recent advances in management of hcc
TRANSCRIPT
1
Recent Advances in Management of HCC
Ronnie T.P. Poon, MBBS, MS, PhD
Chair Professor of Hepatobiliary and Pancreatic Surgery
Chief of Hepatobiliary and Pancreatic Surgery
The University of Hong Kong
Queen Mary Hospital
Hong Kong, China
2
Challenges in Management of HCC
One patient with two diseases
• A highly malignant tumor
- Rapid growth
(tumor volume doubling time 3 months)
- High propensity for venous invasion
• Associated cirrhosis (70-80%)
Impaired liver function
Multifocal disease
Majority of patients presented with symptomatic advanced
disease in Hong Kong, less than 30% detected by screening
Chan et al. Ann Surg 2007
3
Unresectable disease
BCLC Staging and Treatment Algorithm
HCC
Stage 0 PST 0, Child-Pugh A
Single
Very early stage (0)
Single <2 cm
Carcinoma in situ
Resection
Curative treatments (30%) 5-year survival: 40–70%
Randomised controlled trials (RCTs)
(50%) 3-year survival: 10–40%
Symptomatic
(20%) Survival <3 months
Liver transplantation (CLT/LDLT)
PEI/RFA
Portal pressure
bilirubin
Associated diseases Increased
Normal No
Early stage (A)
Single or 3 nodules
<3 cm, PS 0
Intermediate stage (B)
Multimodular PS 0
Advanced stage (C)
Portal invasion, N1,
M1, PS 1–2
Terminal stage (D)
Stage A–C Okuda 1–2, PST 0–2, Child-Pugh A–B
Stage D Okuda 3, PST <2,
Child-Pugh C
3 nodules ≤3 cm
Yes
Llovet JM, et al. J Natl Cancer Inst 2008
TACE Sorafenib
4
BCLC Stage Distribution in Asian Countries
0
10
20
30
40
50
60
70
80
Early stage (A) Intermediate stage (B)
Advanced Stage (C&D)
Hong Kong (QMH)
Seoul (YLCSC)
Taiwan (NTU)
Japan (MRCH)
Asia-Pacific Cancer Conference, 2009
%
5
Extrahepatic metastasis
Main portal vein tumor thrombus
Solitary or multifocal tumor in
noncirrhotic liver or Child A cirrhosis
Sorafenib or systemic therapy trial
Resection /
RFA (for
< 3 cm HCC)
Solitary tumor 5 cm
3 tumors 3 cm
No venous invasion
Child A Child B Child C Child A / B Child’s C
Transplantation TACE Supportive care Local
ablation
Confined to the liver
Main portal vein patent
APASL Consensus on Treatment of HCC
Tumor 5 cm
3 tumors
Invasion of hepatic / portal vein branches
Yes No
Child A / B Child C
Omata, et al. Hepatol Int 2010
6
Recent Advances in Management of HCC
• Surgical treatment
- Better patient selection (liver function assessment, imagings)
- Improving survival results
- Minimally invasive approach
- Role of antiviral therapy
• Ablation therapies
- Expanding role of RFA
- Newer modalities (microwave, HIFU, electroporation)
• Transarterial therapies
- Newer modalities (DEB-TACE, Y-90)
• Systemic therapy
7
Selection Criteria for Liver Resection at QMH
• Tumor status:
– No extrahepatic metastasis
– Anatomically resectable (2 segments free of cancer)
– Large tumor, multifocal tumors or intrahepatic venous
invasion are NOT contraindications for resection
• Liver function reserve:
– Child A cirrhosis for major resection, Child B for minor resection
– ICG-R 15 min. <20% (now by pulse spectrophotometry)
– CT volumetry - liver remnant > 30% estimated standard liver volume,
portal vein embolization if inadequate liver remnant volume
Poon et al. Ann Surg 2002
Cheung et al. Hepatobiliary Pancreat Dis Int 2012
8
Preoperative PV Embolization
Left lobe 272 cc, 24% of
ESLV
Left lobe 358 cc, 30% of
ESLV
4 wk
Percutaneous approach
9
Preoperative PV Embolization
Surgical approach
10
Better Staging Prior to Surgical Treatment
• 3-phase contrast CT scan and MRI are gold-standard
imagings in diagnosis of HCC
• 18F-FDG PET scan has limited sensitivity in staging for
HCC (<50%) – well-differentiated HCC not detected
• C-11 acetate for evaluation of free fatty acid metabolism is
useful in detecting well-diff. HCC
• Analysis of 55 lesions in 32 patients with HCC in Hong
Kong:
- sensitivity of C-11 acetate vs. 18F-FDG: 87% vs. 47%
- 100% sensitivity with dual-tracer scan
Ho et al. J Nuc Med 2003
11
Dual-tracer PET Scan for Preop. Assessment
12
Dual-Tracer PET Scan Prior to Resection or LT
Patients who had HCC and had undergone both preoperative dual-tracer
PET/CT and contrast CT within a 1-mo interval prior to resection or LT
were studied, imaging data were compared with pathologic analysis
• Contrast CT performed reasonably well in the LT group but not in the
PH group for HCC detection (67.6% vs. 37.5%) and TNM staging
(54.5% vs. 28.6%).
