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Prostate Cancer Screening Jonas Hugosson Professor Avd för Urologi, Sahlgrenska Akademin, Göteborgs Universitet Stockholm October 2016

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Prostate Cancer Screening

Jonas Hugosson Professor

Avd fr Urologi, Sahlgrenska Akademin, Gteborgs Universitet

Stockholm October 2016

a) Most commonly diagnosed cancer

among men worldwide, 2008

Second leading cause of

Cancer death after lung cancer

Source: GLOBOCAN 2008 [1]

Center MM, et.al. Eur Urology 2012;61:1079-92 Stockholm October 2016

2014-04-23 Nationella riktlinjer fr brst-, prostata-, tjocktarms- och ndtarmscancer Stockholm October 2016

2014-04-23 Nationella riktlinjer fr brst-, prostata-, tjocktarms- och ndtarmscancer Stockholm October 2016

Size at which cancer become incurable

Size at which cancer is detectable

Stockholm October 2016

Strong arguments for screening Prostate cancer kills a lot of men (2-5 % of all deaths in

European men) Better health and longer life expectancy in men will

immediately result in that more men will suffer and die from PC

Only screen-detected cancers are curable. Those diagnosed because of symptoms are almost always too advanced for cure (Aus et al 1994, J Urol)

Treatment of advanced disease only marginally improves survival and is very costly

Side-effects from radical prostatectomy and radiation have decreased significantly during the last decades and in early cancers side effects are acceptable to most men.

Stockholm October 2016

Strong arguments against screening

The risk of over-diagnosis is high, approximately 50 % of screen-detected cancers will not develop symptoms during their life-time

The time between screen-diagnosis and clinical symptoms (lead time) is long (mean 5-10 ys)

Treatments and surveillance of PC is associated with side-effects

Diagnosis of PC is associated with psychological trauma

Stockholm October 2016

Randomised screening studies Published Number

invited Weakness

Stockholm 2009 1800 Small study, one time screening, few men treated with curative intent

Quebec 1999 (2004)

31 133 Only 24 % participated, not evaluated according to intention to screen

Norrkping 2011 1494 Small study, not designed to evaluate mortality, PSA was included from 3rd round and only 895 men PSA tested

ERSPC 2009, 2012 82816 8 centers with different protocols

PLCO 2009, 2012 37285 52 % contamination, very low mortality in controls, low biopsy rate, no up-front power calculation

Gteborg 2010 9952

Stockholm October 2016

Stockholm October 2016

Published screening studies comparing PSA based screening with current opportunistic screening

Stockholm October 2016

Prostate cancer mortality for individual centers

Center (FU) Rate ratio (95%)

Relative risk reduction

P-value

Netherlands (11.1 ys) 0.71 (0.52-0.96) 29% 0.003

Belgium (12.1 ys) 0.86 (0.48-1.52) 14% NS

Sweden (14 ys) 0.56 (0.38-0.83) 44% 0.001

Finland (11.0 ys) 0.89 (0.72-1.09) 11% NS

Italy (10.7 ys) 0.86 (0.46-1.58) 14% NS

Spain (10.7 ys) 2.15 (0.20-23.77) - -

Switzerland (8.2 ys) 0.89 (0.36-2.20) 11% NS Stockholm October 2016

Stockholm October 2016

Stockholm October 2016

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Stockholm October 2016

Conclusion of ERSPC

PSA screening decreases mortality Over-diagnosis is substantial but how large is

not yet established, the control group is still catching up

There is a long lead-time which means that also non over-diagnosed cases will have to pay with many disease and symptoms free years.

Screening is a long-term investment

Stockholm October 2016

Stockholm October 2016

Stockholm October 2016

NNS=293 NNT=12

RR=0.56 (95% CI 0.39-0.82) (p=0.002)

EAU 2015

18-year follow up of the Gothenburg randomized population-based prostate cancer screening trial

Arnsrud Godtman R, Carlsson S, Grenabo Bergdahl A, Holmberg E,

Stranne J, Lilja H, Hugosson J

Background:

The Gothenburg screening trial has previously

reported a 44% (rate ratio 0.56) relative risk reduction and a 0.4% absolute risk reduction in prostate cancer (PC) mortality after 14 years of follow up

It is not clear how sociodemigraphic factors affect attendance and outcomes of an organized screening program for PC

Stockholm October 2016

Results after 18 years PC incidence rate / 1000 person years - Screening: 9.7 (95% CI, 9.2-10.2) - Controls: 6.5 (95% CI, 6.1-6.9) RR 1.51 (95% CI 1.39-1.64) PC mortality rate / 1000 person years - Screening: 0.51 (95% CI, 0.41-0.64) - Controls: 0.79 (95% CI, 0.66-0.94) RR 0.65 (95% CI, 0.48-0.87) Absolute risk reduction 0.52 (95% CI 0.17-0.87) NNI 231 NND 10

Stockholm October 2016

Results Attendance PC inc. rate / 1000

person yrs Rate ratio PC inc. PC mort. rate /

1000 person years Rate ratio PC mort.

