Nicola Nicolai La sorveglianza attiva per Urologia il ... · Fondazione IRCCS Istituto Nazionale...

Nicola NicolaiUrologia

Fondazione IRCCS Istituto

Nazionale Tumori Milano

La sorveglianza attiva per

il carcinoma della prostata

Any decision is a balance considering

• Clinical benefits, that may be of short term

• AND

• Side effects, that may permanent and durable

Are all Prostatic cancers harmful?Killer bears or teddy bears?

767 pts (55-74 yrs old)

recruited btw 1971-84.

< 20% of men with

GPS ≤ 6 will die OF PCa

Albertsen PC, Hanley JA, Fine J. 20-year

outcomes following conservative management

of clinically localized prostate cancer. JAMA.

2005 May 4;293(17):2095-101

GPS ≤ 6 will die OF PCa

A model of the natural

history of screen-

detected prostate

cancer, and the effectcancer, and the effect

of radical treatment on

overall survival.

Parker et Al, BJ Cancer

2006; 94(10):1361

1% of 15-yr mortality from low grade sceen-detected PCa 55-74-yrs old

who elect conservative management

<1% absolute 15-yr survival benefif of curative treatment

31,137 Medicare pts > 65 yr

Localized prostate cancer in 1992–2009

Initially conservative management: 15 yr survival

5.7% 10.1%

Lu-Yao GL et al. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.03.021

GPS 5-7 66-74 yr ≥ 75 yr

Any Rx 53.6% 44.6%

Radical intent 45.5% 19.9%

Which PCa we diagnose?We are goig to find what we are able to see!

J Urol 2007;178;S14-S19.

10,385 men from CaPSURE™ registry

between 1990 and 2006

localized disease

120,965 new diagnoses of PCa between 1989 and 2006.

Age-adjusted incidence rates increased from 63 to 104 per 100,000 person-years in this period.

Early ‘90 � increase of cT2

�Visits (DRE)?

Age-adjusted incidence rates increased from 63 to 104 per 100,000 person-years in this period.

Since 2001 �increase of cT1

� PSA screening?

Prostatic cancer: general overview and specific findings

General overview

1 yr RS 95%

5 yr RS 83%

5 yrs Cond RS 88%

Specific findings

5-yr RS decreased with

increasing age,

55–64 yrs � 90%

75-85 yrs � 77%

> 85 yrs � 54% Trama A et al EJC 2015:51;2206–2216

Prostatic cancer: geographic variations

> 90% age-

standardised 5-year

RS in non-eastern

European patients

(except: Denmark, (except: Denmark,

69%; Croatia 71%,

Slovenia 74%).

72% 5-yrs RS for

those from Eastern

Europe (Bulgaria, Europe (Bulgaria,

50%; except Lithuania

83%)

Prostatic cancer: survival trends

Survival improved from 73% to 82% �+ 18% in Eastern Europe

+ 11% in UK/Ireland and Northern Europe

+ 8% in Southern Europe

+ 6% in Central Europe

Trama A et al EJC 2015:51;2206–2216

Prostatic cancer: relationship btw age-std incidence and

age-std 5 RS

Incidence is

correlated with

RS (R: 0.74)

In almost all

countries

incidence and 5 -

yr RS increase

In Italy, Germany,

Finland, Austria,

Switzerland, Switzerland,

incidence in the

3rd trienniium

decreased, while

RS still increased

Trama A et al EJC 2015:51;2206–2216

80

100

120

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Prostate Prostate ccancerancer iincidencencidence and and mortalitymortality

estimatesestimates in Italyin Italy

PSA made the difference!

0

20

40

60

1960 1970 1980 1990 2000 2010 2020 2030

Tass

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cid

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za s

tan

da

rdiz

zati

Anni

Nord-ovest

Nord-est

Centro

Sud

* Standardised rates per 100.000 persons/year

0

10

20

30

40

50

60

19

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19

72

19

74

19

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incidenza mortalità

Rossi et al; Estimates of cancer burden in Italy, Tumori 2013; 99: 416-424* Standardised rates per 100.000 persons/year

(standard european population), age 0-99 years

Rossi et al; Estimates of cancer burden in Italy, Tumori 2013; 99: 416-424

80

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Prostate Prostate ccancerancer iincidencencidence and and mortalitymortality

estimatesestimates in Italyin Italy

PSA made the difference!

