jordi bruix head, bclc group, liver unit hospital clínic, university of barcelona new drugs for...
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Jordi Bruix
Head, BCLC Group, Liver Unit
Hospital Clínic, University of Barcelona
New drugs for Hepatocellular Carcinoma
Very early stage (0) Single< 2cm.
Portal pressure/ bilirubin
PST >2, Child-Pugh C
Terminal stage (D)
PST 0-2, Child-Pugh A-B
Stage A - C Stage D
Normal
Single 3 nodules <3cm
Associated diseasesIncreased
No Yes
Early stage ( A)Single or 3 nodules < 3cm, PS
0
Intermediate stage ( B)Multinodular, PS 0
Advanced stage (C)Portal invasion, N1,M1, PS 1-2
Portal invasion, N1,M1
No Yes
Stage 0 PST 0, Child-Pugh A
BCLC Staging and Treatment Strategy HCC
Liver Transplantation
(CLT / LDLT)
ChemoembolizationResection PEI/RF
Sympt. Treat. (20%)
Curative Treatments (30%) 50% - 75% at 5 years
Non-curative treatments (50%) 3 year survival 10-40%
Sem Liv Dis 1999 to JNCI 2008
?
Treatment of advanced HCC Phase II/III studies with systemic treatments
Treatments Studies N Objective response
Systemic chemotherapyDoxorubicin as single agent Phase II/III >1000 10-18%Doxorubicin combination (PIAF) Phase II/III 144 26%Cisplatin Phase II 48 10%Epirubicin Phase II 62 11%Mitoxantrone Phase II 118 16%
5-FU,Paclitaxel, iridotecan, gemcitabine Phase II/III .... <10%
Anti-androgen Phase III 376 <10%Interferon Phase III 60 <10%Tamoxifen Phase III >1000 < 5%Octreotide Phase III 60 <5%Seocalcitol Phase III 746 <5%
The hepatocarcinogenic process Signalling pathways: molecular targets for new therapies.
Hanahan. Cell 2000.
Wnt pathway
EGFR pathway
Raf/MAPK pathway
Akt pathway
Jat/Stat pathway
Molecular targeted therapies in HCC
Akt
PI3K
CELL SURVIVALCELL CYCLE
RapamycinmTOR
Translation(5´ TOP)
TRANSLATION(Cap-Dependent)
4E-BP1p70S6
TSC
EGFR VEGFRPDGFR p85
p110
PIP2
PIP3
PTEN
SorafenibIGFR-I
IGFBP3
RAS
RAF
MEK
ERK
PROLIFERATION
Erlotinib
Sorafenib
Bevacizumab
Growth factors receptor pathway
Targets and agents
EGFR: TKI: Erlotinib, Lapatinib
Gefitinib
Ab: Cetuximab
VEGF TKI: Sorafenib
Ab: Bevacizumab
RAF TKI: Sorafenib
mTOR Rapamycin
Proteasome inhibitors Bortezomib
GROWTH FACTORS (EGF, VEGF,
PDGF…)
IGF-1 / IGF-2
Cetuximab
Targeted agents in development for HCC: overview
Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm Insight, MedTrack
*Sorafenib and sunitinib also have antiproliferative effects through multi-tyrosine kinase inhibition*Sorafenib and sunitinib also have antiproliferative effects through multi-tyrosine kinase inhibition
AgentAnti-angiogenic targets Antiproliferative targets Developmental
statusVEGF VEGFR PDGFR EGFR Raf mTOR
Bevacizumab ● Phase II ongoing
Brivanib ● Phase II recruiting
Cediranib ● Phase II recruiting
Erlotinib ● Phase II complete
Gefitinib ● Phase II complete
Cetuximab ●
Lapatinib ● Phase II ongoing
RAD001 ● Phase I/II recruiting
Sorafenib* ● ● ● Phase III complete
Sunitinib* ● ● Phase II ongoing
Thalidomide ● Phase III recruiting
TSU-68 ● ● Phase I/II recruiting
Phase II complete
Erlotinib: Phase II studies in HCC
Molecular targeted therapies for EGFR pathway
Philip et al. J Clin Oncol 2005
Erlotinib (n=38)
• Characteristics of patients:
Child A/B: 27/11
PST 0/1-2: 10/28
EGFR-1+ in 88%• Treatment : 150 mg/d• Outcomes:
Response rate:
3 PR, 50% SD (3.8 mo)
Toxicity (G3-4): 8 pts.
