Galli_Il Carcinoma della Vescica, del Rene e della Prostata

Galli_Il Carcinoma della Vescica, del Rene e della Prostata

Il Carcinoma della Vescica, del Rene e della Prostata
Luca Galli
U.O. Oncologia Medica 2 Universitaria
Azienda Ospedaliera-Universitaria Pisana
Istituto Toscano Tumori
Il Carcinoma della Vescica
……a che punto siamo
F. Guccini: La Locomotiva
Lo stato dell’arte
Nulla di nuovo sotto il sole!!!
Non largo uso.
Metanalisi
mostrano efficacia
Neoadiuvante
Studi non conclusivi;
Metanalisi mostrano
↓ rischio del 9%
Adiuvante
Non metastatica
STANDARD:
CDDP-Gem o M-VAC
(in fit pts).
1a Linea
Metastatica
STANDARD:
Vinflunina (?)
2a Linea
Il Carcinoma del Rene
Luca Galli
U.O. Oncologia Medica 2 Universitaria
Azienda Ospedaliera-Universitaria Pisana
Istituto Toscano Tumori
Controversie
Citonefrectomia
riduttiva?
Diagnosi RCC
Citonefrectomia riduttiva in mRCC
Citonefrectomia riduttiva in mRCC: OS
Citonefrectomia riduttiva in mRCC: incremento del beneficio
How can we oriented in “TKI Jungle”
of metastatic RCC?
”
Pazopanib
(Oct 2009)6
Sunitinib
(Jan 2006)2
Sorafenib
(Dec 2005)1
High dose IL-2
IFN-α
1992-2005
1.
2.
3.
4.
5.
6.
7.
2005
US FDA. Sorafenib, 2005.
US FDA. Sunitinib malate, 2006.
US FDA. Temsirolimus, 2007.
US FDA. Everolimus, 2009.
US FDA. Bevacizumab, 2009.
US FDA. Pazopanib, 2009.
US FDA. Axitinib, 2012.
Bevacizumab + IFN-α
(Jul 2009)5
Temsirolimus
(May 2007)3
2006
2007
Axitinib
(Jan 2012)7
Everolimus
(Mar 2009)4
2008
2009
2010
2011
2012
Patients’ selection by Heng or IMDC criteria
-Karnofsky perforfance status < 80%
-Haemoglobin < lower limit of normal
-Time from diagnosis to treatment of < 1 year
- Corrected calcium above the upper limit of normal
- Platelets greater than the upper limit of normal
- Neutrophils greater than the upper limit of normal
Number of risk
factors
Risk group
Median OS
(months)
2-years OS (%)
0
Favourable
43
75
1-2
Intermediate
27
53
3-6
Poor
8.8
7
ESMO 2014 guidelines for targeted treatment of clear-cell mRCC
Setting
Longer-term survival
First line
Treatment
group
Standard
Option
Favourable or
intermediate risk
Sunitinib [I,A]
Bevacizumab +
IFN-α [I,A]
Pazopanib [II,B →
I,A]
High-dose IL-2 [III,C]
Sorafenib [II,B]
Bevacizumab +
low-dose IFN-α [III,A]
Poor risk
Temsirolimus [I,B → Sunitinib [II,B]
Sorafenib [III,B]
II,A]
Second line Post-cytokines
Post-TKI
Third
line
Escudier et al. Ann Oncol 2014
Post-two
VEGF-TKIs
Axitinib [I,A]
Sorafenib [I,A]
Pazopanib [II,A]
Axitinib [I,B]
Everolimus [II,A]
Everolimus [II,A]
Post-VEGFR-TKI Sorafenib [I,B]
and mTOR
inhibitor
Sunitinib [III,A]
Sorafenib [II,A]
Other VEGFR-TKI [III,B
→ IV,B]
Rechallenge [IV,B]
And in future?
- Other target therapies
- Immunotherapy
METEOR trial: CABOZANTINIB vs EVEROLIMUS
CABOZANTINIB
(187 pts)
EVEROLIMUS
(188 pts)
OR
21%
5%
p<0.001
SD
62%
62%
ns
Check-mate 025: NIVOLUMAB vs EVEROLIMUS
Il Carcinoma della Prostata
Luca Galli
U.O. Oncologia Medica 2 Universitaria
Azienda Ospedaliera-Universitaria Pisana
Istituto Toscano Tumori
La Terapia ormonale “classica”
Agonisti LH-RH
Antagonisti LH-RH
antiandrogeni
Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum
phosphatases in metastatic carcinoma of the prostate. Arch Surg 1941. Huggins C, Hodges CV.
Ormonoterapia ADIUVANTE/CHIR
Immediate versus deferred androgen deprivation treatment in patients with nodepositive prostate cancer after radical prostatectomy and pelvic lymphadenectomy.
Messing EM et all. Lancet Oncol. 2006
ECOG 3886
98 pts
pN+
47
Goserelin/Orchiectomia
51
Osservazione (Goserelin/orchiectomia a PD)
OS
PFS
Malattia MTS: Quale Ormonoterapia di I linea ?