0

20

40

60

1960 1970 1980 1990 2000 2010 2020 2030

Tass

i d

i in

cid

en

za s

tan

da

rdiz

zati

Anni

Nord-ovest

Nord-est

Centro

Sud

* Standardised rates per 100.000 persons/year

0

10

20

30

40

50

60

19

70

19

72

19

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Rossi et al; Estimates of cancer burden in Italy, Tumori 2013; 99: 416-424* Standardised rates per 100.000 persons/year

(standard european population), age 0-99 years

Rossi et al; Estimates of cancer burden in Italy, Tumori 2013; 99: 416-424

New cases DOD Prevalent cases

1990 12,295 5,567 36,307

2020 32,661 7,155 347,554

STIME project analysis (courtesy Dr. A. Trama)

Are some cases of Pca overtreated?Are we shooting a panda bear?

Predicting 15-year prostate cancer specific mortality

after radical prostatectomy.

11,521 patients treated with radical prostatectomy at a

total of 4 academic centers from 1987 to 2005

The overall 15-year prostate cancerThe overall 15-year prostate cancer

specific mortality rate was 7%

15-yr PCa specific mortality stratified by GPS at diagnosis,

GPS ≤ 6: 0.2% to 1.2%

GPS 3+4: 4.2% to 6.5%

GPS 4+3: 6.6% to 11%

GPS 8-10: 26% to 37%

Organ confined: 0.8% to 1.5%

Only 3 of 9,557 patients with organ confined, pathological Gleason

score 6 or less cancer died of prostate cancer.

Organ confined: 0.8% to 1.5%

Eggener SE et al, J Urol 2011;185(3):869-75

GPS ≤6: 449 (41%),

GPS 3 + 4: 436 (40%)

GPS 4 + 3: 99 (9%)

GPS 8–10: 117 (11%)

Disease-specific death and metastasis do not occur in patients with

Gleason score ≤6 at radical prostatectomy

1101 RP between 1985 and 2013

GPS 8–10: 117 (11%)

Median FU 100 (IQR 48–150) mos

197 men (18%) died

42 (3.8%) died from PCSM

Kweldam CF et al BJUI 2015: doi:10.1111/bju.12879

No adverse events (pN+

or M+) among GPS ≤ 6

No PCSM among GPS ≤ 6

0,8

1

1,2

Low risk

1996-

1999 0,8

1

1,2

Intermediate risk

5 5 yryr and 10 and 10 yryr relative relative survivalsurvival accordingaccording toto periodperiod and and riskrisk

categorycategory

0,8

1Metastatic

0,8

1

High risk*

0

0,2

0,4

0,6

0 1 2 3 4 5 6 7 8 9

2005-

2007

0

0,2

0,4

0,6

0 1 2 3 4 5 6 7 8 9

0

0,2

0,4

0,6

0 1 2 3 4 5 6 7 8 9

0

0,2

0,4

0,6

0 1 2 3 4 5 6 7 8 9

*statistically significant“Prostate “Prostate cancercancer survivalsurvival patientspatients in Italyin Italy” courtesy Dr. A. Trama

