Transcript Limits of Tumorectomy in clinical localized renal cell cancer

New markers and strategies
Oliver Hakenberg
Department of Urology, Rostock University
Rostock, Germany
Prostate cancer
stage definition UICC
• localized
T1 – 2 N0 M0
• locally advanced
T3 – 4 N0 M0
• advanced/metastatic
N1 – 3 and/or M1
Localized prostate cancer
organ-confined: T1–2 N0 M0
D‘Amico risk classification concerning recurrence after localized therapy
•
Low risk
PSA < 10 ng/ml
and
Gleason Score ≤ 6
and
T1c to 2a
•
Intermediate risk
PSA > 10 to 20 ng/ml
or
Gleason 7
or
cT 2b
•
High risk
PSA > 20 ng/ml
or
Gleason Score ≥ 8
or
cT 2c
D‘Amico et al
Prostate cancer
•
•
•
•
•
Most common solid organ malignancy in men
Incidence correlates with age
Long natural course of the disease
Significant vs insignificant disease
PSA= clinical marker for diagnosis and follow-up
Age and incidence of prostate cancer
Germany
AG Bevölkerungsbezogener Krebsregister 2008
Age and prevalence of prostate cancer
Autopsy study, n= 164
prevalence [%]
positive biopsy: 16.5 %
100
75
negative biopsy
Thompson et al., NEJM 2004
50
25
0
Haas et al., JNCI 2007
40
50
60
70
80
years
Demographic developments in Germany
Männer
2.9 million
Männer
4.0 miollion
Mean life
expectancy
of men: 77 years
Mean life
expectancy
of men: 85 years
2005
Statistisches Bundesamt 2006
2050
Natural course of prostate cancer
diagnosis
clinical diagnosis
by symptoms
tumour
development
ehung
40
death of
patient
Screening
possible
early
diagnosis
45
50
55
preclinical phase
60
65
70
75
years
lead time
bias
Incidence and mortality of prostate cancer in Europe 1998
Davidson & Gabbay, WHO Report 2007
Recurrence-free survival after curative localized
monotherapy in prostate cancer
1819 consecutive patients at the Memorial Sloane Kettering Cancer Center
n
median follow-up
(months)
7 year PSA-recurrencefree survival rate
brachytherapy
733
51
74%
EBRT
340
56
77%
radical prostatectomy 746
57
79%
Potters et al, Radiother Oncol 2004
13-year cancer-specific survival after treatment of localized prostate cancer
population-based cohort study (n=1618)
Tumorspezifisches Überleben
Cause specific survival in 3 treatment groups stratified by D’Amico risk category.
S= surgery. R= radiation therapy. O= observation.
Albertsen et al., J Urol 2007
Biochemical recurrence after RPE
(retrospective study, n= 37 centres, n= 5291 patients)
PSA recurrence in 36% of patients
Chun & Djavan et al, Eur Urol 2007
Radical prostatectomy vs watchful waiting
Disease-specific mortality and rate of metastatic progression
The Holmberg study
Disease-specific mortality
Holmberg et al, N Engl J Med 2002
Incidence of metastatic progression
RPE vs ‚Watchful waiting‘
The Holmberg study with a follow-up of 10 years
RPE
WW
progression (M+)
15.2%
25.4%
overall mortality
27%
32%
disease-specific
mortality
9.6%
14.9%
PCa mortality < age 65 Jahre
with RPE
- 11%
PCa mortality > age 65
with RPE
- 0,3%
Bill-Axelson A et al, N Engl J Med 2005
Natural course of prostate cancer
disease
after PSA recurrence (n= 311)
PSA
recurrence
0
distant
metastases
5
death
of disease
10
15
years
Pound et al, JAMA 1999
Natural course of grade* G1/2 prostate cancer
(n=119, 1978-1982, median follow-up 24 years, median age 68 years)
survival
15 %
tumour-specific
overall
44 %
70 %
years
Adolfsson et al, Eur Urol 2007
*conservative treatment on progression only
Risk stratification for biochemical recurrence
(n=1515)
without PSA recurrence [%]
100
80
60
40
20
low
intermediate
high
very high
4
5
0
0
1
2
3
Years after RPE
Moul et al, J Urol 2001
6
7
Overall survival after RPE by age
RPE in Austria: n=16.524
1992-2003
Mohamad et al, Eur Urol 2007, 51, 684-689
Long-term survival after radical prostatectomy
(competing risk analysis; n=1910)
Cumulative mortality [%]
cumulative mortality [%]
35
Froehner, Wirth et al., J Urol 2009
overall
comorbidity
prostate cancer
second cancer
other causes
30
25
overall
20
prostate cancer-specific 12 %
15
10
Second cancer
comorbidity
