Prostate Cancer in 2009, part I. Now and the future! Why we have ‘Active surveillance, its...

Prostate Cancer in 2009, part I. Now and the future!

Why we have ‘Active surveillance, its purpose, its outcome and other matters. 

Monique J. Roobol, PhD, MSc

Overview

The facts of prostate cancer

Screening for prostate cancer

Tumor characteristics over time

Management of prostate cancer

Active Surveillance

Risk indicator

The facts of prostate cancer

0

10

20

30

40

5060

70

30-39

40-49

50-59

60-69

70-79

autopsyincidence

Sakr 1993

The facts of prostate cancer

42

9.5 2.90

5

10

15

20

25

30

35

40

45 Microscopic PC

Clinical PC

Deathly PC

Is PC always a life threatening disease?

The facts of prostate cancer

The diagnosis of low risk prostate cancer is increasing

‘90 ‘92 ‘94 ‘96 ‘98 ‘00

20

40

60

80

100

0

Cooperberg et al, J Urol 2003

The facts of prostate cancer

Cancer death by type of cancer and age, The Netherlands, 2000www.CBS.nl

Cancer mortality increases strongly from 50 years of age onwards, peaking at ages 75-79 years.

Prostate cancer is an important health problem.

The facts of prostate cancer

Conclusions:

1.Prostate cancer is a major health problem

2.Death from prostate cancer and/or metastatic prostate cancer should

be avoided

3.The majority of detectable prostate cancer cases do not give any

complaints or will lead to death

Early detection of especially those prostate cancer cases

that cause symptoms and/or are life threatening is desirable

Overview

The facts of prostate cancer

Screening for prostate cancer

Tumor characteristics over time

Management of prostate cancer

Active Surveillance

Risk indicator

Screening for prostate cancer

Belgium 10.359

Finland 80.379

France 85.414

Italy 14.977

Netherlands 42.376

Spain 4.278

Sweden 19.911

Switzerland 10.307

Total 268.001

www.erspc.org

Screening for prostate cancer

21.166 men in control arm

??

??

?

?

?

42.376 men

21.210 men in screening arm

PSA

DRE

TRUS

Prostate biopsy

Prostate cancer

Death of prostate cancer

Prostate cancer

9.176

2.241933

?

? ??

?

?

Screening for prostate cancer

With applying a relatively non aggressive screening algorithm,

i.e PSA cut-off value >= 3.0 ng/ml

Sextant prostate biopsy

a 4 year screening interval

The number of screen detected PC cancers is already more than twice

as high as compared to the clinical setting

Conclusion: Screening results in a considerable increase of the

incidence of PC

Question: Selective for potentially life threatening PC?

Overview

The facts of prostate cancer

Screening for prostate cancer

Tumor characteristics over time

Management of prostate cancer

Active Surveillance

Risk indicator

Tumor characteristics over time

Screen detected PC, initial screening

76% of T1C cases has Gleason score 6

Screen detected PC, repeat screenings

87% of T1C cases has Gleason score 6

Percentage of potentially indolent PC increases

ERSPC, Rotterdam ( 1993-2009)

Tumor characteristics over time

59% of t1C cases has Gleason score 6

Percentage of potentially indolent PC increases, also in the clinical setting

ERSPC, Rotterdam ( 1993-2009) , PC detected in control arm

Tumor characteristics over time

PSA use in the clinical setting is increasing and subsequently

also the clinical detection of potentially indolent PC.

PSA based screening is becoming more and more common and

is not selective for potentially life threatening prostate cancer

Overview

The facts of prostate cancer

Screening for prostate cancer

Tumor characteristics over time

Management of prostate cancer

Active Surveillance

Risk indicator

Management of prostate cancer

Albertsen tables JAMA ‘05

N=767

Clinical stage ≤ T2

Palliative treatment

Dark grey = PCa †

Light grey = nonPCa †

White = survival

Remember: app 60% of cases had Gleason score <= 6

Much more die with PC than of PC

Management of prostate cancer

ERSPC Rotterdam 1994 – 2002, age 55 – 67, interval 4 years Leadtime

(y) Overdiagnosis

(%) T1 13.2 69 T2 9.3 38 T3+ 8.0 30 Gleason < 7 12.2 62 Gleason 7 9.9 40 Gleason > 7 4.0 8

Management of prostate cancer

Management of prostate cancer

Hormones SurgeryRadio Ther. AS

PC cases detected within ERSPC Rotterdam.

Clinical stage T1C or T2A.

Active treatment in app. 70% of the cases

Overview

The facts of prostate cancer

Screening for prostate cancer

Tumor characteristics over time

Management of prostate cancer

Active Surveillance

Risk Indicator

Active Surveillance

‘primum non nocere’ ("First, not to harm." )

In the case of prostate cancer :

Cure might not be possible in those whom it is needed…

… but cure may not be needed in those whom it is possible…

(Whitmore 1988)

Active Surveillance

Overdiagnosis would not matter if treatment had no adverse effects.  