Introduction to the terminologyLet’s see how the definition of indolent cancer was born

and evolved

Terminology and Definitions

• Low risk cancer (D’Amico criteria): low risk of

progression at 5 yrs (25%) following Rx with radical progression at 5 yrs (25%) following Rx with radical

intent

• Indolent Cancer: an asymptomatic cancer that does

not evolve also if it remains untreated

• Minimal cancer (Stamey criteria) following RP: CaP

GPS ≤ 6; volume ≤ 0,5 cc GPS ≤ 6; volume ≤ 0,5 cc

• Minimal cancer (Epstein criteria) pre-Rx: CaP GPS ≤

6, PSA < 10 ng/ml, no bx + < 3, single core

involvement <50%, PSAD < 0,15

JAMA 1998;280:967-974

# 1872

Period 1989-1997

Intervention

RP 888

Implant 218

Category Features Biochemical PRO at 5 yrs

Low T1c-T2a 1992 TNM and

PSA ≤ 10 ng/ml and

GPS ≤ 3 + ≤ 3

< 25%

Intermediate T2b 1992 TNM and/or 25-50%

RP 888

Implant 218

EBRT 766

Intermediate T2b 1992 TNM and/or

PSA > 10 & ≤ 20 ng/ml and/or

GPS = 7

25-50%

high T2c 1992 TNM and/or

PSA > 20 ng/ml and/or

GPS ≥ 8

> 50%

Indolent Cancer: Epstein-Stamey

criteria

Stamey Criteria

Hypothesis 8% of american men receive a Hypothesis 8% of american men receive a

diagnosis of PCa

Methods 139 specimens of cystprostatectomy

for bladder cancer

Findings 8% of these 139 had a PCa > 0.5 cc

Thesis Indolent cancer:Thesis Indolent cancer:

GPS 3+3 ≤ 0.5 cc

Stamey TA et al, Cancer 1993, 71, 3

Indolent Cancer: Epstein-Stamey

criteria

Stamey Criteria Epstein criteria

Hypothesis 8% of american men receive a Which parameters at biopsy predictHypothesis 8% of american men receive a

diagnosis of PCa

Which parameters at biopsy predict

the Stamey thesis?

Methods 139 specimens of cystprostatectomy

for bladder cancer

Findings 8% of these 139 had a PCa > 0.5 cc

Thesis Indolent cancer: ≤ 2 +ve cores

This has become

the

very low risk

prostatic cancerThesis Indolent cancer:

GPS 3+3 ≤ 0.5 cc

≤ 2 +ve cores

GPS ≤ 3+3

PSA ≤ 10 ng/ml

PSA D ≤ 0.15

Stamey TA et al, Cancer 1993, 71, 3 Epstein JI et al, JAMA, 1994, 271, 5

prostatic cancer

What AS isIt is a deferred treatment program

La sorveglianza attiva

Strategia osservazionale con intento

radicaleradicale

• Sovradiagnosi (Overdiagnosis): diagnosi clinica di una “malattia” che, se non fosse stata rilevata, non avrebbe portato a conseguenze sfavorevoli il

Abbiamo verificato

non avrebbe portato a conseguenze sfavorevoli il soggetto portatore (inclusa la morte)

• Malattia “indolente”: la malattia oggetto della “sovradiagnosi”

• Sovratrattamento (Overtreatment): trattamento di una malattia indolente

Sorveglianza attiva

• Programma di “trattamento con intento

radicale” per malattie organo confinate a radicale” per malattie organo confinate a

prognosi particolarmente favorevole, atta ad

evitare un sovratrattamento a buona parte dei

pazienti senza condizionarne la prognosi

• Prevede un monitoraggio periodico che

include la ripetizione della biopsiainclude la ripetizione della biopsia

Active Surveillance (AS) Watchful waiting (WW)

Objective Individualize the therapy Avoid therapy

Tumour cT1-2; GPS ≤ 3+3; PSA ≤ Any cT & PSA;

Active surveillance Vs Watchful Waiting

Tumourcharacteristics

cT1-2; GPS ≤ 3+3; PSA ≤ 10 (15) ng/ml; PSAD < 0.2

Any cT & PSA;

GPS ≤ 7

Monitoring Frequent PSA

Frequent visits

Repeat biopsy

PSA not fundamental

No re-biopsy

Trigger for treatment

Disease reclassification at repeat biopsy

Symptoms

(PSA kinetics)

Timing of therapy

Early Delayed

Intent of treatment

Radical intent Palliation

Modified from C. Parker et al, Lancet Oncol, 2004

AS protocolsWhat are we going to surveil?