Overall 77% 9.7/6.5 1.51 0.51/0.79 0.65

Age 50-54 55-59 60-65

78% 77% 74%

8.7/4.9 9.9/7.2 11.2/8.1

1.77 1.37 1.39

0.14/0.27 0.47/1.0 1.17/1.37

0.50 0.47 0.85

Cohabitation Yes No

83% 67%

10.2/7.0 8.8/5.4

1.46 1.62

0.52/0.78 0.50/0.81

0.67 0.61

Education Low Medium/high

73% 80%

9.2/6.1 10.2/6.8

1.51 1.50

0.49/1.00 0.53/0.69

0.49 0.76

Country of origin Nordic European Non-European

78% 74% 70%

10.3/6.97 6.8/3.7 6.3/3.4

1.47 1.84 1.82

0.55/0.84 0.27/0.39 0.21/0.71

0.65 0.70 0.29

Comorbidity index 1-2 3-13

78% 73%

9.6/6.1 10.1/7.5

1.57 1.36

0.33/0.60 1.01/1.29

0.55 0.78

Stockholm October 2016

Conclusions

At extended follow up (FU 18 years) the relative risk reduction in PC mortality decreased but the absolute risk reduction increased

Men with a low level of education seem to benefit the most from organized PSA-screening

An organized screening program has the potential to reduce socioeconomic inequalities in PC mortality

Stockholm October 2016

Stockholm October 2016

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Key Results

Mortality Reduction 35 % Every man saved from PC death have an

average lengthening of life with 8 years 23 % of life years gained are lost due to

impaired QoL The main QoL loss is due to permanent side-

effects of treatment Number needed to treat is 5

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NNI screening group = 139, NNI control group = 493 NND screening group=13, NND control group =23

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Stockholm October 2016

Is thus PSA screening good enough for recommending all men regular testing?

Stockholm October 2016

NO!! Why!!

The risk of over-diagnosis is too high At moment all men should be informed about

pros and cons and make an individual decision Can better screening decrease the risk of over-

diagnosis?

Stockholm October 2016

Mechanisms for over-diagnosis

With increasing age small well differentiated cancers increases, 30-50 % of men age 50-70 harbour a cancer in their prostate

80 % of these cancers are small and slow-growing and will not become clinical during life-time

Stockholm October 2016

So how large is over-diagnosis in prostate cancer

The life-time risk of being diagnosed with prostate cancer have doubled in North America and also in Scandinavia, from 8-10 % in the pre PSA era to 16-20 % (Godtman et al 2012)

This is accordance with simulation studies showing that almost 50 % of cancers detected with PSA testing are over-diagnosed (Steyerberg et al)

Stockholm October 2016

Mechanisms of over-diagnosis

A low specificity of PSA, only 15-20 % of men in a screening situation has an elevated PSA due to a significant cancer, the remaining have other causes such as BPH, inflammation etc

Current diagnostic pathway aim to biopsy the whole peripheral zone of the prostate (systematic biopsies) as PSA give no indication of where a possible cancer could be located in the gland

Stockholm October 2016

Mechanisms of over-diagnosis

Systematic blind biopsies risk to hit a small harmless cancer accidentally but also miss large cancers

In the Gteborg study we estimated that each time a man undergo a systematic biopsy there is a 10 % risk of diagnosing a harmless cancer

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CONCLUSIONS: The postscreening PC incidence is reduced after attending three screening rounds, but not after only one or two rounds. Thus, the increased cancer detection at screening is compensated by a subsequent risk reduction only after repeated screening cycles.

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Stockholm October 2016

Abnormal cell

Fast slow Very slow

Detectable with screening

Size when incurable

Clinical symptoms

Distribution of Cancers detected at first screen

Death from PC

Non progressive

Stockholm October 2016

Abnormal cell

Fast

Slow

Very slow

Detectable with screening

Size when incurable

Clinical symptoms

Distribution of Cancers detected at repeat screens

Death from PC

Could we improve current Screning technology

Better and more specific markers, as Phi, 4K panel and the Stockholm 3 test

MRI??

Stockholm October 2016

Stockholm October 2016

Stockholm October 2016

Hur kan diagnostiken frbttras?

Stockholm October 2016

Stockholm October 2016

Is mpMRI of the prostate the solution of current diagnostic problems?

Is the risk of over-diagnosis decreased? What is the sensitivity of significant cancers? What is the features of these cancers missed with

mpMRI What is the equipment needed? 1.5 T or 3T? How large is the interobserver variation in

reading the MRI? How are biopsies best guided towards MRI

lesions?

Stockholm October 2016

Prostate MRI findings with radical prostatectomy

3T MP-MRI (N=133). Lesions were identified on MRI in 126 (95%)

cases. MRI showed sensitivity of 93%, PPV of 57%,

and overall accuracy of 92% in predicting insignificant pathologic disease (defined as tumour volume

MRI of the prostate

Detects 90 % of significant cancers, approximately as many as standard systematic biopsies do.