5
other
0
0
No. at risk: 1910
2
1883
4
6
8
901
486
10
Jahre
RPEprostatectomy
Yearsnach
after radical
1369
288
12
123
14 15 16
32
Cancer-specific survival after RPE
depends on Gleason score
CaP-specific
survival [%] Überleben [%]
prostatakarzinomspezifisches
100
80
(n=1255)
60
40
Category
Events
Gleason-Score
Gleason-Score 2-6
20
Gleason-Score 7
0
2
4/676
1
6/360
2.73
p
Gleason-Score 7 (n=360)
Gleason-Score 8-10
0
Hazard
95 % CI
2-6 ratio
(n=676)
0.74-10.02
Gleason-Score
8-1024.78
(n=219)9.74-63.01
20/219
4
6
8
10
Years
afterProstatektomie
RPE
Jahre nach
radikaler
Patienten: 1255
1232
799
Dept. of Urology, Dresden University 2007
406
183
71
0.13
<0.0001
12
4
Comorbidity-specific vs disease-specific mortality
after radical prostatectomy (n= 444)
Probability of survival [%]
100
100
100
90
90
90
80
80
80
70
comorbidity-specific
70
70
PCa specific
60
60
ASA 1
50
0
2
4
ASA 2
(n=70)
6
8
60
10
Froehner, Wirth et al., Urology 2003
50
0
2
4
ASA 3 (n=42)
(n=332)
6
8
Years after RPE
10
50
0
2
4
6
8
10
Survival after curative treatment
radical prostatectomy
• cancer-specific survival
– Gleason score
– PSA
– tumour extent
• overall survival
– age
– comorbidity
48 cases of prostate cancer needed to be treated
to prevent one death from prostate cancer.
Schroeder et al, N Engl J Med 2009
Prostate cancer cases from the
European Randomized Study of Screening for Prostate Cancer
Screening arm:
n=139 PCa cases from 21210 screened men
Control arm:
n=1149 PCa cases from 21166 control cases
Disease-specific survival
Zhu et al, Eur Urol 2011
Overall survival
Overdiagnosis? Overtreatment?
Management ≠ active treatment
Management options for localized
prostate cancer
•
•
•
•
watchful waiting
active surveillance
radical prostatectomy
radiotherapy
What basis do we have for a management decision?
• type and stage of prostate cancer
– risk stratification
– PSA, Gleason score, tumour extent on biopsy
• age and life extectancy
• comorbidity
• patient preference
Risk stratification according to D‘Amico
Risk stratification for
recurrence
after local treatment
local stage PSA
(ng/ml)
Gleason
score
5 year PSArecurrence-free
survival after
RPE
low risk
T1c-T2a
< 10
6
85%
intermediate risk
T2b
> 10
7
50%
high risk
T2c-T3a
> 20
8-10
33%
For „intermediate“ and „high risk“ it is always „or“
Life expectancy according to age and comorbidity
20,0
18,0
16,0
14,0
12,0
10,0
8,0
6,0
4,0
2,0
0,0
ICED Score 65
70
0
Albertsen et al, J Urol, 1996
1
75
n=
2
3
451
Charlson score nomogram
underestimates survival in healthy over 70 year-olds
(n=329/1910)
% overall survival 10 years after radical prostatectomy
100
100
p<0.0001
90
90
88 %
80
70
p=0.46
80
70
74 %
60
60
69 %
62 %
50
predicted
beobachtet
Charlson-Score 0
Froehner et al, Urology 2009
50
predicted
beobachtet
Charlson-Score 1+
New strategies
Watchful Waiting
• „expectant observation“
• observation = no treatment
• symptomatic/palliative treatment if and
when symptoms occur
• only then: androgen ablation
Watchful Waiting (WW)
option for localized prostate cancer
• if there is no indication for treatment with
curative intent
– age
– comorbidity
– patient preference
– if WW is chosen despite a feasible option and
possibility for curative treatment, extensive informed
consent of the patient is of paramount importance
New strategies
Active Surveillance
• localized low risk prostate cancer with an
indication for curative treatment
• well differentiaited prostate cancer = „insignificant
prostate cancer“
• active curative treatment is only undertaken, if and
when the disease course shows aggressive growth
• Close follow-up including rebiopsies
Conditions for active surveillance
•
•
•
•
•
PSA ≤ 10 ng/ml
Gleason score ≤ 6;
stage T1c und T2a;
tumour seen in ≤ 2 biopsy cores*
≤ 50% tumour tissue in any core
S3-Leitlinie Prostatakarzinom DGU 2009
German interdisciplinary evidence-based guidelines
for the diagnosis and management of prostate cancer, update 2011
What does active surveillance entail?