Systematic review on AS Dall’Era MA et al. Eur Urol, 2012;62:976–983

Not uniform inclusion criteria

Results: Active Treatment Free Survival (biopsy related causes) and proportional Hazard Ratio

PRIAS vs SAINT: comparing two Active Surveillance protocols

Cancer extension SAINT PRIAS

No +ve cores ≤ 2No +ve cores ≤ 2

% of total cores ≤ 25%

Ca extent x core ≤ 50%

PSA density no ≤ 0.2

Rebiopsy 3/3 yr 2/3 yr

EAU 2015


At reBxAt reBx

No cancer in 20-50%

No change in 42-61%

Upgrading in 14-28%

Upsizing in 2-22%

What happens at subsequent biopsies PSA tends to be stable

% of +ve Bx remains low

Vast majority remains GPS 6

Significant no of GPS 7 and GPS 0

Ankerst DP et al, Eur Urol 2015;68:1083-1088

Urologic Oncology: Seminars and Original Investigations ] (2014) ��–��

Original article

Pathologic outcomes for low-risk prostate cancer after delayed radicalprostatectomy in the United States

Adam B. Weiner, B.S., Sanjay G. Patel, M.D., Scott E. Eggener, M.D.*

Section of Urology, University of Chicago Medical Center, Chicago, IL

Source and selection:16,818 RP < 6 mos

Source and selection:

National Cancer Database: 2010-2011

17,943 low-risk patients� (GPS 3+3 PSA < 10 ng/ml, T1-T2)

Radical Prostatectomy (RP)

16,818 RP < 6 mos

894 RP 6-9 mos

169 RP 9-12 mos

62 > 12 mos

Upgrading 43%Upgrading 43%

Upstaging 9%

+ve SM 16%

pN+ 0.3%

Any 45%

Weiner AB et al, Urol Oncol. 2015 Apr;33(4):164.e11-7.


Short-medium FU (1.8-6.8 yrs)

2 yr Rx in 16-22%

Disease Specific Mortality < 1%

All Causes Mortality 2-21%

Is AS safe enough for PCa patients?Is it a safe Bear hug?

SEER 2010 to 2011

low risk histo confirmed PCa

PSA < 10.0 ng/ml,

biopsy Gleason 3+3

clinical T1c-T2a

Undergoing RP

10,273 patients

5,581 complete data

Risk at definitive pathology according to PSA

and no of cores of

UPGRADING

UPSTAGING

5,581 complete data

Dinh KT et al, J Urol 194, 343-349

Clinical staging is

understimating

definitive pathology

Urologic Oncology: Seminars and Original Investigations ] (2014) ��–��

Original article

Pathologic outcomes for low-risk prostate cancer after delayed radicalprostatectomy in the United States

Adam B. Weiner, B.S., Sanjay G. Patel, M.D., Scott E. Eggener, M.D.*

Section of Urology, University of Chicago Medical Center, Chicago, IL

Source and selection:

National Cancer Database: 2010-2011

17,943 low-risk patients� (GPS 3+3 PSA < 10 ng/ml, T1-T2)

Radical Prostatectomy (RP)

16,818 RP < 6 mosUpgrading 43%

16,818 RP < 6 mos

894 RP 6-9 mos

169 RP 9-12 mos

62 > 12 mos

Upgrading 43%

Upstaging 9%

+ve SM 16%

pN+ 0.3%

Any 45%

MVA

PSA > 4 Vs < 2.5 OR1.87 (1.66-2.10)

> 2 +ve biopsy cores OR 1.68 (1.57-1.81)

> 34% +ve biopsy cores OR 1.28 (1.18-1.39)

9,649 (65%) very low risk at lower risk of

pN+ 0.13% Vs 0.43%

Upgrading 37% Vs 47%

Upstaging 6% Vs 11%

+ve SM 12 Vs 18%> 34% +ve biopsy cores OR 1.28 (1.18-1.39)

Black people OR 1.16 (1.05 – 1.28)

Time from biopsy > 12 mos OR 1.7 (1.01-2.84)