Cancers less than 7-8 mm in diameter are seldom detected at MRI especially if well-differentiated

MRI give an estimation of tumor size and anatomical location allowing for targeted biopsies alone

Give information of stage, capsular penetration, seminal vesicle involvement

Also regional lymph-glands and pelvic skeleton

Stockholm October 2016

Gteborg 1 pilot study (Grenabo et al 2015)

Stockholm October 2016

Figure 1.

Cancers detected with mpMRI and targeted bx in the PSA range 1.8-2.99

Stockholm October 2016

A)

PSA

T-stage

Gleason

Biopsy mode

No. of sectors

with cancer

Modified Epstein

criteria

1

2.32

T2a

3+4=7

SB + TB

5/ 10

S

2

2.57

T2a

3+4=7

SB + TB

6/10

S

3

1.82

T1c

3+4=7

SB + TB

5/10

S

4

1.94

T2a

3+3=6

SB + TB

2/10

S

5

2.04

T1c

3+3=6

SB + TB

2/10

IS

6

2.94

T1c

3+3=6

TB

2/10

S

7

2.89

T1c

3+3=6

TB

1/10

IS

B)

Cancers detected with systematic bx and a normal mpMRI

Stockholm October 2016

B)

PSA

T-stage

Gleason

Biopsy mode

No. of sectors

with cancer

Modified Epstein

criteria

1

3.47

T1c

3+3=6

SB

1/10

IS

2

4.05

T1c

3+3=6

SB

3/10

S

3

3.53

T1c

3+3=6

SB

1/10

IS

4

3.32

T1c

3+4=7

SB

1/10

S

5

6.83

T1c

3+4=7

SB

4/10

S

6

4.04

T1c

3+3=6

SB

1/10

S

7

3.03

T1c

3+3=6

SB

1/10

IS

Summary and Conclusions

MRI detected 80-90 % of significant cancers, appr as good as systematic biopsies

MRI decreased the number of men needing biopsy with 65 %

The risk of detecting harmless cancers decreased dramatically with MRI and targeted directed biopsies only compared to PSA plus systematic biopsies.

MRI seemed to work as good in the PSA interval 1.8-3 as above 3 ng/mL.

If replicated in large randomised studies it would lead to a paradigm shift in diagnosing PC

Stockholm October 2016

STUDY BASE N=40,000

50-60 years

CONTROL N=20,000

SCREENING N=20,000

PSA-test & RANDOMISERING

1:1:1

ARM 1

PSA < 3.0

Re-invitation

If PSA

Endpoints

Detection rate of significant and non significant cancers (based upon biopsy data)

Will be reported in 2019/2020

Stockholm October 2016

Sequential screening with biomarkers followed by imaging, next step??

In future PSA (with complementary biomarkers) will be primary screening tool but with a lower threshold (1-2 ng/mL)

If elevated next step is MRI If MRI is negative no biopsy but FU If MRI is positive only targeted lesion directed

biopsies

Stockholm October 2016

Screening for Cancer

A balance between Benefits and Harms

At the heart of the screening debate lies the ethics of information

Ian S Markham. Brittish Medical Bulletin.

1998; 54 (4): p.1012.

Stockholm October 2016

Prostate Cancer Screeninga) Most commonly diagnosed cancer among men worldwide, 2008Bildnummer 3Bildnummer 4Bildnummer 5Strong arguments for screening Strong arguments against screeningRandomised screening studiesBildnummer 9Bildnummer 10Prostate cancer mortality for individual centersBildnummer 12Bildnummer 13Bildnummer 14Bildnummer 15Bildnummer 16Conclusion of ERSPCBildnummer 18Bildnummer 19Bildnummer 2018-year follow up of the Gothenburg randomized population-based prostate cancer screening trialArnsrud Godtman R, Carlsson S, Grenabo Bergdahl A, Holmberg E, Stranne J, Lilja H, Hugosson JResults after 18 yearsResultsConclusionsBildnummer 25Bildnummer 26Key ResultsBildnummer 28Bildnummer 29Bildnummer 30Bildnummer 31Bildnummer 32Bildnummer 33Is thus PSA screening good enough for recommending all men regular testing?NO!! Why!!Mechanisms for over-diagnosisSo how large is over-diagnosis in prostate cancerMechanisms of over-diagnosisMechanisms of over-diagnosisBildnummer 40Bildnummer 41Bildnummer 42Bildnummer 43Bildnummer 44Bildnummer 45Could we improve current Screning technologyBildnummer 47Bildnummer 48Hur kan diagnostiken frbttras?Bildnummer 50Is mpMRI of the prostate the solution of current diagnostic problems?Prostate MRI findings with radical prostatectomy MRI of the prostateGteborg 1 pilot study (Grenabo et al 2015)Cancers detected with mpMRI and targeted bx in the PSA range 1.8-2.99Cancers detected with systematic bx and a normal mpMRISummary and ConclusionsBildnummer 58EndpointsSequential screening with biomarkers followed by imaging, next step??Screening for CancerA balance between Benefits and HarmsAt the heart of the screening debate lies the ethics of information