Median TTP: 3.2 mo
Median survival: 13 mo
Thomas MB, et al. ASCO 2007, JCO 2009
• Patients (n=29) received bevacizumab 10mg/kg every 14 days plus erlotinib 150mg orally daily
• RR (RECIST) in 27
- CR: one patient (4%)
– PR: five patients (19%)
– SD at ≥16 weeks: nine patients (33%)
– SD at 8 weeks: five patients (19%)
• Grade 3–4 toxicities transaminase elevation (1), hyperkalaemia (1), acne (1), diarrhoea (2), proteinuria (2), gastrointestinal bleeding (3), fatigue (4), and hypertension (5).
• Median Survival 19.5 months. (2009 MS 15months)
Erlotinib plus bevacizumab in patients with unresectable advanced HCC
Thomas MB, et al. ASCO 2007, JCO 2009
• Patients (n=29) received bevacizumab 10mg/kg every 14 days plus erlotinib 150mg orally daily
• RR (RECIST) in 27
- CR: one patient (4%)
– PR: five patients (19%)
– SD at ≥16 weeks: nine patients (33%)
– SD at 8 weeks: five patients (19%)
• Grade 3–4 toxicities transaminase elevation (1), hyperkalaemia (1), acne (1), diarrhoea (2), proteinuria (2), gastrointestinal bleeding (3), fatigue (4), and hypertension (5).
• Median Survival 19.5 months. (2009 MS 15months)
Erlotinib plus bevacizumab in patients with unresectable advanced HCC
ASCO 2005, JCO 2008
Bevacizumab (5-10 mg/Kg /2 weeks) in HCC: Phase II (n=46)
Molecular targeted therapies for VEGF
Characteristics of patientsAge 21-81Gender (M/F) 38/8Child-Pugh (A/B) 34/12CLIP (0-4) 2/19/15/8/1ECOG (0/1/2) 19/23/2Tumor stage ?
Adverse events (grade 3-4)Transient ischemic accident : 1Arterial hypertension: 7Hepatic arterial thrombosis: 1Hemoperitoneum 1Gastrointestinal bleeding: 5 (1 death)
Clinical OutcomesResponse rate 1CR, 5 PRMedian PFS: 6.9 monthsMedian survival: 12.4 months
Baseline
16 weeks after
ASCO 2005, JCO 2008
Bevacizumab (5-10 mg/Kg /2 weeks) in HCC: Phase II (n=46)
Molecular targeted therapies for VEGF
Characteristics of patientsAge 21-81Gender (M/F) 38/8Child-Pugh (A/B) 34/12CLIP (0-4) 2/19/15/8/1ECOG (0/1/2) 19/23/2Tumor stage ?
Adverse events (grade 3-4)Transient ischemic accident : 1Arterial hypertension: 7Hepatic arterial thrombosis: 1Hemoperitoneum 1Gastrointestinal bleeding: 5 (1 death)
Clinical OutcomesResponse rate 1CR, 5 PRMedian PFS: 6.9 monthsMedian survival: 12.4 months
Baseline
16 weeks after
Faivre SJ, et al. ASCO 2007, Chicago, IL, USA
Sunitinib in patients with unresectable HCC
• Patients (n=37) received sunitinib 50mg daily for 4 weeks of every 6-week treatment cycle.
• Major (≥50%) tumour necrosis was noted in 46% of patients
• Response (RECIST)– partial response (PR): one patient (3%) – stable disease (SD) >3 months: 13 patients (35%)– SD >6 months: eight patients (22%)
• Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and haemorrhage (14%)
– four patients experienced grade 5 toxicity (bleeding, drowsiness, hepatic encephalopathy and renal failure)
RECIST = Response Evaluation Criteria In Solid Tumors; CNS = central nervous system
Treatment of advanced HCC Phase II: sorafenib as a primary treatment of HCC (n=137)
Characteristics of the study– Sorafenib 400mg bid in 28-day cycles in 137 patients with advanced HCC.