Platinum Priority – Review – Prostate CancerEditorial by XXX on pp. x–y of this issue

Systematic Review and Meta-analysis of Factors Determining

Change to Radical Treatment in Active Surveillance for Localized

Prostate Cancer

Andrew J. Simpkina,*, Kate Tillinga,y, Richard M. Martina,b, J. Athene Lanea, Freddie C. Hamdyc,

Lars Holmbergd, David E. Neal e, Chris Metcalfea,y, Jenny L. Donovana,y

2015 26 AS cohorts

included 7627 men

Median FU 3.5 yr (1.5–7.5 yr)

Wide range of inclusion and

monitoring criteria, and triggers

for Rxfor Rx

8 PCa deaths and 5 cases of

metastases in 24 981 person-

years of follow-up

Each year, 8.8% of men (95% CI

6.7–11.0%) received Rx

Reason for Rx

Upgrading 38%

Other Bx info 29%

PSA 29%

Choice 20%

Platinum Priority – Review – Prostate CancerEditorial by XXX on pp. x–y of this issue

Systematic Review and Meta-analysis of Factors Determining

Change to Radical Treatment in Active Surveillance for Localized

Prostate Cancer

Andrew J. Simpkina,*, Kate Tillinga,y, Richard M. Martina,b, J. Athene Lanea, Freddie C. Hamdyc,

Lars Holmbergd, David E. Neal e, Chris Metcalfea,y, Jenny L. Donovana,y

2015Probability of Rx increases as

The GPS is 3+3 (Vs 7)

The no of scheduled rebiopsy increase

The year of protocol is

recent (4 pts more/yr)

Dataset All causes deathsDataset All causes deaths

RP 171 (47%)

Obs 183 (50%)

HR 0.88 (0.71-1.08 p: 0.22

No difference in age,

ethnicity, PS, Histology

according do deaths to

all causes (DAC) and

PCa deaths

RP deaths 21(5.8%)

Obs Deaths 31(8.4%)

HR 0.63 (0.36-1.09 p: 0.02

all causes (DAC) and

deaths due to PC (DPC)

DAC:

PSA > 10 ng/ml (p: 0.04)

High/Intermediate Vs Low (p: 0.07)

Surgery Vs Observation:

PSA < 10 ng/ml HR 1.03; CI: 0.79-1.35)

PSA ≥ 10 ng/ml HR 0.67; CI: 0.48-0.94 (-

13.2%)

Low risk & High risk: NS

Intermediate risk HR 0.69; CI: 0.49-0.98

DPC: DPC:

PSA > 10 ng/ml and risk category (p:

0,11)

Surgery Vs Observation:

PSA > 10 ng/ml (5.6% vs 12.8%, p: 0.02)

high-risk (9.1% vs 17.5%, p: 0.04)

Bill-Axelson A R et al. NEJM

2014;370:932-42

Bill-Axelson A R et al. NEJM

2014;370:932-42

< 65 years RR of DOD 0.45

SPCG-4: RP vs WW

23.2 years of FU

WW (348) RP (247)

Deaths 247 200

DOD 99 63 (RR 0.56)

Mets 138 89 (RR 0.57)

ADT 235 145 (RR 0.49)

Intermediate risk

RR of DOD 0.38

Number Needed to

Treat � 8!

Active Surveillance Drop Out: Anxiety

AS drop out Anxiety

van den Bergh et al. 20091.6%

(8/500)

Eggener et al. 20095.3%

(14/262)Eggener et al. 2009

(14/262)

Bellardita et al. (INT PRIAS) 20121.6%

(4/254)

Does AS actually reduce overtreatment?Are you a blade runner?