• Dual-tracer PET/CT performed very well in both LT and PH groups for
HCC detection (94.1% vs. 95.8%) and TNM staging (90.9% vs. 90.5%)
• The overall sensitivity (96.8%) and specificity (91.7%) of dual-tracer
PET/CT for patient selection for LT were significantly higher than those
of contrast CT (41.9% and 33.0%, respectively)
Cheung et al, J Nuc Med 2013
13
Perioperative Outcome of Liver Resection
1222 patients with hepatectomy for malignancy
1989-2003, QMH
- Operative mortality <5% (recent 5 years - 1%)
- Postoperative hemorrhage and bile leakage < 5%
- Liver failure < 4%
- Major hepatectomy in Child A cirrhosis is safe with
modern surgical techniques
- Upper limit of ICG R-15 for major hepatectomy
extends from 14% in 1990s to 20% in 2000s
Poon et al. Ann Surg 2004
14
Improving Long-term Survival after Resection
of HCC
Comparison of two 10-yr. period 1990-99 (group 1) and 2000-09 (group 2)
• 5-yr. overall survival increased from 42% to 55%
• 5-yr. disease-free survival increased from 24% to 35%
Fan et al. Ann Surg 2011
15
Improving Long-term Survival after Resection
of HCC
• Improved survival observed
in patients with relatively
advanced stage HCC (large
tumor >5cm, multifocal
tumors or macroscopic
vascular invasion)
• The period in which patients
were operated was an
independent prognostic factor
of survival in multivariate
analysis
16
Liver Resection for HCC at QMH
2000 - 2009
Patient characteristics Total number of
resection patients
(n=1111)*
Age [Median (Range)] 56(5-86)
Sex, M:F 895:216
Non-cirrhotic / cirrhotic 453 (40.7%) / 658 (59.3%)
Hepatitis B carrier (%) 946 (85.3%)
Hepatitis C carrier (%) 47 (4.6%)
Tumor size [Median (Range)] 5.5 (0.7-28) cm
Solitary / multiple 759 (68.3%) / 352 (31.7%)
Macroscopic vascular invasion 88 (8%)
*25.5% of 4354 HCC patients seen in the period
Resection for Multifocal HCC
18
Long-term Survival after Resection of
Multifocal HCC at QMH
Median survival = 94 mos (solitary)
vs 34.4 mos (multifocal)
5-year survival = 62.4% (solitary)
vs 34.0% (multifocal)
Cum
ula
tive s
urv
ival (%
)
Survival time (years)
Multifocal (n=261)
Solitary (n=761)
M/67 HBsAg +ve, Child A cirrhosis
Presented with RUQ pain and obstructive jaundice – ERCP with stenting
Right lobe HCC with right PV invasion and bile duct invasion in 2006
HCC with Macroscopic Venous Invasion
Treatment : ? Resection ? TACE ? Systemic therapy
Right hepatectomy + excision of bile duct + left hepaticojejunostomy July 06
Latest CT scan in Dec 2012 – no recurrence
21
Aggressive Surgery for HCC with Main PV
Tumor Thrombus
• 42 yrs. old HBV carrier, R lobe HCC with R, main and L portal vein
tumor throumbus
- R trisectionectomy and main portal vein resection
with Gor with Gortex graft reconstruction
- Survived 32 months
22
Long-term Results of Resection for HCC
with Macroscopic Venous Invasion
Overall survival Disease-free survival
88 patients with macroscopic portal vein invasion underwent liver
resection from 2000-2009
Median survival = 11.3 mos
5-year survival rate = 15.2% Median DF survival = 4.1 mos
5-year DF survival rate = 13%
23
Laparoscopic Liver Resection
Laparoscopic right and left hepatectomy feasible –
lower blood loss, less pain, shorter hospital stay
24
Laparoscopic vs. Open Resection for
HCC
Case-matched comparison of 32 patients with pure lap.
