Post on 16-Feb-2019
transcript
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
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Prostate Prostate ccancerancer iincidencencidence and and mortalitymortality
estimatesestimates in Italyin Italy
PSA made the difference!
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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
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Rossi et al; Estimates of cancer burden in Italy, Tumori 2013; 99: 416-424
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Prostate Prostate ccancerancer iincidencencidence and and mortalitymortality
estimatesestimates in Italyin Italy
PSA made the difference!
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Tass
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Centro
Sud
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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
Systematic review on AS Dall’Era MA et al. Eur Urol, 2012;62:976–983
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.
Systematic review on AS Dall’Era MA et al. Eur Urol, 2012;62:976–983
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
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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
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
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
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
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
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
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
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
La sorveglianza attiva per il
carcinoma della prostataprostata
nicola.nicolai@istitutotumori.mi.it