Current Surgical
Management of
Hepatoma/HCC
Panayiotis Hadjicostas
M.D., PhD, F.A.C.S.
Chief, Department of Surgery
LARNACA GEN. HOSPITAL
Hepatocellular Carcinoma
17,000 new cases / year in USA
major cause of cancer death worldwide (5th)
•Associated with chronic liver disease (70 – 90%)
•10 – 30 % amenable & transplant or resection
no treatment: median survival 6-20 months
doubling time: median 6 months (range 1-19)
Ca-A Cancer 2001; 51:15-36
Semin Liv Dis 1993; 13:374-383
Epidemiology
Alterkruse et al. JCO 2009
Mortality
Alterkruse et al. JCO 2009
Cirrhosis
Cancer
B Vs C Does it matter?
• Hepatitis B:– 80% cirrhosis, most Child’s A, less portal HTN
– Often larger in size but tend to be more well –differentiated with less vascular invasion
– Effective medication to treat HBV
– Incidence of HCC is 0,5 – 2% per year
• Hepatitis C:– 100% cirrhosis, most Child B,C with portal HTN
– Moderately – differentiated, more likely to have microvascular invasion even in small tumors (2 – 3 cm)
– Incidence of HCV is 1,4 – 5,8% per year
– Correlation with degree of fibrosis and continue to rise over time
HCC Vs CirrhosisMust consider survival related to cirrhosis independed of malignancy.
Child –Turcotte- 1year Liver
Pugh score Related mortality
5-6 (A) 0%
7-9 (B ) 20%
10-15(C) 55%
HCC in a cirrhotic Liver
with PHTN
Schneider Surg. Clin.N. America 2004
Therapeutic Approach
Typical Malignancy
Liver Specific Factors
Cirrhosis / Fibrosis
Ascites
Portal Hypertension
Thrombocytopenia
Bilirubin
Size of Remnant Liver
Tumor Specific Factors
Size
Location
Number
Relation to adjacent
structures
Distant Spread
Hepatocellular Carcinoma
Hepatocellular Carcinoma
Treatment and disease extend
• Local– Simple Tumor
– Milan Criteria
• Regional– Multifocal, liver
confined
• Systemic– Extrahepatic
metastasis
Resection
Transplantation
Ablation
Embolization
?Chemotherapy
Chemotherapy
?Embo + Chemotherapy
Disease
Extent
Performance
Status
Hepatic
Functional
Reserve
Better Worse
Worse
Surgical Clinical Decision Making
Surgical Treatment Options
Ablation:
Small Lesions
Inoperable/Unresectable
Bridge
Resection:
All size HCC
Normal liver and early
fibrosis/cirrhosis
Transplantation:
Single 5 cm and
Multiple 3 cm up to 3
Advanced cirrhosis
Classical Contraindications
• Poor liver function (especially
portal HTN)
• Multifocal disease
• Major vascular invasion
• Major biliary invasion
Recurence
• 75 – 100 % overall
• 78 – 96 % Intrahepatic
– Intrahepatic metastasis
– Micro/ macro – portal vein invasion
– New primary tumor
– Ongoing carcinogenesis
Poon Ann Surg 2000
Surgical Resection: Liver Factors
• Quality of underlying liver
• Quantity of underlying liver
0
10
20
30
40
50
60
70
80
90
100
Surgery in Patients with CirrhosisNon-transplant Operative Mortality by CTP Class
Garrison et al, Ann Surg 1984
Mansour et al, Surgery 1997
Garrison et al.
Mansour et al.