It would be acceptable to treat all cases, including those destined never to cause

symptoms.  

However, while radical treatment for

prostate cancer may or may not improve

a man’s longevity, it can certainly have

a big impact on his lifestyle.   

Ideally, such intervention should

be restricted to those who need it.  

Active Surveillance

Aims to individualise the management of PC by offering curative

treatment in those cases with evidence of biochemical or

histological progression.

Watchful waiting, a policy of observation with the use of palliative treatment for symptomatic progression.

I would have been here sooner

Active Surveillance

Prostate Cancer Research International: Active Surveillance

Spin off from the European Randomized Study of Screening for

Prostate Cancer (ERSPC)

Initiative of the Department of Urology of the Erasmus Medical Centre

Based on available literature

Prospective study design, ongoing evaluation, aid in decision making

Main goal is to reduce over treatment

It also provides an ideal setting for research to identify new markers,

which, in the future, could improve our ability to determine which men

need, and which men do not need, treatment for their prostate cancer.  

Web based study, accessible for urologists all over the world

Active Surveillance

Active Surveillance

Inclusion criteria:

PSA 10

PSA density <0,2

T2

Gleason 3+3=6

2 positive biopsies

Active Surveillance

Follow-up criteria:

PSA doubling time (DT) >3 yr

T2

Gleason 3+3=6

2 positive biopsies

If PSA >20: Bonescan

If PSA DT 3-10 yr: Yearly rebiopsies

Active Surveillance

Timetable:

PSA (1x / 3 mo) (1x / 6 after na 2 yr)

DRE (1x / 6 mo) (1x / 12 mo after 2 yr)

Rebiopsies (standard after 1, 4 and 7 yr)

Active Surveillance

Active surveillance

Baseline characteristics (N=500)

Active Surveillance

PSA-DT and rebiopsy findings

Active Surveillance

Deferred active therapies and reasons for treatment change

Active Surveillance

Anxiety and distress during active surveillance (N=129)

Management of prostate cancer

Outcomes of PC eligible for Active Surveillance who were managedexpectantly (ERSPC, N=616)Van den Bergh et al. Eur urol 2008.

PSA < 10.0 ng/mlPSA-density <0.2 ng/ml per mlStage T1C/T2Gleason score 3 + 3 = 6<= 2 positive biopsy cores

Management of prostate cancer

The calculated (Kaplan-Meier) 10-yr PCa-specific survival was 100%,

which sharply contrasted with 77% overall survival. Men still alive

showed favourable PSA characteristics.

The calculated 10-yr treatment-free survival was only 43%, objective

signs of progression often did not indicate the shift to radical treatment.

Conclusions: AS seems justified in selected men. Prospective

protocolbased AS programs are necessary to optimise selection criteria

and to find the appropriate trigger points for switching to active therapy.

Follow-up regimen and preliminary results (Klotz et al 2007, Choo et al 2002)

Visits every 3 months for 2 years, later 6 monthly, PSA, DRE, one

biopsy month 18

Active treatment: either PSADT < 2 years (later < 3 years), upgrade

biopsy or clinical progression

331 men, follow-up 5.8 years, 34% are off surveillance

15% had PSA progression

3% clinical progression

4% histological progression

3 patients died of PC after treatment (99% DSS) at 7 year follow-up

Follow-up regimen and preliminary results (Carter et al 2007)

Biannual visits, annual biopsy (>= 12 core), PSA and DRE

Active treatment: biopsy decisive, Gleason pattern 4 or 5, > 2 cores+,

more than 50% PC in one core, PSA change no trigger

407 men, follow-up 3-4 years, 103 (25%) treated

10/49 treated by RP (20%) potentially non curable

Active Surveillance

Make the PRIAS website accessible for more (European) countries

Inclusion based on nomogram use?

Inclusion and/or follow-up based on new biomarkers?

Establishment of biorepository ( PROCABIO)

Individual active surveillance protocol, depending on comorbidity and

age?

Quality of Life on long term?

Is delay in radical treatment dangerous? ( evaluations ongoing)

Costs?

PRIAS will be a important source of information with respect to

application and safety of active surveillance

Overview

The facts of prostate cancer

Screening for prostate cancer

Tumor characteristics over time

Management of prostate cancer

Active Surveillance

Risk Indicator

Prostate Cancer Risk Indicator

A decision aid for lay men and urologist to help them in the question

prostate cancer screening yes or no

www.urosource.com

Gives balanced information on pro’s and con’s

Gives risk estimates on having a biopsy detectable prostate cancer on

5 different levels

Gives risk estimate on potentially indolent prostate cancer

Validated for understanding and effect.

PRIAS, THE study for Active Surveillance

Questions ? Interested in future participation ?

Protocol and PIF’s can be translated into own language

(Europa Uomo)

Always acces to own data

Participation in scientific research

www.prias-project.org

r.vandenbergh@erasmusmc.nl

m.roobol@erasmusmc.nl