Transcript Active Surveillance - Europa Uomo Europa Uomo Slovensko

Overdetection of prostate cancer
ESMO Brussel 2007
Chris H.Bangma
Erasmus University Medical Centre
Rotterdam, The Netherlands
Increasing Pca incidence with age
225.000 in Europe annually
PSA and cancer incidence in men aged 50-75
40
36
30
31
Proportion
Prostate Cancer
20
13
10
11
%
7
2
0
< 1.0
>= 2.0 - < 3.0
>= 1.0 - < 2.0
PSA (ng/ml)
>= 4.0 - < 10.0
>= 3.0 - < 4.0
>= 10.0
Clinical incidence over time increases (Netherlands)
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
2000 2001 2002 2003 2004 2005
new Pca
The diagnosis of low risk prostate cancer is
increasing
100
80
% of
patients
60
40
20
0
‘90
Cooperberg et al, J Urol 2003
‘92
‘94
‘96
Year
‘98
‘00
Natural course of Pca
 Albertsen tables JAMA ‘97
 N=767
 Clinical stage ≤ T2
 Palliative treatment
 Dark grey = PCa †
 Light grey = nonPCa †
 White = survival
There is more cancer than we can detect currently
 Autopsy data (Gosselaer 2005)
 Cystoprostatectomy data (Damiano R, Eur Urol 2007)
70
60
50
40
30
20
10
0
Sakr 1993
autopsy
incidence
screening
incidence
30- 40- 50- 60- 7039 49 59 69 79
Pca detection frequency in screening
ERSPC first round
2.6
2.4
5.1
2.5
3.2
1.1
1.7
1.6
260.000 participants
aged 50-75
in 8 EC countries
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 tumor
volume in ml (range)
% minimal
tumor
Median, mean tumor
volume in ml (range)
%
minimal
tumor
PSA range
(ng/mL)**
< 3.0
Round 1 (n=386)
Round 2 (n=164)
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
2
2=
** Correlation tumor volume/PSA level. round 1: R = 0.15, round 2: R 0.12 (p=0.0001)
Overdiagnosis estimated to be 54 % in screening (Draisma 2003)
Conclusion 1: Big wave of small cancers…big threat
of overdiagnosis (and subsequent overtreatment!)
Hokusai 1830
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
Score chart for the prediction of indolent
prostate cancer (Steyerberg et al 2007)
Variable
Serum PSA (ng/mL)
Ultrasound volume (cc)
Values
20
13
9.0
6.0
5.0
4.0
3.3
2.2
1.0
20
Score
0
2
4
6
7
8
9
11
15
0
Variable
Biopsy Gleason
Scores 1 and 2
Values
3+3
2+3
2+2
Score
0
1
4
mm cancerous
tissue (total
over biopsy cores)
20
10
8
4
2
1
0
2
3
5
7
9
40
60
80
2
4
6
mm non-cancerous
tissue (total over
biopsy cores)
Score (sum all
scores)
40
60
80
0
2
4
Sum
24
Predicted probability of indolent cancer according to sum
of scores
100%
Probability of indolent cancer
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
11 8
12 13 16 24 27 27 28 28 21 16 15 7
7
9
9
13% 16% 19% 23% 28% 33% 39% 45% 52% 58% 64% 69% 74% 79% 83% 86% 89%
N
Prediction
<= 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 >=
Score
Active surveillance: strategy to deminish
overtreatment of minimal cancers
Active surveillance: regular monitoring, and delayed invasive treatment
on signs of tumour progression
Watchful Waiting
Active Surveillance
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/
PRIAS inclusion: conservative approach
 Criteria for inclusion in PRIAS:
1. Histologically proven adenocarcinoma of the prostate
2. Men should be fit for curative treatment
3. PSA-level at diagnosis ≤ 10 ng/mL
4. PSA density (PSA D) less than 0,2
5. Clinical stage T1C or T2
6. Adequate biopsy sampling (see 'biopsy protocol')
7. Gleason score 3+3=6
8. One or 2 biopsy cores invaded with prostate cancer
9. 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 operated
2. A former therapy for prostate cancer
Schedule active surveillance study
Analysing biologic tumour behavior
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 time
Visit
At 4, 7 and 10 years, thereafter every 5
years
Correcting
for sampling
2 times
1 time errors
1 time
PSA kinetics can indicate a biopsy or
treatment shift
Flowchart for follow-up
Active Surveillance
Yes
PSA < 20 ng/ml
Yes
Yes
No
End of Study
Metastases on bone scan?
No
Clinical stage < cT 3
No
Yes
Definitive therapy
PSA DT > 3 years
No
Yes
Repeat biopsy indicated by time path?
Yes
No
PSA DT > 10 years
No
Yes
Continue Active Surveillance
Repeat biopsy:
Maximal 2 cores with PC
AND Gleason score 3+3
Yes
No
Unique protected individualised entry
Modification of followup data feasible: curves
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)
Overall and cancer specific survival
minimal (cGleason  6, PSA  10, T1c)
versus relevant cancers (> Gleason 6, cT2)
Survival
Functions
Overall
survival
Survival Functions
Pca specific
survival
Indolent
1,0
Ja
Nee
Onbekend
Ja-censored
0,8
Nee-censored
Onbekendcensored
1,0
Cum Survival
Cum Survival
0,8
0,6
0,4
0,2
Indolent
Ja
Nee
Onbekend
Ja-censored
Nee-censored
Onbekendcensored
0,6
0,4
0,2
10 year
10 year
0,0
0,0
0
50
100
150
200
250
LastFUMnthSinceRP
months
300
350
0
50
100
150
200
250
LastFUMnthSinceRP
months
300
350
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?
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)
Conclusion 2: overdiagnosis in Europe
Can 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 (EAUwebsite:www.urolog.org)
 Active Surveillance policies should be improved with respect to patient
inclusion and monitoring by validated markers
Europe as a scaffold to integrate research
for prostate cancer patients
Biomarker research: P-MARK, PROCABIO
Patient organisations:
Europa Uomo
Research programs:
ERSPC , EORTC
Industry
Health care professionals: EAU
Tailored treatment (Active Surveillance) by
PROstate CAncer BIOmarkers: PROCABIO
year 1
years 2-4
outcome
WP1: Biorepository management
Management serum
and tissue validation set
Management prospective biomaterials from active
surveillance study
Active surveillance
biorepository
WP2: Proteomics biomarkers & WP3: Genomics biomarkers
Marker validation for
discrimination indolent
and progressive PCa
Clinical implementation selected markers in active
surveillance study
Marker format optimisation
Marker
implementation in
treatment policies
WP4: Clinical study
Preparatory phase
participating clinical
centres
European multi-centre active surveillance study
Cohort A: entry by set parameters
Cohort 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
Detection of
indolent cancers
PSAirways
…risk of flying…