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IL NODULO EPATICOdalla diagnosi….. alla terapia
Sala Conferenze, Biblioteca "Rosanna Benzi"Genova Voltri – 21 Settembre 2013
QUANDO LA TERAPIA MEDICADott. Gianfranco PercarioU.O.S.
di Gastroenterologia
OEI Presidio di Genova Voltri
Staging Strategy and Treatment for Patients With HCC
Liver transplant PEI/RF
Curative
treatments
TACE
HCC
Single
Increased Associated
diseases
Normal No Yes No Yes
Terminal
stage
PST 0‐2, Child‐Pugh A‐B
Multinodular, PST 0
Portal invasion,
N1, M1
Portal pressure/bilirubin
3 nodules ≤
3 cm
Intermediate stage
PST > 2, Child‐Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
≤
3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1‐2
PST 0, Child‐Pugh A
Resection
Symptomatic
Llovet
JM, et al. J Natl
Cancer Inst 2008;100: 698‐711
Bruix
J, et al. Hepatology
2005; 42:1208‐1236.
Sorafenib
Palliative
treatments
Sorafenib: duplice meccanismo d‘azione
Wilhelm S, et al. Mol Cancer Ther 2008;7:3129–40
Cellula Endoteliale o pericytaCellula Endoteliale o pericytaCellula TumoraleCellula Tumorale
PDGFVEGF
PDGFVEGF
GF
GFR
x
x
PDGF-BB
xxx
VEGF-C
MEK P
Raf-1 P
Mitocondrio
x
RASP
x
Proliferazione Sopravvivenza
ERK P
MEK P
Raf-1 P
RAS
PDGFR- P P P
VEGFR-2VEGFR-3
Nexavar®
X
Angiogenesi: Differenziazione Proliferazione Migrazione Formazione dei Tubuli
Apoptosi
Mitocondrio
Nucleus
VEGF-A
Apoptosi
HIF-2ERK P
HIF-1
Nucleus
Phase III SHARP Trial: SHARP trial designMulticenter, double blind, placebo-controlled trial
Primary endpoints
OS
TTSP
Secondary endpoints
TTP
DCR
Safety*
Sorafenib 400 mg b.i.d.
Placebo
Eligibility criteria
Advanced HCC
Child–Pugh A status
ECOG PS 0–2
No prior systemic therapy
Stratification
Region
ECOG PS (0 vs 1–2)
MVI/EHS (present/absent)
Ran
dom
izat
ion
(1:1
)(n
=602
)
ECOG PS = Eastern Cooperative Oncology Group Performance Status; MVI = macroscopic vascular invasion; EHS = extrahepatic spread; BID = twice daily; OS = overall survival; TTSP = time to symptomatic progression; TTP = time to progression; DCR = disease control rate *Assessed using version 3.0 of the USA National Cancer Institute Common Terminology Criteria for Adverse Events
Llovet JM, et al. N Engl J Med 2008;359:378-90
Summary of Trial Conduct
Sorafenib (n=299)Intent-to-treat
Placebo (n=303) Intent-to-treat
2° interim analysis OS Events: 321 deaths date: Oct 17°, 2006
DMC (Data Monitoring Committee) recommended stopping the trial in February 2007
602 patients randomised
Not randomised n=300Protocol exclusion criteria n=244
Consent withdrawn n=24
Adverse events n=15
Death n=4Lost to follow-up/missing n=6
902 HCC patients screened
2 did not receive treatment 1 did not receive treatment
Accrual: March 2005 to April 2006
Llovet JM, et al. N Engl J Med 2008;359:378-90
Overall Survival (OS)
100
50
25
17
75
0
Sur
viva
l pro
babi
lity
Months from randomizationCI, confidence interval
16151312109876543210 1411
Placebo (n=303) Sorafenib (n=299)
HR: 0.69 (95% CI: 0.55-0.88) p<0.001
Median OS (intention-to-treat) Sorafenib: 10.7 months – Placebo: 7.9 months
Llovet JM, et al. N Engl J Med 2008;359:378-90
Conclusions
Sorafenib prolonged OS versus placebo in advanced HCC– median OS 10.7 versus 7.9 months– HR: 0.69 (95% CI: 0.55-0.88) p<0.001
Sorafenib prolonged TTP versus placebo – median TTP 5.5 vs 2.8 months– HR: 0.58 (95% CI: 0.44-0.74) p<0.001
Sorafenib improve OS and TTP in all subgrup patients
Sorafenib was well tolerated with manageable side effects
Llovet JM, et al. N Engl J Med 2008;359:378-90
Asia-Pacific Study Phase III
Sorafenib 400 mg b.i.d.
