Call Girls Service in Bommanahalli - 7001305949 with real photos and phone nu...
Role of molecular targeted therapy in HCC Dubai
1. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
By
Heba El-Zawahry M.D.
Prof. Medical Oncology
Head of Medical Oncology Department
National Cancer Institute, Cairo University
Role of Molecular Targeted
Therapy in HCC
2. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Malignant Transformation
Multistep (pathogenesis of HCC)
Potential Targets
Oxidative stress and
inflammation
Viral oncogenes Carcinogens
Growth factors Telomere
shortening
Cancer stem
cells
Loss of cell cycle
checkpoints
Antiapoptosis Angiogenesis
Normal liver
Liver cirrhosis
Hepatitis C
Hepatitis B
Ethanol
NASH
Epigenetic alterations
Genetic alterations
HCC[2]
Dysplastic nodules[1]
1. Tornillo L, et al. Lab Invest. 2002;82:547-553.
2. Verslype C, et al. AASLD 2007. Abstract 24.
3. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Prognostic factors in HCC: dismal prognosis
Prognosis of HCC and treatment options are determined
by
– A natomical extent of tumor (stage)
– B iological aggressiveness (grade)
– C irrhosis severity and functional status
– D isease extension; through staging workup include
multiphase CT/MRI of abdomen, chest CT, and bone scan
4. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Anatomic Staging : TNM
Goodman J, et al. Arch Surg. 2005;140:459-464.
Stage TNM
I Single tumor < 2 cm
II 1 tumor 2-5 cm or 2 or 3 tumors, largest < 3 cm
III 1 tumor > 5 cm or 2 or 3 tumors, largest > 3 cm
IV
4 or more intrahepatic tumors or vascular invasion
or
extrahepatic metastasis
5. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Survival by HCC Tumor Stage
Survival of HCC is
strongly related to
stage at diagnosis
Earlier detection
of HCC could
improve outcome
Stravitz RT, et al. Am J Med. 2008;121:119-126.
II
III
IV
I
0
0.2
0.6
0.4
0.8
1.0
0 1 2 3 4 5
Yrs
Survival
6. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Child-Pugh Classification of Severity of Liver
Cirrhosis and functions
Pugh RN, et al. Br J Surg. 1973;60:646-649. Lucey MR, et al. Liver Transpl Surg. 1997;3:628-637.
Measure 1 Point 2 Points 3 Points
Bilirubin, mg/dL < 2.0 2.0-3.0 > 3.0
Albumin, g/dL > 3.5 2.8-3.5 < 2.8
Prothrombin time, sec < 4.0 4.0-6.0 > 6.0
Ascites None Slight Moderate
Encephalopathy, grade None I-II III-IV
Grade Total Points Surgical Risk
2-Yr Survival,
%
A (well-compensated disease) 1-6 Good 85
B (significant functional compromise) 7-9 Moderate 60
C (decompensated disease) 10-15 Poor 35
7. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Biologically Aggressive HCC
Features
– Microvascular invasion
– Satellite nodules
– Diffuse infiltrating growth
– Poorly differentiated
– Mixed cholangio-
carcinoma
– Bad molecular signature
– FDG-PET scan positive
– High AFP and AFP-L3%
– Rapid growth
Associated with
– Early metastasis
– High risk of recurrence
after resection or liver
transplantation
– Failure of local control
with RFA/TACE
– Poor prognosis
There is no consensus on
how to incorporate biology
into tumor staging
8. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Treatment Options for HCC
Curative (stage I-II)
– Thermal ablation (radiofrequency, microwave)
– Resection (partial hepatectomy)
– Liver transplantation (total hepatectomy)
Palliative (stage III-IV)
– Transarterial therapies
– Systemic therapy
– Targeted therapy
Out of each 10 HCC
patients only one can be
offered curative intent
therapy. (~10%)
11. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Systemic chemotherapy/hormone therapy
no proven efficacy in the treatment of advanced HCC
Trial Phase N
Objective response,
%
Systemic chemotherapy
Doxorubicin as a single agent 2/3 203 10
Doxorubicin combination (PIAF) 2/3 144 24
Cisplatin 2 28 15
Epirubicin 2 62 11
Mitoxantrone 2 22 27
Irinotecan, paclitaxel, gemcitabine, 5-
fluorouracil
2/3 < 10
Anti-androgen (flutamide + leuprorelin) 3 376 No benefit vs. control
Interferon 3 30 < 10
Octreotide 3 35 < 5
Seocalcitol 3 746 < 5
PIAF = cisplatin, IFN α-2b,
doxorubicin, adriamycin,
and 5-fluorouracil.
12. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
1. Villanueva A, et al. Gastroenterology. 2008;135:1972-83.
2. Tovar V, et al. J Hepatol. 2010; 52:550-9.
3. Newell P, et al. J Hepatol. 2009;51;725-33.
Growth factor signaling pathways in HCC:
upregulated proliferation pathways
• IGF-IR, p-AKT, p-ERK, and p-S6 are differentially expressed in
malignant vs. nonmalignant tissue (p < 0.01)
10x
p-Akt
10x
20x
p-ERK
20x 20x
p-S6
20x
Cirrhosis HCC
IGF-IR
20x 20x
Cirrhosis HCC
IGF-IR expressed in 16/79 (20%)
of HCC samples
p-AKT expressed in 29/92 (31%)
of HCC samples
p-ERK expressed in 8/78 (10%)
of HCC samples*,3
p-S6 expressed in 41/86 (48%)
of HCC samples
*47/78 (60%) tumors contained positive endothelial cells.
13. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Molecular pathogenesis of HCC
hepatocyte transformation can occur in the context of
inflammation, regeneration, hyperplasia, cirrhosis, and
genetic or epigenetic alterations
Cellular signaling pathways that are often dysregulated in
HCC include1,2
– VEGF/VEGFR2 → tumor neoangiogenesis
– RTK/Ras/Raf/MEK/ERK → tumor cell proliferation
– RTK/PI3K/Akt/mTOR → tumor cell survival
– Wnt/β-catenin → de-differentiation
1. Thorgeirsson S, et al. Hepatology. 2006;43(2 Suppl 1):S145-50.
2. Avila MA, et al. Oncogene. 2006;25:3866-84.
Key
pathways
and targets
for
molecular
therapy
14. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Targeted Therapy:
Multispecific, blocks tyrosine kinase receptors regulating tumor
proliferation and angiogenesis
Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109. Wilhelm SM, et al. Mol Cancer Ther. 2008;7:3129-3140.
RAS
Vascular cell
Angiogenesis:
VEGFF
VEGFR-2PDGFR-β
Paracrine
stimulation
Mitochondria
Apoptosis
Tumor cell
PDGF
VEGF
EGF / HGF
Proliferation
Survival
Mitochondria
HIF-2
Nucleus
Autocrine loop
Apoptosis
ERK
RAS
MEK
RAF
Nucleus
ERK
MEK
RAF
Differentiation
Proliferation
Migration
Tubule
formation
PDGF-β
EGF/HGF
Sorafenib
15. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Targeted therapy of HCC: Sorafenib
Prior to 2007, no therapy was of
benefit in advanced HCC
SHARP trial: patients with
advanced HCC randomized to
sorafenib 400 BID vs placebo
Sorafenib delayed progression
and prolonged survival from 7.9
to 10.7 mos
Led to approval by the FDA in
2008 for palliation of advanced-
stage HCC
Llovet J, et al. N Engl J Med. 2008;359:378-390.
Sorafenib
Placebo
P < .001
Time to Radiologic Progression
Mos Since Randomization
0 1 2 3 4 5 6 7 8 9 10 11 12
1.00
0.75
0.50
0.25
0
ProbabilityofRadiologic
Progression
299 267 155 101 91 65 37 23 18 10 4 2 0
303 275 142 78 62 41 21 11 10 3 1 1 0
Pts at Risk, n
Sorafenib
Placebo
Sorafenib
Placebo
P < .001
OS
Mos Since Randomization
1.00
0.75
0.50
0.25
0
ProbabilityofSurvival
Pts at Risk. n
Sorafenib
Placebo
0 1 2 3 4 5 6 7 8 9 10111213141516 17
299 290 270 249 234 213 200 172 140 111 89 68 48 37 24 7 1 0
303 295 272 243 217 189 174 143 108 83 69 47 31 23 14 6 3 0
16. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Phase III SHARP Study: Sorafenib vs Placebo in
Advanced HCC
Primary endpoints: OS, time to symptomatic progression
Secondary endpoint: TTP (independent review), disease control rate, safety
Llovet JM, et al. N Engl J Med. 2008;359:378-390.