resection vs. 64 patients with open resection for HCC at
QMH from 2002-2009
• Majority had TNM stage I (< 5 cm) in Child A cirrhosis
(median tumor size 3 vs. 2.5 cm, range 1-10 cm)
• Lap. resection resulted in:
- lower blood loss (median 150 vs. 300 mL)
- shorter hospital stay (median 4 vs. 7 days)
- lower complication rate (6.3 vs. 18.8%)
- no hospital mortality (vs. 1.6% in open resection)
Cheung et al. Ann Surg 2013
25
Laparoscopic vs. Open Resection for
HCC
• Overall 5-year survival:
77% vs. 57% (p=0.142)
• For TNM stage 1 HCC
(18 vs. 39 patients):
5-yr. survival 100% vs.
75% (p=0.126)
Cheung et al. Ann Surg 2013
26
High HBV-DNA Level Increases Risk of Recurrence
after Resection of HBV-related HCC
72 patients with HBV-related HCC undergoing resection between 2004
2006 at QMH had preop. serum HBV DNA measurement and
prospectively studied (only 3 with preop. antiviral therapy)
• Patients with high HBV viral load >2,000 IU/mL
at the time of resection had a significantly higher
tumor recurrence rate
• By multivariate analysis, HBV viral load >2,000 IU/mL (P = 0.001, odds
ratio [OR] 22.3), AFP >1,000 ng/mL (P = 0.02, OR 7.4), tumor size >5 cm
(P = 0.02, OR 5.1) were independent risk factors of recurrence
Hung et al. Am J Gastroenterol 2008
27
Antiviral Therapy after Resection of HCC Improves
Prognosis
136 patients received major hepatectomy for HBV-related HCC from
2003-2007: 42 received antiviral therapy (treatment group) after
hepatectomy, whereas 94 did not (control group)
• Disease-free and overall survival rates were significantly prolonged
in the treatment group (5-yr. overall survival 71.2% vs. 43.5%, p=0.005;
5-yr. disease-free survival 51.4% vs. 33.8%, p=0.05)
• Post-hepatectomy antiviral therapy conferred significant survival benefit
in TNM stages I and II tumors or HCCs without major venous invasion
Chan et al. Arch Surg 2011
28
Antiviral Therapy after Resection of HBV-
Related HCC: Meta-analysis
• Meta-analysis of 9 cohort studies with a total number of 551 patients:
204 patients with anti-viral treatment group and 347 patients without
anti-viral treatment (control group)
• Antiviral therapy using nucleoside analogues significantly reduced risk
recurrence by 41%, mortality from liver failure by 87% and overall
mortality by 73%
Wong et al. Aliment Pharmacol Ther 2011
29
Local Ablative Therapies for HCC
• Ethanol injection - 1980s-1990s
• Cryotherapy - 1990s
• Radiofreqency ablation - 2000s
• Microwave - 2010s
• High intensity focused ultrasound - 2010s
• Electroporation - 2010s
30
Role of RFA for HCC
• Widely accepted indications:
- unresectable < 5 cm liver tumor, < 4 tumor nodules
- absence of macroscopic venous invasion or
extrahepatic disease
• Recurrent small HCC after previous resection
• Bridge therapy prior to liver transplantation
Long-term Results of RFA for HCC
Study No. of
patients
Mean /
Median
FU (mo)
Recurrence
rate
5-year
survival
5-year
disease-free
survival
Rossi 1996 39 22.6 41% 40% NA
Buscarini 2001 88 34 29% 33% 3%
Lencioni 2005 187 24 50% 48% NA
Machi 2005 65 24.8 57% 40% 28%
Cabassa 2006 59 24.1 58% 43% 17% (3-year)
Choi 2007 570 30.7 52% 58% NA