The 8.8% per year rate of change to Rx

from the meta-regression of 2015 is

MUCH HIGHER

than expected on the basis of the

natural history of the disease:

14% DOD IN 18 years of FU among low-

Simpkin AJ et al, Eur Urol 2015,http://dx.doi.org/10.1016/j.eururo.2015.01.004

14% DOD IN 18 years of FU among low-

risk in SPCG-4 study

Bill-Axelson A et al, NEJM 2014;370:932-42

Upgrading predicted by

Age (CV)

Prostate volume < 60 cc

One explanation may be that reclassification includes

up-sizing and up-grading: probably 2 definitely different phenomena

Prostate volume < 60 cc

PSA D (CV)

Upsizing predicted by Upsizing predicted by

Age (CV)

Max core containing cancer > 5%

No. of positive cores > 1

Nicolai N, Rancati T et al. unpublished

Is AS currently accepted?May AS be invited at dinner and use your restroom?

Guidelines

EAU Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis,

and Local Treatment with Curative Intent—Update 2013

Axel Heidenreicha,*, Patrick J. Bastian b, Joaquim Bellmunt c, Michel Bollad, Steven Joniau e,

Theodor van der Kwast f, Malcolm Masong, Vsevolod Matveevh, Thomas Wiegel i,

F. Zattoni j, Nicolas Mottet k

Impossibile v isualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se v iene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo.

Very Low Risk:

Life expectancy > 20 y AS/RP/RTLife expectancy > 20 y AS/RP/RT

< 20 y > 10 y AS

< 10 y Observation

Low Risk:

Life expectancy > 10 y AS/RP/RT

< 10 y Observation

Offer AS as an option to men with low

risk localised prostate cancer suitable

for radical Rxfor radical Rx

Consider AS for men with intermediate

risk localised prostate cancer who do

not wish to have immediate radical Rx

Very low risk Pca : AS a standard option

Low risk Pca: : AS a individualized

option

Is AS currently adopted?“Rari nantes in gurgite vasto”

J Clin Oncol 2010;28:1117-1123.

Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry

11,892 men analyzed 4.0% cryoablation

6.8% surveillance 14.4% Androgen Deprivation Therapy

49.9% prostatectomy49.9% prostatectomy

11.6% external-beam radiation

13.3% brachytherapy

CAPRA Score: the higher, the worse

Treatment according to period and ageTreatment according to period and age

100%

1996-1999 100%

2005-2007

30%

40%

50%

60%

70%

80%

90%

20%

30%

40%

50%

60%

70%

80%

90%

High resolution study on Pca in Italy; courtesy of Dr. Annalisa Trama

0%

10%

20%

Low Intermediate High and very

high

Metastatic

0%

10%

20%

Low Intermediate High and very

high

Metastatic

radiotherapy prostatectomy hormonal therapy unknown none/other

HAROW: the first comprehensive prospective observational

study comparing treatment options in localized prostate cancer

No pts 3169 T1-T2 Period 7-2008 � 3-2013

Pts valuable 2957Pts valuable 2957

(by 257 sites)

RP 56.6% Low risk 38.9%

RT 16.4% Intermediate risk 32.6%

HT 6.9% High risk 26.6 %

AS 15.8%AS 15.8%

WW 4.3% Mean FU 28.4 mos

Weissbach L et al World J Urol, s00345-015-1675-4

Which perspective for AS?

New perspectives make you see differently!

Nuovi protocolli: quali risposte?

• Nuova concezione dei parametri di ingresso

• Individuazione dei pazienti con patologia • Individuazione dei pazienti con patologia

sfavorevole

• Nuovi biomarkers di istologia sfavorevole

• Ruolo della MRI nella diagnosi e

nell’integrazione con la bxnell’integrazione con la bx

Godtman RA et al. Eur Urol 2013;63:101-107Godtman RA et al. Eur Urol 2013;63:101-107

• Il 60% dei pazienti che ricevono una diagnosi da un

programma di screening (Goteborg: 968 pz)

ha malattia di rischio basso/molto basso.

• Circa la metà è arruolabile in un programma di SA.

• La prognosi è particolarmente favorevole.