• PSA + DRE every 3 months for the first 2 years
• if PSA remains stable, further follow-up every 6
months
• repeat biopsies every 12-18 months
S3-Leitlinie Prostatakarzinom DGU 2009
German interdisciplinary evidence-based guidelines
for the diagnosis and management of prostate cancer, update 2011
When to stop active surveillance?
if and when
– PSA doubling time < 3 years
– repeat biopsy
• Gleason score > 6
• tumour extent > 2 cores and/or > 50%/core
– patient preference
Life expectancy
> 10 years?
No
Yes
Watchful Waiting
Active curative treatment
S3-Leitlinie Prostatakarzinom DGU 2009
Pathologic results of AS
primary vs delayed RPE
National Swedish Cancer registry
Holmström et al, Eur Urol 2010
Warlick et al, J Natl Cancer Inst 2006
Khatami et al, Scand J Urol Nephrol 2003
Khatami et al, Int J Cancer 2007
Prostate cancer mortality is not influenced by AS
Holmström et al, Eur Urol 2010
Which decisions must be taken?
1. is curative treatment indicated?
age + comorbidity
life expectancy
risk stratification for
recurrence
2. active treatment or active
surveillance?
Gleason score
Extent of tumour in
biopsy
patient preference
2a.
Active Surveillance
feasible?
3. surgery or radiotherapy
nomograms
Risk estimation
nomograms
• probability of organ-confined disease with RPE
(Partin tables)
• likelihood of biochemical recurrence after RPE
(Han tables)
• likelihood of 10-year survival after RPE
(Walz
nomogram)
Partin tables
Likelihood of organ-confined stage (%)
with PSA < 2.5 ng/ml
GleasonScore
cT-Stadium
T1c
T2a
T2b
T2c
2-4
95%
(89-99)
91%
(79-98)
88%
(73-97)
86%
(71-97)
5-6
90%
(88-93)
81%
(77-85)
75%
(69-81)
73%
(63-81)
3+4 = 7
79%
(74-85)
64%
(56-71)
54%
(46-63)
51%
(38-63)
Partin et al, JAMA 1997; Urology 2001
Partin tables
Likelihood of organ-confined disease
probability (%)
PSA range 4.1-10 ng/ml
100
80
60
40
20
6
0
7
8-10
cT1a
cT1b
cT1c
cT2a
cT2b
clinical stage
Partin et al, JAMA 1997
cT2c
cT3a
5
2-4
Gleason
score
Probability of PSA recurrence after RPE
with organ-confined prostate cancer
% PSA recurrence after 10 years (0.2 ng/ml)
(n=2091)
100
80
PSA
60
40
20+ ng/ml
10.1-20 ng/ml
4.1-10 ng/ml
0-4 ng/ml
20
0
6-
3+4
4+3
Gleason score
Han & Partin et al, J Urol 2003
8-10
Nomogram for the probability of 10 year survival after RPE
(n=5955)
points
age (years)
comorbidity
(Charlson score)
points (sum)
survival (10 years)
71 %
Example: 75 years, Charlson score 0
Walz et al., J Clin Oncol 2007
Markers
• Evolving diagnositic issues
• Evolving therapeutic issues
• Evolving long-term strategies
PSA screening
Rotterdam Screening Study, 1997
%
40
35
30
25
benign
PCa
20
15
10
5
0
0,2
0,5
1
2
5
10
20
50
100
PSA ng/ml)
PSA-based diagnosis
% of men
30
25
20
15
PSA
10
5
0
0-0.5
0.6-1
1,1-2
Thompson et al, N Engl J Med 2004, 350, 2239ff
2,1-3
3,1-4
(ng/ml)
Number of biopsy cores and prostate cancer detection rate
(n=1000)
Biopsy cores
n
6
12
18
21
prostate volume
<35
35-55
>55
444
336
220
37%
32%
21%
45%
36%
28%
48%
39%
29%
50%
40%
31%
PSA
<4
4-10
10-20
>20
101
631
188
80
16%
26%
43%
67%
22%
33%
50%
76%
23%
36%
54%
79%
25%
37%
54%
79%
Guichard et al, Eur Urol 2007, 52, 430-35
kidney
blood sample
blood
prostate cell shedding
urine
urine sample
PCa markers
• markers of genetic polymorphism
– CYP3A4*1B
• epigenetic changes
– glutathione S-transferase 1 (GSTP1) hypermethylation
• overexpressed genes
– PCa3DD3
– PSMA
• gene fusion
– ETS gene fusion
• markers of bone metabolism (type I collagen crosslinks/fragments)
–
–
–
–
deoxypyridinoline DPD
α-carboxyl terminal telopeptide α-CTX
bone morphogenetic protien 6 BMP6
osteoprotegerin
> 100 different potential markers
van Gils et al, Eur Urol 2005
PSA in urine
• PSA – serine protease (kK3)
• serum/urine ratio
– serum PSA range 4-10 ng/ml
– sensitivity 42-84%, specificity 80-89% 1,2
• PSA reported in urine after RPE 3 – periurethral
glands?