Ng 2008 207 26 81% 42% 28%
32
Role of RFA for Resectable HCC < 5 cm
• Controversial results from 2 randomized trials comparing
RFA and resection for HCC < 5 cm
- similar 4-yr survival (68% vs. 64%) in a RCT of 180 patients1
- significantly worse overall survival (5-yr. 55% vs. 76%,p=0.024) and
recurrence-free survival (5-yr. 29% vs. 51%,p=0.017) with RFA compared
with resection in another RCT of 230 patients2
1Chen et al. Ann Surg 2006 2Huang et al. Ann Surg 2010
33
Combined Resection and Ablation
• Bilobar multifocal tumors – resection of predominant
lesion(s) in one lobe and ablation of lesion(s) in the
other lobe
• Multiple tumors in cirrhotic liver with inadequate liver
function reserve (resection of peripheral lesions,
ablation of central lesions or lesions close to vital
vessels)
34
Match-controlled Study of Combnied
Resection/RFA vs. Resection Alone
Combined treatment vs. resection alone
• No hospital mortality in both groups
• Median survival:
53.0 vs. 44.5 months
• Overall survival rates:
3-year 63% vs. 52%
Overall survival
months
706050403020100
Cum
ula
tive
surv
ival
(%)
100
90
80
70
60
50
40
30
20
10
0
combination
resection alone
p=0.496
Cheung et al. World J Gastroenterol 2010
N=19
N=54
Microwave Ablation
• New generations of microwave system allow faster ablation of a large volume – diameter of 5-6 cm in 6 mins
- particularly suited for operative ablation of large tumors
• Minimal heat-sink effect in tumors close to major vessels
Sharp tip Antenna Temperature sensor
38
HIFU Centre at Queen Mary Hospital
185 HCC patients and 13 patients with liver
metastasis treated (0.9 – 8.7 cm)
39
2.5 cm tumor, 6.8 cm tumor
total treatment time 25 mins total treatment time 122 minutes
Pre-HIFU
Post-HIFU
Results of First 50 Cases
(Oct 2006 – March 2009)
2006 - 2009
(n=50)
Treatment-related complications 3 (8%)
Second degree skin burn 3
Chest wall bruising 1
Hospital stay, days 4 (2-16)
Complete tumor ablation* 38 (78%)
*Complete ablation in second 25 patients 88% vs. 64% in first 25
patients
Tumor size 1-8 cm
Ng et al. Ann Surg 2011
41
Comparison of HIFU vs. RFA for < 3 cm HCC
47 patients who received HIFU ablation and 59 patients who
received RFA for < 3 cm HCC at QMH
• More patients in the HIFU group patients had Child–Pugh
B cirrhosis (34% versus 8.5%; P = 0.001)
• 1- year overall survival 97.4% versus 94.6%
3-year overall survival 81.2% versus 79.8% p=0.530
Cheung et al. HBP 2012
42
Comparison of HIFU vs. RFA for Recurrent
HCC
• 27 patients who received HIFU ablation and 76 patients
who received RFA for recurrent HCC at QMH from Oct
2006 to Oct 2009 were reviewed
Chan et al. Ann Surg 2013
43
Comparison of HIFU vs. RFA
• The procedure-related morbidity rate was 7.4% in the HIFU
group and 22.4% in the RFA group (P = 0.44)
• No hospital mortality with HIFU, 2 deaths (2.6%) after RFA
Chan et al. Ann Surg 2013
44
Irreversible Electroporation
• A novel technology that uses a series of microsecond
electrical pulses to permanently open cell membranes and
induce death in cancer cells
• Non-thermal ablation technology that is safe near vital
nerve, vascular and ductal structures
