DrBracarda, Drssa Ori Ishiwa

15° anno di fondazione del GUONE
MULTIDISCIPLINARITA’
IN URO-ONCOLOGIA
Aviano, 10 settembre 2010
INTEGRAZIONE TERAPIA SISTEMICA-TRATTAMENTO
LOCALE
PROSTATA
Dr.ssa Ori Ishiwa
Dr Sergio Bracarda
UOC Oncologia Medica Arezzo
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Patients affected by locally advanced prostate cancer present
an high risk of relapse or death after exclusive local treatment,
especially if:
D’Amico JCO 2002
- Clinical stage T3
- PSA > 20 ng/ml
- Gleason Score 8-10
Standard Txt: - RRP
- RT+ adj ADT
EORTC 22863 T3-T4 o N1: RT ±3 yr OT (goserelin):
(Bollà, Lancet 2002)
> OS
RTOG 85-31 T3-T4 o N+: RT ± OT fino a PD:
(Pilepich, Int J Radiat Oncol Biol Phys 2005)
> OS
But … recent increasing evidence for harmful effects
of long-term ADT
!
"
?
Which is the optimal duration for
ADT combined with RT ?
EORTC 22961, Bolla, ASCO 2007
# $%#$&
%#&
# $& #$' (#&
)* +%,( .
&
(
!
&!
Non-inferiority Trial
"#$%
0#
2#
/$
*
1"
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1
34 #5
RESULTS:
significant
differences in OS
between treatment
arms
OS !!
p = 0.0191
Long Term ADT >>> Short Term ADT
And in PFS
any clinical
progression in
20.1 vs 8.2%
La Chemioterapia, come la Terapia
Ormonale, è una terapia sistemica.
Potrebbe avere un ruolo nella gestione
della malattia Loc-Avanzata ?
No, nessuno ….
.. tuttavia …..
…. Non ora,
per lo meno….
From 2004 DCT standard CT approach in CRPC
Overall. More than
1.600 met CRPC pts
treated !!
Treatment of Choice
for CRPC since 2004:
Docetaxel (>OS)
TAX-327
OS = +2.5m
Docetaxel 3-Weekly,
significantly improves:
- OS (18.9 vs 16.5 m)
p =.009)
(24% ↓ in the risk of death, HR=0.76, 95% CI 0.62-0.94)
45 vs. 32%,
p = .0005
- PSA response:
- Objective response:
12 vs 7%,
p = 0.11
- Pain response:
35 vs. 22%,
p = .01
- Quality of Life (FACT-P): 22 vs 13%,
p = .009
- Safe but with ↑ toxicity (Grade 3/4 neutropenia: 32 vs 21.%)
SWOG 99-16
OS = +2m
Docetaxel 3-W plus
Estramustine Ph.
significantly improves:
p = 0.02
- OS (17.5 vs 15.6 m)
(20% ↓ in the risk of death. HR = 0.80 (95% CI, 0.67-0.97)
- PSA response:
50 vs 27%,
- Objective response: 17 vs 11%,
- PFS:
+27% (95% CI, 14 to 37%;
p<0.0001
p=0.15
p<0.0001
- But also toxicity, even if without differences in toxic death rates
2007 Updated OS Analysis of TAX-327 Study
Initial report with 557 of 1006 pts died.
Survival updated to Jan 2007 (by contacting
investigators at each site by mail, email or phone).
310 additional deaths recorded resulting in a total of
867 deaths
Comparison of initial and updated OS data
Median OS
2003 Data
p-value
Update 2007
p-value
- DCT Q3w
18.9 (17.0-21.2)
0.009
19.2 (17.5-21.3)
0.004
- DCT wk
17.4 (15.7-19.0)
17.8 (16.2-19.2)
- Mitox.
16.5 (14.4-18.6)
16.3 (14.3-17.9)
1.0
* 95% confidence interval indicated
Docetaxel
Docetaxel
Mitoxantrone
Q3W (n=335) Weekly (n=334)
(n=337)
3-yr survival rate
17.9%
16.7%
13.7%
0.6
0.4
0.2
Survival > 3 years
0.0
Propotion Alive
0.8
Docetaxel 3-Weekly
Docetaxel Weekly
Mitoxantrone
0
1
2
3
4
Years
5
6
7
Questi dati sono applicabili
solo all’ CRPC ?
a "Proof of Principle“:
evidence of docetaxel activity also in HDPC.