– Characteristics: 48% HCV+, TNM Stage III/IV (31%/66%), Child A:72%
– Response WHO: PR: 3 (2.2%), MR: 8 (5.8%), stable disease >4m 33.6%
0 100 200 300 400 500 600 700 8000
0.25
0.50
0.75
1.00
Surv
ival
Dis
trib
utio
n Fu
nctio
n
Time (days from start of study treatment)
0 100 200 300 400 500 600 700 8000
0.25
0.50
0.75
1.00
Surv
ival
Dis
trib
utio
n Fu
nctio
n
Time (days from start of study treatment)
Overall survival: 9.2 moTime-to-progression (TTP): 5.5 mo
Abou-Alfa G et al, JCO 2006
0 100 200 300 400 5000
0.25
0.50
0.75
1.00
Sur
viva
l Dis
trib
utio
n Fu
nctio
n
Time (days from start of study treatment)
0 100 200 300 400 5000
0.25
0.50
0.75
1.00
Sur
viva
l Dis
trib
utio
n Fu
nctio
n
Time (days from start of study treatment)
Sorafenib (n=299)
400mg po bid
continuous dosing
PIs: JM Llovet and J Bruix, S Ricci, V Mazzaferro, P Hilgard, J-L Raoul, S Zeuzem, A Santoro, MS Shan, M Moscovici, Dimitris Voliotis, A Forner, M Schwartz for the SHARP Investigators Study Group
Sorafenib improves survival in hepatocellular carcinoma:Phase III randomized, placebo-controlled trial (SHARP)
Stratification:
* Macroscopic vascular invasion (portal vein) and/or extrahepatic spread
* ECOG PS
* Geographical region
Ran
do
mis
atio
n
N=
602
Placebo (n=303)
2 tablets po bid
continuous dosing
Llovet et al, NEJM 2008
Child-Pugh A : to avoid liver deaths of Child-Pugh B patients obscuring outcome to capture the impact on HCC progression (competing risk)
SorafenibMedian: 10.7 mo (95% CI: 9.4, 13.3)
Su
rviv
al p
rob
abili
ty
Weeks
Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.87). P<0.001*
PlaceboMedian: 7.9 mo(95% CI: 6.8, 9.1)
1.00
0
0.75
0.50
0.25
0 808 16 24 32 40 48 56 64 72
*O’Brien-Fleming threshold for statistical significance was P=0.0077.
0274 241 205 161 108 67 38 12 0Patients at risk
Sorafenib:0276 224 179 126 78 47 25 7 2Placebo:
299303
Overall survival (intention-to-treat)
Llovet et al, NEJM 2008
Phase III SHARP trial
0196 126 80 50 28 14 8 20192 101 57 31 12 8 2 1
Pro
bab
ility
of
pro
gre
ssio
n
546 12 18 24 30 36 42 480 Weeks
SorafenibMedian: 5.5 mo(95% CI: 4.1, 6.9)
PlaceboMedian: 2.8 mo(95% CI:2.7, 3.9)
1.00
0
0.75
0.50
0.25
Patients at risk Sorafenib:
Placebo:299303
Phase III SHARP trialTime to progression (independent central review)
Llovet et al, NEJM 2008
Hazard ratio (S/P): 0.58 (95% CI: 0.45, 0.74) P<0.001
Phase III SHARP trialExploratory subgroup survival analysis
Sorafenib benefit
Placebo benefit
Hazard Ratio (95%CI)
ECOG PS 0
ECOG PS 1 & 2
0.5 1.0 1.50.0
Macroscopic vascular invasion
No macroscopic vascular invasion
No macroscopic VI/extrahepatic spread
Macroscopic VI and/or extrahepatic spread
No extrahepatic spread
Extrahepatic spread
Llovet et al, NEJM 2008
Usual comments about SHARP
• SHARP is just informative for HCV European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B
Asian-Pacific sorafenib study
Cheng, et al. ASCO 2008
End points:– Overall survival, time to symptomatic progression (FSHI8-TSP),
time to progression, response (RECIST), and safety– No primary end point defined
Sorafenib400 mg bid
Placebon=76
Eligibility • Advanced HCC• ECOG 0-2• Child-Pugh A• No prior systemic therapy
Stratification • Macroscopic vascular invasion (portal vein) and/or extrahepatic spread
• ECOG PS• Geographic area
RANDOMIZE
n=150
2:1
Overall survivalS
urvi
val p
roba
bilit
y
SorafenibMedian: 6.5 months
(95% CI: 5.6, 7.6)PlaceboMedian: 4.2 months (95% CI: 3.7, 5.5)
HR (S/P): 0.68 95% CI: 0.50, 0.93P=0.014
0.25
0.50
0.75
1.00
00
Months2 4 8 10 12 14 16 20 22
150 134 103 78 53 32 21 15 13 4 1 076 62 41 26 23 15 9 5 4 1 0 0
SorafenibPatients at Risk
Placebo
6 18
Asian-Pacific sorafenib study
Cheng, et al. ASCO 2008
Time to progression
HR (S/P): 0.57 95% CI: 0.42, 0.79P<0.001
SorafenibMedian: 2.8 months(95% CI: 2.6, 3.6)
PlaceboMedian: 1.4 months (95% CI: 1.3, 1.5)
SorafenibPatients at risk
Placebo
0.25
0.50
0.75
1.00
0
Months150 80 38 19 11 8 5 2 1 0 0 076 19 10 8 3 0 0 0 0 0 0 0
Pro
gre
ssio
n-fr
ee
pro
bab
ility
0 2 4 8 10 12 14 16 20 226 18
Adapted from Cheng, et al. ASCO 2008
Asian-Pacific sorafenib study
Very early stage (0) Single< 2cm.