• Approved by FDA for cancer ablation
Nanoknife system
45
Irreversible Electroporation
• Single-center study ay Memorial Sloane Kettering Cancer Center:
- 28 patients with 65 perivascular malignant liver tumors
(unresectable and not suitable for thermal ablation)
treated by percutaneous or open approach
- median tumor size 1 cm (0.5-5cm), 16 tumors < 1 cm
from major portal pedicle
- morbidity 3%, no mortality
- 6-month FU imaging: only 1 tumor (1.9%) had persistent disease
Kingham et al. J Am Coll Surg 2012
TACE for Unresectable HCC
484 patients (1989 - 1997)
Response rate: 50%
Morbidity: 23%
Mortality: 4.3%
Survival: 1-yr 49%, 3-yr 23%, 5-yr 17%
Adverse prognostic factors:
tumor size > 10 cm,
serum albumin < 35 g/L
Poon et al. J Surg Oncol 2000
Lipiodol-TACE with cisplatin or doxorubicin
47 Llovet et al. Lancet 2002
0 12 24 36 48 60 0 6 12 18 24 30 36 42
Chemoembolisation
Control
Chemoembolisation
Control
Pro
bab
ilit
y o
f su
rviv
al
(%)
Pro
bab
ilit
y o
f su
rviv
al
(%)
• Vascular invasion: Barcelona: 0%; Hong Kong 27%
• 2-year OS of untreated group: Barcelona: 27%; Hong-Kong 11%
Months from randomization Months from randomization
RCTs of TACE vs Best Supportive Care
Barcelona Hong-Kong
Lo et al. Hepatology 2002
P = 0.009 P = 0.002
A New Technique of TACE: Doxorubicin-eluting Beads
• Soft deformable microspheres loaded
with doxorubicin of uniform size 200-
500 µm, slowly degradable
- Reduces blood flow to tumor
- Slow release of doxorubicin
enhances local anti-tumor effect
and decreases systemic exposure
49
A Phase I/II Trial of DEB for HCC
• A prospective phase I/II clinical trial of 35 patients at QMH
- No doxorubicin-related toxicity (marrow suppression, cardiotoxicity)
- Overall treatment-related complication rate 11.4%
- No treatment-related deaths
Poon et al. Clin Gastroenterol & Hepatol 2007
Complete response: n = 2 (6.7%)
Partial response: n = 19 (63.3%)
Stable disease: n = 2 (6.7%)
Progressive disease: n = 7 (23.3%)
Objective response: 70%
50
Randomized Controlled Trial
• European multi-centre randomized trial to compare safety
and efficacy of doxorubicin-eluting bead with conventional
TACE using doxorubicin
(100 patients in each arm)
Malagari et al. Cardiovasc Intervent Radiol 2010
51
52
• No prospective randomized comparison with TACE
• Single institution comparative study (n=245)
TACE (n=123) Y-90 (n=122) p-value
Response 36% 49% 0.104
TTP 8.4 mo 13.3 mo 0.046
OS 17.4 mo 20.5 mo 0.232
• Response observed even in patients with portal vein tumor
thrombus
• Less abdominal pain and transaminase rise after Y-90
Salem et al Gastroenterol 2012
Transarterial Yttrium-90 Radioembolization
53
Transarterial Radioembolization
M/50 HBsAg +ve,
Child A cirrhosis
Right lobe HCC with
PV tumor thrombus
extending to SMV
Transarterial Yttrium-
90 radioemebolization
induced partial
response
Y90
54
Molecular Targeted Therapy - Sorafenib
55
Months
0
0.25
0.50
0.75
1.00
0 2 4 6 8 10 12 14 16
Sorafenib Median: 10.7 months (95% CI: 9.4–13.3)
Placebo Median: 7.9 months (95% CI: 6.8–9.1)
HR (S/P): 0.69 (95% CI: 0.55–0.87) P<0.001
Llovet JM et al. N Engl J Med 2008
SHARP trial