Vantaggio a favore del BAT con AA non steroideo
– Soprav. 5 anni: 27.6 vs 24.7 (p = 0.005)
(PCTCG: Lancet 355(9214):1491-98, 2000)
Ormonoterapia di II linea
Nonsteroidalantiandrogens
Adrenal androgen
inhibitors
Estrogens
AWS
Secondary HT
PSA decline > 50%
High-dose Bicalutamide
20-25%
Flutamide
22%
Nilutamide
29-50%
High-dose ketoconazole
27-63%
Low-dose ketoconazole
46%
Low-dose steroids
20-22%
DES
21-86%
Estrogeni coniugati naturali
32.1%
Antiandrogen Withdrawal
20%
Nuove vie d’inibizione…
Abiraterone Acetato
Abiraterone PRE-TXT: COU-AA 302
Patients
• Progressive chemonaïve mCRPC patients
(Planned N = 1088)
• Asymptomatic or
mildly symptomatic
R
A
N
D
O
M
I
Z
E
D
Efficacy end points
AA 1000 mg daily
Prednisone 5 mg BID
(Actual n = 546)
Placebo daily
Prednisone 5 mg BID
(Actual n = 542)
1:1
Co-Primary:
• rPFS by central review
• OS
Secondary:
• Time to opiate use (cancerrelated pain)
• Time to initiation of
chemotherapy
• Time to ECOG-PS
deterioration
• TTPP
Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted
at 151 sites in 12 countries; USA, Europe, Australia, Canada
Stratification by ECOG performance status 0 vs. 1
Abiraterone
PRE-TXT: OS definitiva
Final
OS Analysis
•
•
Median follow-up of 49.2 months
Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone
patients who received subsequent abiraterone (HR = 0.74)
Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)
RisultatiTossicità
tossicità
Abiraterone PRE-TXT:
Enzalutamide
Triple-acting, oral AR antagonist:
1.
Blocks testosterone binding to
the AR
2.
Impedes movement of the AR
to the nucleus of prostate
cancer cells (nuclear
translocation)
3.
Inhibits binding to DNA
Enzalutamide PRE-TXT: Prevail
Patient population:
• 1717 men with
progressive
mCRPC
• Asymptomatic/
mildly symptomatic
• Chemotherapynaïve
• Steroids allowed
but not required
R
A
N
D
O
M
I
Z
E
D
1:1
Enzalutamide
160 mg/day
(capsules)
n=872
Co-primary
endpoints:
• OS
• rPFS
Placebo
n=845
ADT=androgen-deprivation therapy; mCRPC=metastatic castration-resistant prostate cancer;
OS=overall survival; rPFS=radiographic progression-free survival.
Beer TM, et al. ASCO-GU 2014;
Beer TM et al. N Engl J Med. 2014 Jun 1
29
Enzalutamide PRE-TXT: OS
HR=0.706 (95% CI: 0.60–0.84); p<0.0001
100
Estimated median OS, months (95% CI):
Enzalutamide: 32.4 (30.1, NYR);
Placebo: 30.2 (28.0, NYR)
80
Survival (%)
Placebo
Enzalutamide
60
40
20
0
0
3
6
9
12
15
18
21
Months
Enzalutamide, n 872
863
850
824
797
745
566
Placebo, n 845
835
781
744
701
644
484
24
27
30
33
36
395
244
128
33
2
0
328
213
102
27
2
0
NYR = Not Yet Reached
Beer TM, et al. ASCO-GU 2014; Oral presentation.
Beer TM et al. N Engl J Med. 2014
30
EnzalutamideRisultati
PRE-TXT:tossicità
Tossicità
Beer TM, et al. ASCO-GU 2014; Oral presentation.
Beer TM et al. N Engl J Med. 2014
31
Enzalutamide vs Abiraterone
Dal 2004 CT I linea : docetaxel !!
I linea: TAX 327 update 2007
Berthold et al JCO 2008
+ 3 mesi in OS
Linee Guida AIOM 2008
Linee Guida EAU 2007
Chemioterapia di II linea
TROPIC: primary end point OS
MP
Median OS, Mos
HR
CBZP
12.7
15.1
0.72
95% Cl
0.61-0.84
P value
< 0.0001
28% reduction in risk of death
Lancet Vol 376 October 2, 2010
La seconda linea: Abiraterone
Efficacy
de Bono et al. NEJM 20II; Fizazi et al. Lancet 20I2
La seconda linea: Enzalutamide
18,4 mesi
(95%CI,17,3 NYR)
13,6 mesi
(95%CI, 11.3 to15.8)
Scher et al. NEJM 2012
… a possible Near Treatment
Scenario in EU (2015 ?)
mCRPC
mHDPC
HDPC - HSPC
DCT sensitive mCRPC
Sipuleucel-T
ADT
Enzalutamide
Wait & See ?
Abiraterone
Abiraterone
Docetaxel
± AWS
Asymptomatic:
- W&S or AA/Enz.
Bone Symptoms:
- DCT or Alphar.
Enzalutamide
Docetaxel
Visceral Mets:
DCT
Denosumab ?
Abiraterone
Cabazitaxel
Alpharadin
Enzalutamide
DCT
Rechallenge
Alpharadin
Zoledronic Acid ?
DCT Refractory
mCRPC
Mitox. + Pdn