Portal pressure/ bilirubin
PST >2, Child-Pugh C
Terminal stage (D)
PST 0-2, Child-Pugh A-B
Stage A - C Stage D
Normal
Single 3 nodules <3cm
Associated diseasesIncreased
No Yes
Early stage ( A)Single or 3 nodules < 3cm, PS
0
Intermediate stage ( B)Multinodular, PS 0
Advanced stage (C)Portal invasion, N1,M1, PS 1-2
Portal invasion, N1,M1
No Yes
Stage 0 PST 0, Child-Pugh A
BCLC Staging and Treatment Strategy HCC
Liver Transplantation
(CLT / LDLT)
ChemoembolizationResection PEI/RF Sorafenib
Sharp
Asia
10.7 months
6.5 months
Usual comments about SHARP
• SHARP is just informative for HCV European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B
Predictors of Survival
• High c-KIT levels and low HGF and VEGF levels correlated with longer OS in the univariate analysis.
c-Kit VEGF
High HGFMedian OS =6.0 months (n=122)
Low HGFMedian OS =10.8 months (n=366)
Time (Months)
HR = 0.775 (95% CI: 0.620,0.970)P=0.026
High c-KitMedian OS = 10.4 months (n=244)
Low c-KitMedian OS =8.8 months (n=245)
HGF
Time (Months)
HR = 1.780 (95% CI: 1.390,2.280)P<0.001
Time (Months)
HR = 1.530 (95% CI: 1.191,1.965)P<0.001
High VEGFMedian OS =6.2 months (n=122)
Low VEGFMedian OS =10.6 months (n=368)
0
0.25
0.50
0.75
1.00
Su
rviv
al P
rob
abili
ty
0 2 4 6 8 10 12 14 16 18 20 22
0
0.25
0.50
0.75
1.00
Su
rviv
al P
rob
abili
ty
0 2 4 6 8 10 12 14 16 18 20 22
0
0.25
0.50
0.75
1.00
Su
rviv
al P
rob
abili
ty
0 2 4 6 8 10 12 14 16 18 20 22
All patients (univariate analysis)
Llovet et al AASLD 2008
Baseline plasma c-KIT and Sorafenib
• Patients with high c-KIT showed a trend of better survival benefit from sorafenib (interaction P-value=0.081).
Patients with Low* Baseline c-KIT
Su
rviv
al P
rob
abil
ity
HR = 0.90 (95% CI: 0.66, 1.22)
(n=245)
Su
rviv
al P
rob
abil
ity
SorafenibMedian OS = 9.4 months
PlaceboMedian OS = 7.4 months
0
0.25
0.50
0.75
1.00
0 2 4 6 8 10 12 14 16 18 20 22
Patients with High* Baseline c-KIT
HR = 0.58(95% CI: 0.41, 0.81)
(n=244)
SorafenibMedian OS = 14.1 months
PlaceboMedian OS = 8.7 months
0
0.25
0.50
0.75
1.00
mo 0 2 4 6 8 10 12 14 16 18 20 22
Prediction of survival
Llovet et al AASLD 2008
• Patients with high c-KIT showed a better time to progression with sorafenib (interaction P-value=0.05).