Godtman RA et al. Eur Urol 2013;63:101-107Godtman RA et al. Eur Urol 2013;63:101-107

The 10-yr Kaplan-Meier estimates

OS: 81.1%

treatment-free survival 45.4%

Failure-free survival were: 86.4%hazard ratio for failure compared to very low-risk tumoursLow- 2.1 (p=0.09)intermediate, 3.6 (p=0.0029)

high-risk 4.6 (p=0.15)

325 valuable RP specimens in current setting

Lifetime risk of a diagnosis of PCa in a screening situation Lifetime risk of a diagnosis of PCa in a screening situation (ERSPC: q 4 yrs, 55 to 75 yrs old) was 130/1,000 men(13.0%)

Lifetime risk of 64/1,000 men (6.4%) of clinicallydetectable prostate cancer.

Thus, only 49.2% (64 of 130) would have been clinicallydetected.

Using the rate of 49.2% for clinically significant disease, Using the rate of 49.2% for clinically significant disease, regardless og stage anf grade, we found an index TV threshold of 0.55 ml and a total TV threshold of 0.70 ml.

Index TV threshold of 1.3 ml and a total TV threshold of2.5 ml in the selection of men with organ confined PC without Gleason pattern 4/5




sfavorevole




757 pazienti in SA (PRIAS) con una prima rebiopsia (reBx) dopo un FU mediano di 1,03 anni

Risultato reBx: favorevole (neg o low-risk CaP) 594 (78.5%)

riclassificazione 163 (21.5%)

Bul M et al. Predictors of Unfavourable Repeat Biopsy Results in Men Participating in a

Prospective Active Surveillance Program. EUROPEAN UROLOGY 61 (2012) 370–377

Riclassificazione associata a: numero di cores positivi iniziali (2 vs 1) (OR: 1.8; p = 0.002)

PSA density più elevata (OR:2.1; p = 0.003)

PSA-DT < 3 a all’epoca della reBx (OR: 1.7; p = 0.015)

Upgrading predicted by

Age (CV)

Prostate volume > 60 cc

La riclassificazione include sia up-grading che up-sizing

I due fenomeni sono associati a biomarcatori distinti:

Situazioni diverse!

Prostate volume > 60 cc

PSA D (CV)

Upsizing predicted by

Age (CV)

Max core containing cancer > 5%

No. of positive cores > 1No. of positive cores > 1

Nicolai N, Rancati T et al. unpublished




sfavorevole




T PSA, PSA ratio, [-2]proPSA and AS

Dati da John Hopkins su pts in SA: biomarkers serici in 167 pz

al fine di predire la riclassificazione a biopsiaPresented by Trock ESO Active Surveillance PRIAS meeting Amsterdam January 2012

variable TV < 0.5 cc ECE R1 GPS > 6 a PR

OR p OR P OR P OR P

PCA3 ≤ 1 1 1 1

Analisi multivariata in 160 pazienti sottoposti al test PCA3 prima di prostatectomia radicale

PCA3 ≤

35

1 1 1 1

PCA > 35 2.2 (1.02-4.8) 0.04 1.6 (0.7-3.8) 0.2 2.4 (0.7-3.8) 0.04 1.3 (0.6-2.9) 0.5

GPS ≤ 6 1 1 1

GPS > 6 2 (0.9-4.6) 0.1 2 (0.9-4.5) 0.08 16.3 (4.6-57.7) < 0.001

< 1/3 +ve

bx

1 1 1

bx

≥ 1/3 +ve

bx

7.8 (1-61.2) 0.05 3.2 (1.3-7.6) 0.009 2.3 (0.8-6.6) 0.1

Durand et al BJUI 2012 doi:10.1111/j.1464-410X.2011.10682.x

The Prolaris® Gene Signature

• An RNA expression signature

• Measures cell cycle progression (CCP) genes• Measures cell cycle progression (CCP) genes

• Assessment of the aggressiveness of a prostate

cancer tumor

• Prognostic of disease progression

• CCP score• CCP score

– Based on expression profile of 31 predefined genes involved in

the cell cycle developed in a previous study (plus 15

housekeeping genes)

– Expression profiles averaged on the across gene panel , after

exclusion of genes with unstable expression in triplicates

Platinum Priority – Prostate CancerEditorial by Ian G. Mills on pp. 568–569 of this issue