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 2 4 6 8 10 12 14 16 18 20 22
HR (S/P): 0.68 (95% CI: 0.50–0.93) P=0.014
Asian trial
Cheng AL et al. Lancet Oncol 2009
Pro
babili
ty o
f su
rviv
al
Months
Phase 3 Randomized Sorafenib Trials in
Advanced HCC with Child A Cirrhosis
Pro
babili
ty o
f su
rviv
al
56
Sorafenib Clinical Experience in HCC:
SHARP and Asia-Pacific Studies
SHARP1 Asia-Pacific2
Sorafenib vs placebo Sorafenib vs placebo
Endpoint Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value
OS 10.7 vs 7.9 months
0.69 (0.55-0.87) <.001
6.5 vs 4.2 months
0.68 (0.50-0.93) .014
TTSP 1.08 (0.88-1.31) .768 0.90 (0.67-1.22) .50
TTP 5.5 vs 2.8 months
0.58 (0.45-0.74) <.001
2.8 vs 1.4 months
0.57 (0.42-0.79) <.001
RR 2% vs. 1% 3.3% vs 1.3%
1Llovet J, et al. N Engl J Med. 2008;359(4):378-90; 2Cheng A, et al. Lancet Oncol. 2009;10(1):25-34
TTSP = time to symptomatic progression; TTP = time to progression; RR = response rate
Limitations of sorafenib
•Limited survival gain (median 3 months)
•Low tumour response <5%
•Significant toxicities, especially hand-foot reaction
57
Treatment of Advanced HCC in Asia
• Sorafenib is considered the standard of care BUT not
reimbursed in many Asian countries
• Systemic chemotherapy (Doxorubicin, 5-FU, cisplatin,
FOLFOX) still used in some Asian countries
- FOLFOX approved by China FDA for HCC
• Transarterial infusional chemotherapy (5-FU+cisplatin, 5-
FU+interferon) popular in Japan
58
Phase 3 Trials of First-line Therapy in
Advanced HCC
• Phase 3 study of sunitinib versus sorafenib in advanced HCC (N=1200)
terminated in April 2010 due to sunitinib toxicity and inferior efficacy5,6
1. NCT01009593. ClinicalTrials.gov; 2. NCT01015833. ClinicalTrials.gov; 3. NCT00901901. ClinicalTrials.gov;
4. NCT00858871. ClinicalTrials.gov
Study drug
(trial acronym) Mechanism Control N
Primary
endpoint
Data
expected
Linifanib (ABT-869)1 RTKI of VEGF + PDGF Sorafenib 900 OS Completed -ve
Brivanib (BRISK-FL)4 RTKI of FGF + VEGF Sorafenib 1050 OS Completed -ve
Sorafenib +
doxorubicin
(CALGB-80802)2
Sorafenib: multikinase
inhibitor
Doxorubicin: cytotoxic
Sorafenib 480 OS 2017
Sorafenib + erlotinib
(SEARCH)3
Sorafenib: multikinase
inhibitor
Erlotinib: RTKI of EGFR1 Sorafenib 700 OS Completed -ve
59
Phase 3 Trials of Second-line Therapy in
Advanced HCC
Study drug
(trial acronym)
Mechanism
Control
N
Primary
endpoint
Data
expected
Brivanib
(CA182-034)1
RTKI of FGF +
VEGF
Placebo
414
OS Completed -ve
Everolimus
(EVOLVE-1)2
mTOR inhibitor
Placebo
531 OS 2013
Ramucirumab
(REACH)3 MAb to VEGFR-2 Placebo 544 OS 2013
1. NCT00825955. ClinicalTrials.gov
2. NCT01035229. ClinicalTrials.gov
3. NCT01140347. ClinicalTrials.gov Mab = monoclonal antibody
60
Sorafenib with
Capecitabine and
Oxaliplatin (SECOX)
single-arm phase II trial
for HCC
• # of pts recruited = 51
• 4 centres in Hong Kong
• 1 centre in Singapore
Sorafenib + Oxaliplatin
+Capecitabine x 8 cycles
every 2-weekly
• IV Oxaliplatin (85 mg/m2)
on day 1 of each cycle q 2wks)
• Capecitabine (850 mg/m2
BID) from day 1 to 7
• Sorafenib (400 mg BID) from
day 1 to 14 (continuously)
Cycle 4 – CT scan