Patients with advanced
HCC, Child-Pugh A,
ECOG PS ≤ 2, no previous
systemic treatment
(N = 602)
Sorafenib
400 mg PO BID, continuous dosing
(n = 299)
Placebo
2 tablets PO BID, continuous dosing
(n = 303)
17. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
0 1 2 3 4 5 6 7 8 9 10 11 12
1.00
0.75
0.50
0.25
Sorafenib
Median: 5.5 months
(n = 299)
Placebo
Median: 2.8 months
(n = 303)
1.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
0.75
0.50
0.25
0 0
Time from randomization (months) Time from randomization (months)
Survivalprobability
Llovet JM, et al. N Engl J Med. 2008;359:378–90.
Time to progressionOverall survival
Sorafenib
Median: 10.7 months
(n = 299)
Placebo
Median: 7.9 months
(n = 303)
Probabilityofprogression
OS and TTP in the SHARP trial:
sorafenib prolonged OS by 44% and TTP by 73%
in patients with advanced HCC
HR = 0.58
(95% CI: 0.45–0.74; P < 0.001)
HR = 0.69
(95% CI: 0.55–0.87; P < 0.001)
TTP = time to progression.
18. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Phase III Sorafenib vs Placebo in Asian
Patients With Advanced HCC
No predefined primary endpoint
Secondary endpoints: OS, TTP, TTSP (FHSI-8), disease control
rate (RECIST), safety
Patients with
advanced HCC, Child-
Pugh A, ECOG PS 0-2,
no previous systemic
treatment, life
expectancy ≥ 12 wks
Stratified by macroscopic vascular
invasion and/or extrahepatic
spread, ECOG PS, geographic
region
Sorafenib
400 mg PO BID
(n = 150)
Placebo
PO BID
(n = 76)
Randomized 2:1
Cheng AL, et al. Lancet Oncol. 2009;10:25-34.
226 HCC
patients
226 HCC
patients
19. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
0
0.25
0.50
0.75
1.00
0 12 2214108642 1816 20
Sorafenib
Median: 2.8 months
(95% CI: 2.6–3.6)
Placebo
Median: 1.4 months
(95% CI: 1.3–1.5)
HR = 0.57
(95% CI: 0.42–0.79; P < 0.001)
HR = 0.68
(95% CI: 0.50–0.93; P = 0.014)
Sorafenib
Median: 6.5 months
(95% CI: 5.6–7.6)
Placebo
Median: 4.2 months
(95% CI: 3.7–5.5)
0
0.25
0.50
0.75
1.00
0 12 2214108642 1816 20
Cheng A-L, et al. Lancet Oncol. 2009;10:25–34.
Progression-freeprobability
OS and TTP in the Asia–Pacific trial:
sorafenib prolonged OS by 47% and TTP by 74%
in patients with advanced HCC
Time to progressionOverall survival
Time from randomization (months) Time from randomization (months)
Survivalprobability
20. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Comparison between endpoints for the SHARP and
Asia–Pacific trials
Outcome Sorafeni
b
(n = 299)
Placebo
(n =
303)
P
OS , months 10.7 7.9 <0.001
Time to
symptomatic
progression,
months
4.1 4.9 0.77
response, %
CR 0 0 NA
PR 2 1 0.05
SD 71 67 0.17
Sorafenib
(n = 150)
Placebo
(n = 76)
P
6.5 4.2 0.014
2.8 1.4 0.0005
0 0
3.3 1.3
54.0 27.6
SHARP trial1 Asia–Pacific trial2
1. Llovet JM, et al. N Engl J Med. 2008;359:378–90.
2. Cheng A-L, et al. Lancet Oncol. 2009;10:25–34.
1. Llovet JM, et al. N Engl J Med. 2008;359:378–90.
2. Cheng A-L, et al. Lancet Oncol. 2009;10:25–34.
21. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Drug-related AEs,* %
Sorafenib
(n = 86)
Placebo
(n = 89)
Grade Grade
Any 3/4 Any 3/4
HFSR 20.9 7.0/0 4.5 0/0
Diarrhea………………………….