Irani et al, Urology 2005
Irani et al, J Urol 1997
Iwakiri et al, J Urol 1993
DD3
PCa3
• prostate-specific gene
• overexpressed in PCa (median 66x)
– identified by differential display analysis
• non-coding
– special RT-PCR needed
• high negative predictive value (90%) shown
in men with PSA > 3 ng/ml before biopsy
Hessels et al, Eur Urol 2003
PCa3DD3 in urine
Hessels et al, Eur Urol 2003
urine-based PCa3DD3 diagnosis
detection of PCa cells by RNA detection
Hessels et al, Eur Urol 2003
PCa3DD3 values and repeat biopsies
prospective, multicentre
n= 467 men with 1 or 2 previous biopsies
„attentive“ DRE + urine sample
Urine sample: quantitate PCa3DD3 and PSA mRNA
PCa3DD3 score: [PCa3 mRNA]/ [PSA RNA]
Haese et al, Eur Urol 2008
Relationship between PSA, PCA3 and prostate volume
30
10
9
25
8
7
20
Mean PCA3 value
Mean PSA value
6
5
4
3
2
1
0
15
10
5
0
<30
Haese et al. Eur Urol 2008
30-50
>50
Prostate volume
(ml)
<30
30-50
>50
Diagnostic value of PCa3DD3 at different cut-offs
cut-off
sensitivity
specificity
PCa3 score 20
73%
51%
35
47%
72%
50
35%
82%
25%
83%
23%
%fPSA
Haese et al, Eur Urol 2008
Diagnostic value of PCa3DD3 at different serum PSA levels
PCa3DD3 sensitivity specificity
mean
serum PSA n
<4
43
41.8
50%
65%
4 – 10
303 41.6
49%
74%
> 10
112 47.3
43%
69%
Haese et al, Eur Urol 2008
A new nomogram?
n=1206 men with 10-core biopsy from 2 multicentre prospective studies
•
•
•
•
•
•
age 30-85
PSA 0-50
DRE suspicious yes - no
prostate volume 20-220
previous biopsy yes - no
PCa3DD3 score < 17 yes - no
Chun et al, Eur Urol 2009
5% gain in predictive
accuracy of model by
addition of PCa3DD3 at
cutoff of 17
detection of tumour cells based on
DNA detection
GSTP 1
MSP for GSTP 1 hypermethylation
Woodson et al, J Urol 2008
GSTP1 hypermethylation
% positive
n/n
specificity
Goessl et al, 2000
36%
4/11
100%
Cairns et al, 2001
21.4%
6/28
n.d.
Goessl et al, 2001
73%
29/40
98%
Jeronimo et al, 2002
30.4%
21/69
95%
18.4%
13/69
93%
7/18
n.r.
Gonzalgo et al, 2003 38.9%
Henrique & Jeronimo, Eur Urol 2004
ETS gene fusion in PCa
• gene fusion discovered in PCa
• TMPRSS2:ERG
– 5‘untranslated region of the prostate-specific androgeninduced transmembrane protease serine 2 gene
– E26 (ETS) family of transcription factors
• in 42% of men with PCa 1
• sensitivity 37%, specificity 93% before biopsy 2
• sensitivity 32%, specificity 93% before biopsy3
Laxman et al, Cancer Res 2008
Hessels et al,Clin Cancer Res 2007
Groskopf et al, 2008
Tomlins et al, Eur Urol 2009
Rostock