Baseline plasma c-KIT and SorafenibPrediction of time to progression
Patients with High* Baseline c-KIT
Pro
gre
ssio
n
Pro
bab
ilit
y
Time (Months)
1.00
0.75
0.50
0.25
0.00
0 2 4 6 8 1012
SorafenibMedian TTP = 6.7 mo
PlaceboMedian TTP = 2.8 mo
HR = 0.45(95% CI: 0.30, 0.66)
(n=244)
Pro
gre
ssio
n
Pro
bab
ilit
y
Patients with Low* Baseline c-KIT
1.00
0.75
0.50
0.25
0.00
0 2 4 6 8 1012
HR = 0.80 (95% CI: 0.55, 1.17)
(n=245)
SorafenibMedian TTP = 4.1 mo
PlaceboMedian TTP = 3.9 mo
Time (Months)
Llovet et al AASLD 2008
Patients with Low Baseline HGF
Patients with High Baseline HGF1.00
0.75
0.50
0.25
0
Time (Months)
Su
rviv
al P
rob
abil
ity
HR = 1.10(95% CI: 0.72, 1.67)(n=122)
1.00
0.75
0.50
0.25
0
Time (Months)
Su
rviv
al P
rob
abil
ity
HR = 0.69(95% CI: 0.53, 0.90)(n=366)
SorafenibMedian OS = 6.3 months
PlaceboMedian OS = 5.3 months
SorafenibMedian OS = 12.4 months
PlaceboMedian OS = 9.8 months
0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 12 14 16 18 20 22
Baseline plasma HGF and Sorafenib Effect
• Patients with low HGF showed a trend of better survival benefit from sorafenib (interaction P-value=0.073), but not with TTP (p=0.3)
Llovet et al AASLD 2008
Usual comments about SHARP
• SHARP is just informative for HCV + European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B
Hepatocellular carcinoma (advanced) Survival (3 m)Sorafenib (n=299) vs placebo (n=303)1 0.69 (0.55–0.87)
Colorectal (metastatic) Survival (4.7 m)IFL+ bevacizumab (n=402) vs IFL (n=411) 2 0.66 (NA)
Cetuximab (n=287) vs BSCare (n=285) 3 Survival (1.5 m) 0.77 (0.64–0.92)
Lung cancerPaclitax. + carbo + vs – bevacizumab (n=434 vs n=444) 4 Survival (2 m)
0.79 (0.69–0.93)
Erlotinib (n=488) vs placebo (n=243) 5 Survival (2 m)0.79 (0.58–0.85)
Breast cancer (Advanced (HER2+)Chemotherapy + vs – trastuzumab (n=235 vs n=234) 6 TTP
0.51 (0.39–0.59)
Paclitaxel + vs – bevacizumab (n=347 vs n=326) 7 PFS0.60 (0.51–0.70)
Impact of molecular agents in cancer outcomesEndpoint, absolute gain
HR (95% CI)
Llovet and Bruix, Hepatology 2008
1. Llovet et al NEJM 2008, 2. Hurwitz et al NEJM 2004, 3. Jonkers et al NEJM 2007, 4. Sandler et al NEJM 2006,
5. Shepherd et al NEJM 2005, 6. Slamon et al NEJM 200 7. Miller et al. NEJM 2007
Usual comments about SHARP
• SHARP is just informative for HCV European HCC
• There is no attempt for biomarker assessment
• 3 months survival improvement is marginal
• Unknown efficacy in Child-Pugh B
Sorafenib in HCC. Phase I PK:
Non-HCC vs HCC, Non-Japanese vs Japanese; and CPA vs CPB
0
2
4
6
8
10
12
14
16
18
20
Ctr
ou
gh
,ss
(mg
/L)
Advanced Solid Tumor Patients
HCC Patients(CPA)
HCC Patients(CPB)
Non-Japanese with advanced solid tumorsJapanese with advanced solid tumorsNon-Japanese with HCC (CPA)Japanese with HCC (CPA)Non-Japanese with HCC (CPB)Japanese with HCC (CPB)
ss = steady state
• PK equivalent irrespective of ethnicity or Child-Pugh status
Data on file. Bayer HealthCare
Sorafenib for HCC and Child-Pugh B patients
• Child-Pugh B includes a wide range of profile and outcome
• Impact on tumor biology is not modulated by liver function
• PK, Safety and AEs in Child-Pugh B are the same
• Child-Pugh B 7 can be safely treated.