. 44.2 7.0/0 13.5 3.4/0
Alopecia 15.1 0/0 4.5 0/0
Fatigue…………………………... 24.4 3.5/1.2 21.3 3.4/0
Rash/desquamation 18.6 2.3/0 12.4 0/0
Weight loss 11.6 3.5/0 2.2 0/0
Anorexia 12.8 0/0 4.5 1.1/0
*Reported in ≥ 10% of patients
AE profile in the SHARP study
Galle P, et al. J Hepatol. 2008;50 suppl 2:S372 [abstract 994]. Presented at EASL 20
22. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
SHARP Trial ; subanalysis
Sorafenib
Placebo
0
4
6
8
10
12
14
16
MVI
and EHS
HR = 0.77
95%CI:
0.60–0.99
ECOG
PS 1/2
HR = 0.71
95%CI:
0.52–0.96
ECOG
PS 0
HR = 0.68
95%CI:
0.50–0.95
Overall
SHARP
population
10.7
7.9
HR = 0.69
95%CI:
0.55–0.87
Intermediate*
HCC
HR = 0.72
95%CI:
0.38–1.38
Advanced
HCC
HR = 0.70
95%CI:
0.56–0.89
No MVI
or EHS
HR = 0.52
95%CI:
0.32–0.85
10.2
14.5
11.4
14.5
n=161
n=164
n=138
n=139
n=90
n=91
n=209
n=212
n=54
n=51
n=245
n=252
2
Prior
TACE
HR = 0.75
95%CI:
0.49–1.14
n=86
n=90
MedianOS(months)
SHARP subanalysis shows a trend of survival benefit in patients with prior
TACE treatment, in patients without MVI/EHS and in patients with
intermediate HCC
*Intermediate patients = BCLC B patients in SHARP trial.
11.9
9.9
Bruix J, et al. J Hepatol. 2012;57:821–9.
n=299
n=303
23. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Primary endpoint: Recurrence-free survival
Secondary endpoints: Time to recurrence
Overall survival
STORM adjuvant trial: Sorafenib vs placebo
after curative resection/ablation
Stratification:
-Resection vs local ablation
-Intermediate vs high risk
of recurrence
-Child–Pugh A vs B
-Geographical region
Sorafenib
400 mg p.o.
b.i.d.
Continuous
dosingRandomization
N=1100
Placebo
2 tablets p.o. b.i.d.
www.clinicaltrials.gov/ct2/show/NCT00692770.
24. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Biomarkers for Sorafenib?
Not Ready for Prime Time !!
Tissue Biomarkers
Nuclear pERK IHC 2-4+
associated with prolonged TTP
in phase 2 study of sorafenib[1]
– 33/137 (24%) had available
tissue for pERK testing; 18/33
scored 2-4+
Tissue pERK staining was not
associated with outcomes in
SHARP[2]
(N = 110/602, 18%)
Circulating Biomarkers
Plasma biomarkers studied in
SHARP trial[3]
(N = 491/602,
~ 81%)
– Baseline ↑ sc-Kit, ↓ HGF (SOR
arm) and ↓ Ang2 and ↓ VEGF
(placebo arm) associated with
↑ OS in multivariate analyses
– sVEGFR2, sVEGFR3, Ras,
EGF, FGF, IGF2 were not
prognostic
None predicted benefit
– Trend towards improved OS in
subset with baseline ↑ sc-Kit in
SOR arm over placebo
1. Abou-Alfa GK, et al. J Clin Oncol. 2006;24:4293-4300. 2. Llovet JM, et al. N Engl J Med. 2008;359:378-
390. 3. Llovet JM, et al. Clin Cancer Res. 2012;18:2290-2300.
25. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Light Trial
multicenter multinational randomized clinical trial for
the use of linifenib vs sorafenib in advanced HCC
900 HCC (A/B)
Randomized between
sorafenib 400mg bid vs
linifenib 400mg bid for
28days to be continued
Evaluation after 4
months
RECIST response
Radiological response
Interim report March 2013
Non inferiority result for
Linifenib
Diarrhea and neutropenia
were more in Sorafenib
arm
DFP was superior in
Sorafenib arm bur NS
26. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Egyptian National trial for Sorafenib vs Sorafenib and UFT
for systemic treatment of advanced HCC
Egyptian Trial include 5
big centers
Aimed for 715 advanced
HCC
Randomized between
Sorafenib vs Sorafenib
and UFT as first line of
treatment for HCC
Started November 2011
still ongoing
Recruitment of more than
100 cases up till now
Still interim analysis not
yet
The advantage of this
study is to evaluate the
response of HCC following
HCV in one genotype with
some basic biological
marker that may identify a
target to HCC following
this genotype
27. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Beyond Sorafenib: New Agents in HCC
Agent
Molecular
Targets
Phase
Response,
%
Median OS,
Mos
Median TTP,
Mos
Median PFS,
Mos
Safety:
Grade 3-4 AEs, %
Doxorubicin
± sorafenib[1] II PR: 4.0 13.7 6.4 6.0
Fatigue (6)
Hand–foot skin
reaction
(6.4)
Sunitinib[2]
VEGFR,
PDGFR,
FLT3, KIT,
RET
III CR+PR: <7 7.9 4.1 3.6
Significant
toxicities;
discontinued
Brivanib[3] VEGFR,
FGFR
II ORR: 4.3 9.8 1.8 2.0
HTN (7.3)
Diarrhea (6.5)
Headache (4.3)
Linifanib
(ABT-869)[4]
VEGFR,
PDGFR
II ORR: 6.8 9.7 3.7 NR
HTN (18)
Fatigue (14)
Cabozantinib
(XL184)[5]
c-MET,
VEGFR2
II PR: 9.0 NR NR 4.2
Hand-foot
syndrome (15)
Diarrhea(9)
TP (9)
Tivantinib
(ARQ197)[6] c-MET II NR MET high: 7.2 MET high: 2.9 MET high: 2.4
Neutropenic
sepsis (4.2)
1. Abou-Alfa GK, et al. JAMA. 2010;304:2154-2160. 2. Cheng A, et al. ASCO 2011. Abstract 4000. 3. Finn
RS, et al. Clin Cancer Res. 2012;18:2090-2098. 4. Toh H, et al. ASCO 2010. Abstract 4038. 5. Cohn AL,
et al. ASCO GI. 2012. Abstract 261. 6. Rimassa, L, et al. ASCO 2012. Abstract 4006.
28. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Molecular classification of HCC
HCC genomic-based classification
In a meta-analysis of 603 HCC patients
– 3 HCC subtypes were observed: S1–S3
– Distinguished by molecular phenotype, tumor size, cellular
differentiation, and AFP levels
S1 S2 S3
Molecular pathways
TGF-β
Wnt ↑ MYC
AKT
Retained hepatocyte-like phenotype
E2F1 ↑, p53 ↓
IFN ↓
Published subclasses
Poor survival Good survival
Proliferation CTNNB1
Late
TGF-β
EpCAM (+)
Clinical phenotype
Moderately/poorly differentiated Well differentiated
Large tumor Smaller tumor
AFP ↑
Hoshida Y, et al. Cancer Res. 2009;69:7385–92.
29. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Tivantinib (ARQ 197): Target MET in HCC
Ongoing efforts to study hepatocarcinogenesis
have identified an important role for c-MET
signaling in the promotion of tumor growth,
angiogenesis, and metastasis.
– Only known receptor for hepatocyte growth factor
– Correlated with poor prognosis
c-MET inhibitors fhave been evaluated in many
phase I tilas for or more rational clinical trial
design.
Tivantinib is a selective oral MET inhibitor
30. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Tivantinib vs Placebo in Previously Treated
Unresectable HCC
Multicenter, randomized phase II trial
Primary endpoint: TTP
Stratification: MET status, HBV vs HCV, and duration of previous therapy
Crossover on PD
Rimassa L, et al. ASCO 2012. Abstract 4006.
Patients with
unresectable HCC
following failure of
1 systemic therapy,
ECOG PS < 2
(N = 107)
Placebo PO BID
(n = 36)
Tivantinib 360 mg PO BID
(n = 38)
Tivantinib 240 mg PO BID
(n = 33)
31. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Tivantinib vs Placebo in Previously Treated
Unresectable HCC
MET level predictive of tivantinib benefit: TTP and OS similar with tivantinib vs placebo among
patients with low MET expression
ITTITT
Rimassa L, et al. ASCO 2012. Abstract 4006.