"Effect of Docetaxel in Pts With Hormone-Dependent PSA
Progression After Local Therapy for Prostate Cancer"
Goodin, et Al. JCO 2005
25 pts with PSA relapse after RP (14), RT (6), RP+RT (5)
- Median baseline PSA 31.5 (2.2 – 160.6)
- Median Gleason Score 7 (6-9)
PSA response in 10/23 ev. pts (43%) PSA nadir ≥ 5m
- Testosterone level: not affected
(Docetaxel plus Pdn active in HDPC and not influencing the
hormonal status) (not affecting eventual HT) .........
Local therapy
Hormonal therapy
Chemotherapy
Local therapy
ADJUVANT CHEMOTHERAPY
Hormonal therapy
Chemotherapy
“Adjuvant” Chemotherapy Trials
• Only 1 modern randomized trial
• Of 93 patients enrolled, only 38 had T3/T4
disease
• No radiotherapy administered!
• Randomized to leuprolide vs leuprolide +
mitoxantrone x 4 cycles (not an actual
standard)
Wang BJU Int 2000
'" ( )
*
+#
,
P=0.044
Wang BJU Int 2000
SWOG 9921: HT vs HT+CT after RP
Adjuvant CT trials
ongoing or closed
(n = 1360)
High Risk
after RP
R
A
N
D
O
M
I
Z
E
Hormonal therapy x 2 yr
Hormonal therapy x 2 yrs
Mitoxantrone + Prednisone x 6 cycles
TAX- 3501 (2.172 pts)
Primary Endpoint: OS
RP
R
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Observation r
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ADT
ADT+Taxotere
ADT – LH-RH x 18 mos
Taxotere- 75mg/m2 q.3wks x 6 cycles
ADT
ADT
+
Taxotere
2nd
Pr
og
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ss
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P
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NEOADJUVANT CHEMOTHERAPY
Local therapy
ADJUVANT CHEMOTHERAPY
Hormonal therapy
Chemotherapy
Why Neoadjuvant Therapy?
•
•
•
•
Well characterized high risk groups
Ability to assess in vivo chemosensitivity
Early treatment of micrometastases
Ability to assess molecular determinants of response
in pathologic specimens
• Rapid ability to assess effect of new agents
compared with adjuvant trials
Neoadjuvant Docetaxel Prior To Radical
Prostatectomy
• Phase II trial
• Up to 6 months of weekly docetaxel prior to RP in
high risk localized prostate cancer
• Monthly PSA, DRE assessments
• Endorectal coil MRI at 0, 2, and 6 months
• Primary endpoint: Pathologic CR
Febbo Clin Cancer Res 2005
Clinical Response
•
•
PSA decline
– > 50% in 11/19 (58%)
Measurable tumor response by erMRI
– > 25% in 13/19 (68%)
Toxicity
•
•
•
•
•
Overall well tolerated
Most common side effect: grade
1-2 fatigue
No neutropenia or
thrombocytopenia
No serious N/V, neuropathy,
diarrhea, infection
Unusual side effects: nail
changes, excess tearing
Pathology Results (N=16)
Pathologic
Stage
pT0
pT2
pT3a
pT3b
pT4
N (+)
# Patients
(%)
0
6 (38%)
2 (13%)
7 (44%)
1 (6%)
0
Neoadjuvant CT
trials ongoing
CALGB 90203: Neoadjuvant CT In High Risk
Prostate Cancer (n = 610)
High Risk
40% DFS
(n = 610)
R
A
N
D
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Z
E
RP
Docetaxel x 6 cycles
Primary Endpoint: 5 yr DFS
RP
CONCLUSIONI
• La chemioterapia sistemica precoce potrebbe
essere un approccio potenzialmente vantaggioso
(ritardato sviluppo di cloni CRPC).
• Tale approccio, tuttavia, va ancor oggi impiegato
solo nell’ambito di protocolli di ricerca clinica.
La RT+HT (trattamento integrato) rimane ancor oggi
lo standard terapeutico ottimale del Ca. Prostatico
Loc. Avanzato

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