Sorafenib with Xeloda and Oxaliplatin
(SECOX) Single-arm Phase II Trial
SECOX
Cycle 5-8
CT Scan at
Cycle 8
SECOX Cycle 1-4
SD
Tumour
response
Sorafenib
Regular CT
Primary endpoint: Overall survival
Secondary endpoints: Progression-free survival
Tumor response (RECIST)
Safety
61
Best Tumor Response
Tumor Response
(RECIST criteria)
SECOX
No. of Patients (%)
N=51
Complete response (CR) 0
Partial response (PR) 7 (14%)
Stable disease (SD) 31 (61%)
Progressive disease (PD) 12 (23%)
Disease-control rate 75%
Yau & Poon, ECCO 2009. Abstract 47LBA
62
Overall and Progression-Free Survival
Overall survival
months
1815129630
Cum
ula
tive
surv
ival
(%)
100
80
60
40
20
0
Median overall survival: 6 months
Median PF survival: 3 months
(Oriental phase 3 trial: OS 6.5 months
TTP 2.8 months)
Sorafenib1 SECOX2
Median overall survival: 11.9 months
Median PF survival: 7.0 months
Months
201714129630
Cum
ulat
ive
Surv
ival
(%
)
100
80
60
40
20
0
1. Yau et al. Cancer 2009
2. Yau et al. ECCO 2009. Abstract 47LBA
63
Pre-treatment Post-SECOX
SECOX Therapy Followed by Resection
64
65
New Molecular Targeting Agents in HCC
• Epidermal Growth Factor Receptor
- Erlotinib, Gefitinib, Lapatinib and Cetuximab evaluated in phase 2
single arm studies with mixed survival results
• PI3K/AKT/mTOR pathway
- Dysregulation of the pathway in 40-60% of human HCC
- Drugs evaluated in HCC e.g. Rapamycin, Everolimus
• cMET
- Overexpression of c-Met in 20-48% of human HCC
- Drugs evaluated e.g. Tivatinib, Foretinib, Cabozantinib
• Others
- IGFR inhibitor e.g. monoclonal antibody IMC-A12
- MEK inhibitor e.g. Selumetinib, BAY 86-9766
- Histone deacetylase inhibitor e.g. Belinostat
66
New Promising Target in HCC:
c-MET Inhibitor
Randomized, phase 2 trial of Tivantinib vs. placebo in 2nd line therapy for
advanced HCC (N=107; 2:1 ratio)
• Met primary endpoint of improved TTP (1.6 vs. 1.4 months) by central
radiological review: HR=0.54, P=0.04
• Patients with high MET expression in tumor:
- median TTP 6.1 weeks with placebo vs. 11.7 weeks with tivantinib
(HR: 0.43; p = 0.03)
- a 3.4-month improvement in overall survival with tivantinib compared
with placebo (7.2 vs. 3.8 months, respectively; HR: 0.38; p = 0.01)
• Patients with low MET expression in tumor: no benefit in TTP or OS
Rimassa et al. ASCO 2012; Abstract 2006
67
Conclusions
• Hepatic resection is the mainstay of curative treatment for
both early and advanced HCC confined to the liver, with
improving perioperative and long-term outcomes;
laparoscopic approach will further expand the role of
resection
• Ablation is a curative treatment for early HCC not
amenable to resection; new modalities of ablation will
increase its use
68
Conclusions
• TACE is the mainstay of palliative treatment for
unresectable advanced HCC confined to the liver; new
methods such as DEB may improve outcomes
• Transarterial radioembolization is an alternative to TACE in
selected patients, especially those with PV tumor thrombus
• Sorafenib can prolong survival of patients with advanced
HCC; new agents targeting other pathways are needed to
extend the benefit of molecular targeted therapy for HCC
69
Thank you!