MET Diagnostic High PopulationMET Diagnostic High Population
ProportionofPatients
ProgressionFree
1.0
0.8
0.6
0.4
0
0.2
Wks to Tumor Progression
0 10 20 30 40 50 60
Median TTP
6.9 wks
6.0 wks
Tivantinib
Placebo
Patients
71
36
Events
46
30
HR: 0.64 (90% CI: 0.43-0.94;
log-rank P = .04)
ProportionofPatients
Surviving
1.0
0.8
0.6
0.4
0
0.2
Wks From Date of Randomization
0 5 10 15 20 25
Median TTP
6.6 wks
6.2 wks
Tivantinib
Placebo
Patients
71
38
Events
56
30
HR: 0.90 (90% CI: 0.57-1.40;
log-rank P = .63)
ProportionofPatients
ProgressionFree
1.0
0.8
0.6
0.4
0
0.2
Wks to Tumor Progression
0 10 20 30 40
Median TTP
11.7 wks
6.1 wks
Tivantinib
Placebo
Patients
22
15
Events
14
13
HR: 0.43 (95% CI: 0.19-0.97;
log-rank P = .03)
ProportionofPatients
Surviving
1.0
0.8
0.6
0.4
0
0.2
Mos From Date of Randomization
0 5 10 15 20
Median TTP
7.2 wks
3.8 wks
Tivantinib
Placebo
Patients
22
15
Events
17
15
HR: 0.38 (90% CI: 0.18-0.81;
log-rank P = .01)
32. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
• Imaging every 3–6 months for
2 years, then every 6–12 months
• AFP, if initially elevated, every
3–6 months for 2 years, then every
6–12 months
Options:
• Sorafenib
(Child–Pugh class A [category 1] or B)c, d, e, f
• Chemotherapy + RT only in the context of a clinical trial
• Clinical trial
• Locoregional therapya
• RT (conformal or stereotactic)v
(category 2B)
• Supportive care
• Systemic or intra-arterial chemotherapy in clinical trial
Options:
• Sorafenib
(Child–Pugh class A [category 1] or B) c, d, e, f
• Clinical trial
• Locoregional therapya
• RT (conformal or stereotactic)g
(category 2B)
• Sorafenib
(Child–Pugh class A [category 1] or B) c, d, e, f
• Supportive care
• Clinical trial
SurveillanceTreatmentClinical
presentation • Transplant
• Consider
bridging
therapy as
indicated
Transplant
candidate
• Inadequate
hepatic
reservec
• Tumor
location
Evaluate whether
patient is a candidate
for transplant (See
UNOS criteria under
Surgical Assessment
HCC-5)b Not a
transplant
candidate
Extensive
liver disease
Unresectable
Inoperable by Perfomance
Status or comorbidity,
local disease only
Metastatic
disease
33. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Portal pressure/
bilirubin
HCC
RFA Sorafenib
Stage 0
PST 0, Child–Pugh A
Very early stage (0)
1 HCC < 2 cm
Carcinoma in situ
Early stage (A)
1 HCC or 3 nodules
< 3 cm, PST 0
End stage (D)
Liver transplantation TACEResection Symptomatic
treatment (20%)
Survival < 3 months
Symptomatic
treatment (20%)
Survival < 3 months
Curative treatments (30%)
5-year survival 40–70%
Curative treatments (30%)
5-year survival 40–70%
Palliative treatments (50%)
Median survival 11–20 months
Palliative treatments (50%)
Median survival 11–20 months
Associated diseases
YesNo
3 nodules ≤ 3 cm
Increased
Normal
1 HCC
Stage D
PST > 2, Child–Pugh C
Intermediate stage (B)
Multinodular,
PST 0
Advanced stage (C)
Portal invasion,
N1, M1, PST 1–2
Stage A–C
PST 0–2, Child–Pugh A–B
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
Barcelona Clinic Liver Cancer (BCLC) staging
system and treatment strategy
34. clinicaloptions.com/oncology
Multidisciplinary Approaches to a Growing Clinical Challenge
Conclusions
Early-stage HCC may be
cured with
– Thermal ablation
– Resection
– Liver transplantation
Advanced-stage HCC may
be palliated with
– TACE or XRT
– Sorafenib/or as adjuvant
– Experimental therapies
Local measures often fail
in tumors with aggressive
biology
Application of therapies
may be limited by severity
of cirrhosis
Choosing the optimal
treatment requires
collaboration of multiple
specialties
Mr chair persones , ladies and gentle men it my honor to highlight in the next 15 minutes what is the most recent therapy for HCC
HCC, hepatocellular carcinoma; NASH, nonalcoholic steatohepatitis.
