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

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

Clinical incidence over time increases (Netherlands)

0100020003000400050006000700080009000

10000

2000 2001 2002 2003 2004 2005

new Pca

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

Albertsen tables JAMA ‘97

N=767

Clinical stage ≤ T2

Palliative treatment

Dark grey = PCa †

Light grey = nonPCa †

White = survival

Natural course of Pca

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

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

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)

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 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

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

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

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 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

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

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

Unique protected individualised entry

Modification of follow-up 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)

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

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 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

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

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

Detection ofindolent cancers

PSAirways

…risk of flying…