Placebo
Eligibility criteria
Advanced HCC
Child–Pugh A status
ECOG PS 0–2
No prior systemic therapy
Stratification
Region
ECOG PS (0 vs 1–2)
MVI/EHS (present/absent)
Ran
dom
izat
ion
(2:1
)(n
=226
)
End points
Overall survival
Time to symptom progression
Time to progression
Response (RECIST)
Safety
n=150
n=76
Asia-Pacific Study was requested by Asian health authorities
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Patients at riskSorafenib 150 134 103 78 53 32 21 15 13 4 1 0Placebo 76 62 41 26 23 15 9 5 4 1 0 0
Overall Survival (OS)
1.00
0.50
0.25
22
0.75
0
Sur
viva
l pro
babi
lity
Months16121086420 14
Placebo Sorafenib
HR (S/P): 0.68 (95% CI: 0.50-0.93) p=0.014
2018
Sorafenib : 6.5 months (95% Cl: 5.6-7.6) –Placebo: 4.2 months (95% Cl: 3.7-5.5)
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Analysis of Sorafenib RCT in HCC
Summary of efficacy measures and toxicities
Variables Asia Pacific SHARPOverall survival
Median OS 6.5 mo vs 4.2 mo 10.7 mo vs 7.9 mo
Magnitude benefit (HR)p value
0.68 (95%CI, 0.50-0.93)0.014
0.69 (95% CI, 0.55-0.87)<0.001
Time to progression
Median TTP 2.8 mo vs 1.4 mo 5.5 mo vs 2.8 mo
Magnitude benefit (HR)p value
0.57 (95% CI, 0.42-0.79)<0.001
0.58 (95% CI, 0.45-0.74)<0.001
Objective response rate <3% <3%
Drug-related AEs
Overall Hand-foot Sd. (Any: grade 3-4)
81.9 % 45% (11%)
80%21% (8%)
Llovet JM, et al. N Engl J Med 2008;359:378-90. Cheng AL et al. Lancet Oncol 2009; 10: 25–34
Studio SHARP: eventi avversi
Llovet JM et al. NEJM 2008; 24;359(4):378-90
Evento avverso
Sorafenib (n=297) Placebo (n=302) pQualsiasi
grado Grado 3 Grado 4qualsiasi
grado Grado 3 Grado 4Qualsiasi
grado Grado 3 o 4
Incidenza globale 80 52Sintomi costituzionali
Fatigue 22 3 1 16 3 <1 0.07 1.00Calo ponderale 9 2 0 1 0 0 <0.001 0.03
Disturbi dermatologiciAlopecia 14 0 0 2 0 0 <0.001 NASecchezza cutanea 8 0 0 4 0 0 0.04 NAReazione cutanea mano-piede 21 8 0 3 <1 0 <0.001 <0.001Prurito 8 0 0 7 <1 0 0.65 1.0Rash o desquamazione 16 1 0 11 0 0 0.12 0.12Altro 5 1 0 1 0 0 <0.001 0.12
Disturbi gastrointestinaliAnoressia 14 <1 0 3 1 0 <0.001 1.00Diarrea 39 8 0 11 2 0 <0.001 <0.001Nausea 11 <1 0 8 1 0 0.16 0.62Vomito 5 1 0 3 1 0 0.14 0.68
Alterazioni della voce 6 0 0 1 0 0 <0.001 NAIpertensione 5 2 0 2 1 0 0.05 0.28Disfunzione epatica <1 <1 0 0 0 0 0.50 0.50Dolore addominale non altrimenti specificato 8 2 0 3 1 0 0.007 0.17
Sanguinamento 7 1 0 4 1 <1 0.07 1.00
Sorafenib in the treatment of HCC: conclusions
• Sorafenib is a multikinase inhibitor that target both tumor cell proliferation and tumor angiogenesis
• Sorafenib is the first systemic therapy to prolong survival in HCC patients
• Sorafenib has been shown to prolong survival and delay progression across a broad range of patient groups
• Sorafenib is generically weel tolerated with a predictable side-effect profile
• Sorafenib is the new reference standard for systemic therapy of HCC patients