One of the features that separates HCC from other tumors is the fact that it occurs in the setting of cirrhosis of the liver or chronic liver disease. Liver disease, which is primarily due to hepatitis C in Western countries and hepatitis B in Asia, leads to cirrhosis of the liver followed by dysplasia and HCC. This progression is because of several epigenetic and genetic alterations, many of which have been identified as potential therapeutic targets.
Two principal mechanisms are implicated in hepatocarcinogenesis:
Liver cirrhosis following tissue damage
Mutations occurring in 1 or more oncogenic or tumor suppressor genes
In each disease we would like to set an known prognostic factors that help us for proper patients selection and proper persenolized therapy
Hepatic function assessed often using the Child‑Pugh score. First developed to predict surgical mortality, the Child-Pugh scoring system was unique in stratifying the severity of end-stage liver disease based on 5 liver function parameters. However, the Child-Pugh scoring system does not include any parameters pertaining to the cancer itself.
The prognosis of hepatocellular carcinoma (HCC) is affected by tumoral factors and liver functions; therefore it is often difficult to select the appropriate therapeutic methods for HCC. Recently, two global phase III trials showed that sorafenib, which is a tyrosine kinase inhibitor, improved the prognosis of patients with advanced HCC.
This oral multikinase inhibitor blocks tumor cell proliferation by targeting the RAF / MEK / ERK signaling pathway.
Angiogenesis is disrupted by targeting tyrisone kinases of VEGF-R and PDGFR-β.
BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; OS, overall survival; PO, orally; SHARP, Sorafenib HCC Assessment Randomized Protocol; TTP, time to progression.
BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; FHSI-8, Functional Assessment of Cancer Therapy–Hepatobiliary Symptom Index; HCC, hepatocellular carcinoma; OS, overall survival; PO, orally; RECIST, Response Evaluation Criteria in Solid Tumors; TTP, time to progression; TTSP, time to symptomatic progression.
The key findings from the SHARP trial have been confirmed this phase III, double-blind, randomized, placebo-controlled study.
The prognosis of hepatocellular carcinoma (HCC) is affected by many factors and liver functions; therefore it is often difficult to select the appropriate therapeutic methods for HCC. Recently, there are many research to evaluate biomarker that may help for whom will respond to Sorafenib.
HTN, hypertension; NR; not reported; OS, overall survival; PFS, progression-free survival; TTP, time to progression; PPE, palmar-plantar erythrodysesthesia; TP, thrombocytopenia
BID, twice daily; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance score; HCC, hepatocellular carcinoma; PFS, progression-free survival; PO, orally; OS, overall survival; TTP, time to progression.
Tivantinib has also been tested in other tumor types. For example, several presentations at the 2012 annual meeting of the American Society of Clinical Oncology focused on the use of tivantinib in hepatocellular carcinoma. Rimassa and colleagues[21] conducted a multicenter, randomized phase II trial of tivantinib compared with placebo in patients (N = 107) with unresectable hepatocellular carcinoma who had failed 1 systemic therapy and had a good Eastern Cooperative Oncology Group performance score. Patients were randomly assigned to receive a high dose of tivantinib at 360 mg orally twice daily or 240 mg orally twice daily or a placebo. The primary endpoint was time to progression, and the secondary endpoints included the disease-control rate, PFS, and OS.
21. Rimassa L, Porta C, Borbath I, et al. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: results of a randomized controlled phase II trial (RCT). Program and abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, Illinois. Abstract 4006.
HCC, hepatocellular carcinoma; OS, overall survival; TTP, time to progression.
The MET level (by IHC) was predictive of benefit from tivantinib in both the intent-to-treat population and patients with high MET expression.[22] In studies of onartuzumab in NSCLC, MET-high patients responded better than MET-low patients, and these results with tivantinib in hepatocellular carcinoma appear to be quite similar. That is, the time to progression and median OS were similar with tivantinib vs placebo among patients with low MET expression but significantly different in those with high MET expression.
Regarding adverse events, tivantinib is a well-tolerated agent overall, but there are effects, especially at the higher dose of 360 mg twice daily, where more grade 3-5 neutropenia has been reported (21% vs 6% with 240 mg twice daily). Other adverse events were less common.
22. Rimassa L, Porta C, Borbath I, et al. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: results of a randomized controlled phase II trial (RCT). Program and abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, Illinois. Abstract 4006.