredJa-censoredOnbekendNeeJa
Indolent
Survival FunctionsOverall survival Pca specific survival
months months
10 year 10 year
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What can we offer European men?Men want to know their risks….how can we reduce overdiagnosis?
Level 1: Man age 55 – 74: do I need to screen?
Level 2: PSA known: shall I visit a urologist?
Level 3: Levels 1+2, DRE, TRUS, and prostate volume
known: do I need a biopsy?
Level 4: Biopsy result known: do I need a therapy? PRIAS?
Level 5: first biopsy shows no cancer: do I need a second
screen?
Level 6: in case of cancer: what is my risk to get metastases?
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Future: reducing overdiagnosis will reduce overtreatment.Risk calculators
We may offer risk analysis to decrease wild screening / rescreening in low-risk groups
Avoid screening of asymptomatic cancers in the elderly: only 0.09% of men aged 70-75 in ERSPC died in six years of Pca (Roobol 2007)
Avoid rescreen within 5 years in men with PSA< 1.0 (Roobol, Prostate. 2006 , Crawford, J Urol. 2006)
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Conclusion 2: overdiagnosis in EuropeCan men be protected?
Overtreatment of indolent tumours can be avoided with active
surveillance (www.prias-project.org)
Introduction of step-wise risc-calculation will likely reduce
overdiagnosis in men aware of prostate cancer (EAU-website:
www.urolog.org)
Active Surveillance policies should be improved with respect to patient
inclusion and monitoring by validated markers
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Europe as a scaffold to integrate research for prostate cancer patients
Industry
Biomarker research: P-MARK, PROCABIO
Patient organisations:Europa Uomo
Health care professionals: EAU
Research programs: ERSPC , EORTC
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year 1 years 2-4
WP1: Biorepository management
Management serum and tissue validation set
Management prospective biomaterials from active surveillance study
WP2: Proteomics biomarkers & WP3: Genomics biomarkers
Marker validation for discrimination indolent and progressive PCa
Clinical implementation selected markers in active surveillance studyMarker format optimisation
Active surveillance biorepository
outcome
Marker implementation in treatment policies
WP4: Clinical study
Preparatory phase participating clinical centres
European multi-centre active surveillance studyCohort A: entry by set parametersCohort B: entry by risk calculator
Evaluation intermediate
endpoints
WP5: Public relations
Informing stakeholders on active surveillance
Informing stakeholders on progress and outcome active surveillance study and marker implementation
Guidelines on active surveillance
year 1 years 2-4
WP1: Biorepository management
Management serum and tissue validation set
Management prospective biomaterials from active surveillance study
WP2: Proteomics biomarkers & WP3: Genomics biomarkers
Marker validation for discrimination indolent and progressive PCa
Clinical implementation selected markers in active surveillance studyMarker format optimisation
Active surveillance biorepository
outcome
Marker implementation in treatment policies
WP4: Clinical study
Preparatory phase participating clinical centres
European multi-centre active surveillance studyCohort A: entry by set parametersCohort B: entry by risk calculator
Evaluation intermediate
endpoints
WP5: Public relations
Informing stakeholders on active surveillance
Informing stakeholders on progress and outcome active surveillance study and marker implementation
Guidelines on active surveillance
Tailored treatment (Active Surveillance) by PROstate CAncer BIOmarkers: PROCABIO
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Detection ofindolent cancers
PSAirways
…risk of flying…