Characterization of 1577 Primary Prostate Cancers Reveals Novel

Biological and Clinicopathologic Insights into Molecular Subtypes

Scott A.Tomlinsa,b,c,d,*,MohammedAlshalalfae,Elai Davicioni e,NicholasErhoe,KasraYousefi e,

Shuang Zhao f, Zaid Haddade, Robert B. Deng, Adam P. Dicker g, Bruce J. Trock h,

Angelo M. DeMarzoh, Ashley E. Rossh, Edward M. Schaeffer h, Eric A. Klein i,

Cristina Magi-Galluzzi i, R. Jeffrey Karnesj, Robert B. Jenkinsk, Felix Y. Fenga,d,f,*

1577 patient PCa GEP from 8 RP

cohorts: Mayo Clinic (MCI and II),

Thomas Jefferson University (TJU),

Cleveland Clinic (CCF),

Johns Hopkins (JHMI),

Memorial Sloan Kettering (MSKCC),

Erasmus MC (EMC),

the German National Cancer Registry (DKFZ)

mERG and non ERG (ETV1, ETV4, ETV5, FLI1, SPINK1) GEPEur Urol 68, epub, 2015

mERG and non ERG (ETV1, ETV4, ETV5, FLI1, SPINK1) GEP

�4 arrangements: Eur Urol 68, epub, 2015




sfavorevole




Ruolo della mpMRI

• Diagnosi prebioptica

– Futuribile?– Futuribile?

– A basso costo e non-invasiva (bip-MRI)

• Diagnosi con biopsia

– Sotto guida MRI

– Tecniche di fusione con US

• Cognitiva• Cognitiva

• Elastica

• Rigida

A domanda rispondi

• Prima diagnosi?

• Rebiopsia?

• Sorveglianza attiva?

Conclusioni

• Non è pensabile di fermare il ricorso opportunistico al PSA e alla cascata diagnostica che porta al riscontro di CaPCaP

• Buona parte dei riscontri attuali riguardano malattia a rischio molto basso/basso (la sovradiagnosi esiste)

• La SA è un trattamento che mantiene l’intento radicale

• La SA è un’alternativa che deve attualmente essere considerata per evitare che alla sovradiagnosi segua comunque un sovratrattamentocomunque un sovratrattamento

• La SA comunque LIMITA ma NON RIDUCE il rischio di sovratrattamento.

Conclusioni (cont)

• Esistono limiti importanti di undersampling

• Allo stato questi non si associano a differenze di patologia sfavorevole dopo PRpatologia sfavorevole dopo PR

• La % di pazienti che rimangono in SA è variabile

• La CSS dei pazienti sfiora il 100%

• Nuove concezioni (riduzione del valore del volume tumorale) e strategie (mpMRI + MRGB) sono in evoluzione rispettivamente per sono in evoluzione rispettivamente per incrementare la proporzione dei pazienti candidabili e migliorare la selezione di quelli con malattia più favorevole

Waiting for

• Reducing overdiagnosis through a different approach to screening– Individualized screening (e.g. as recommended by AUA)

– Other criteria to be introduced: genetic drivers as BRCA1/BRCA2 carriers (IMPACT study)carriers (IMPACT study)

– mpMRI prior to biopsy

• A better selection of patients at diagnosis and during follow-up– Reasons why patients drop out are still too heterogeneous

• Reducing overtreatment through new tools in diagnosis and follow-up– Genomics (e.g. Prolaris)

IMPACT Collaborators, Moss S, et alEur Urol. 2014 Sep;66(3):489-99.

Mullins JK et al. BJUI 2013;111:1037–1045Mullins JK et al. BJUI 2013;111:1037–1045

– Genomics (e.g. Prolaris)

– Proteomics (miRNA?)

– MRI guided biopsies

Pokorny MR et al. Eur Urol 2014 Eur Urol. 2014 Jul;66(1):22-9Pokorny MR et al. Eur Urol 2014 Eur Urol. 2014 Jul;66(1):22-9

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