• RCT vs placebo unlikely
Very early stage (0) Single< 2cm.
Portal pressure/ bilirubin
PST >2, Child-Pugh C
Terminal stage (D)
PST 0-2, Child-Pugh A-B
Stage A - C Stage D
Normal
Single 3 nodules <3cm
Associated diseasesIncreased
No Yes
Early stage ( A)Single or 3 nodules < 3cm, PS
0
Intermediate stage ( B)Multinodular, PS 0
Advanced stage (C)Portal invasion, N1,M1, PS 1-2
Portal invasion, N1,M1
No Yes
Stage 0 PST 0, Child-Pugh A
BCLC Staging and Treatment Strategy HCC
Liver Transplantation
(CLT / LDLT)
ChemoembolizationResection PEI/RF
Sympt. Treat. (20%)
Curative Treatments (30%) 50% - 75% at 5 years
Non-curative treatments (50%) 3 year survival 10-40%
Sem Liv Dis 1999 to JNCI 2008
Sorafenib
Future prospects for Sorafenib
Impact of sorafenib results
• Effective first-line option for advanced HCC available
should be standard first line therapy
• Proves the hope of molecular targeted therapy in HCC
new agents to be investigated in second line/failures
• Opens the path to multipathway blockade
• Evaluation in the adjuvant setting (surgery, ablation, TACE)
Critical issues in combination therapy
• Selection of best partner for sorafenib
• Optimal dosage for efficacy and safety
Underlying cirrhosis: variceal bleeding, renal failure, ascites, encephaloptahy,HBV/HCV flares
• How to define efficacy: RR by RECIST (No meaning), TTP?
• Transition from phase 1 into phase 2. RCT phase 2.
• Target population
Llovet et al, JNCI 2008
Impact of sorafenib results
• Effective first-line option for advanced HCC available
• Proves the hope of molecular targeted therapy in HCC
• Opens the path to multipathway blockade
• Evaluation in the adjuvant setting (surgery, ablation, TACE)
8 weeksrandomise
Stratify:- prior curative tx- geographical region- CP status
Sorafenib 400mg bid
Placebo
RFS
TTR
OSBiomarkers
1:1
Design: double-blind RCT
Resection RFA PEI
• Significant OS benefit in phase III gives rationale to go into adjuvant setting
• Prospective, randomized, double-blind, placebo-controlled, company sponsored phase III study
• Primary endpoint: recurrence-free survival
• Patients: n=1100 (randomised)
• Global trial, significant number of patients from China
• FPFV: August 2008Clinicaltrials.gov
TACE for HCC
Sorafenib as coadjuvant
Trial in the pipeline – SPACE (2009): Target population: Child-Pugh ATechnique: DCBeads End-point: TTP, Survival
Very early stage (0) Single< 2cm.
Portal pressure/ bilirubin
PST >2, Child-Pugh C
Terminal stage (D)
PST 0-2, Child-Pugh A-B
Stage A - C Stage D
Normal
Single 3 nodules <3cm
Associated diseasesIncreased
No Yes
Early stage ( A)Single or 3 nodules < 3cm, PS
0
Intermediate stage ( B)Multinodular, PS 0
Advanced stage (C)Portal invasion, N1,M1, PS 1-2
Portal invasion, N1,M1
No Yes
Stage 0 PST 0, Child-Pugh A
BCLC Staging and Treatment Strategy HCC
Liver Transplantation
(CLT / LDLT)
ChemoembolizationResection PEI/RF Sorafenib
Combination trial
SPACEAdjuvant trial
STORMAdjuvant trial
Barcelona-Clínic Liver Cancer (BCLC) Group
Liver Unit: J. Bruix, JM. Llovet, A. Forner, M. Reig,, C Rodriguez
Radiology: C. Brú, R. Vilana, Ll. Bianchi, C. Ayuso, J. Rimola,, X. Montañá, I. Real, M. Burrel
Surgery : J. Fuster Pathology : M. Solé Oncology: J. Maurel Nurse: A. Godoy
Oct. 2008
Ad .support
N. Perez
D. Segarra
Laboratory:
L. Boix
A. Villanueva
V. Tovar
C. Alsinet
L. Cabellos
JM. Lopez
J. Peix
H. Cornellà