CTP-A CTP-B CTP-C
Peri
-Opera
tive
Mort
alit
y%
5-10%
9-30%
50-90%
0 1 2 3 4 5 6 7
Years
Ris
k o
f Liv
er
Decom
pensation (
%)
≥ 10 mmHg
< 10 mmHg
Ripoll, et al. Gastroenterology 2007Bruix J, et al. Gastroenterology 1996
Non-decompensated
(n = 18)
Decompensated
(n = 11)
0
5
10
15
20
HP
VG
(m
mH
g)
Surgery in Patients with CirrhosisHepato-Portal Veinous Gradient (HPVG)
HPVG
1.0
0.8
0.6
0.4
0.2
0.0
0 5 10 15 20 25 30 0 10 20 30 40 50 60 70 80 90
Days Following Surgery Days Following Surgery
100
80
60
40
20
0
Peri
-Opera
tive S
urv
ival (%
)
P < 0.001 P < 0.001
― 6-10 (n=432)― 11-15 (n=243)― 16-20 (n=68)― 21-25 (n=15)― 26-39 (n=10)
Teh et al. Gastroenterology 2007
Surgery in Patients with CirrhosisBiologic MELD and Post-Operative Outcome
30-Day Mortality 90-Day Mortality
Liver Volumetry
Future Liver Remnant
(FLR)
40-50%
Portal Vein Embolization (PVE)
R. Liver L. Liver
Hepatic Hypertrophy
Pre-operative portal vein embolization
ANNALS OF SURGERY
Vol. 237, No. 2, 208–217
© 2003 Lippincott Williams & Wilkins, Inc.
Portal Vein Embolization Before Right
Hepatectomy: Prospective Clinical Trial
Olivier Farges, MD, PhD,* Jacques Belghiti, MD,*
Reza Kianmanesh, MD,* Jean Marc Regimbeau,
MD,* Roberto Santoro, MD,* Valerie Vilgrain, MD,†
Alban Denys, MD,† and Alain Sauvanet, MD*
From the Hepatobiliary Service and Department of *Digestive
Surgery and †Radiology, Beaujon Hospital, Assistance
Publique, Clichy, France
Variable
Pre-Operative PVE
Yes (14) No (14) p
Mortality 1 1 0.8
Morbidity 7 13 0.012
Liver Failure 1 7 0.01
Hospital Stay
(days)13 4 30 15 0.002
Post-operative Course After R. Hepatectomy:
Patients with Chronic Liver Disease
Improved outcome in patients with chronic liver disease
Hepatocellular Carcinoma: Resection
Surgical Resection: Tumor Factors
• Tumor size
• Tumor number (multi-focality)
• Presence of vascular invasion
Barcelona-Clinic Liver Cancer Classification and Treatment Schedule
RFAblation
Curative treatment Palliative treatment
Intermediate Stage HCC
or
“Group 2”
???
Liau et al. Cancer; 104:1948-1955, 2005
Tumor Size
Months
250200150100500
Pro
port
ion
Su
rviv
ing
1.0
.8
.6
.4
.2
0.0
T1
T2
T3
T4
P < .001
Tumor Size ≥ 10 cm
Pawlik et al. Arch Surg; 140:450-457, 2005
Vauthey et al. J Clin Oncol; 20:1527-1536, 2002
Tumor Size + Tumor Number
Solitary Tumors Multiple Tumors
Vauthey et al. J Clin Oncol; 20:1527-1536 2002
Morbidity Mortality
Ng et al. 27 2.2
Wang et al. - 2.7
Torizilli et al. 26 0
Bellevance et al. 49 2
Teh et al. - 0
Resection of Multi-Nodular HCC
Percent (%)
Overall Survival 25-30%
Disease-Free Survival 18%
Wang et. al. 2008
Resection of Multi-Nodular HCC
Multifocal Disease
• Classical Contraindication
• Intrahepatic Metastasis Vs synchronous
primary Tumors
• Very high recurrence( Universal?)
• Poor Survival ( < 25% 5 year)
• Selected patients can do well
• Selection criteria not well studied
• Ng Ann Surg Onc 2005
Major Vascular Invasion
Resection: Major Vascular Invasion
Portal Vein 5-yr Survival
Vp0 50%
Vp1 31%
Vp2 26%
Vp3 12%
Vp4 7%
Hepatic Vein 5-yr Survival
Vv0 43%
Vv1 19%
Vv2 11%
Vv3 0%
Ikai et al. Surg Oncol Clin N Am; 12:65-75, 2003
Major Vascular Invasion
• Advanced Disease
• Technically challenging and risky
• Associated with large tumors
• Near Universal recurrence
• Poor survival (<20%)
• Occasional long term survival
Pawlik, Surgery 2005
Pawlik et al. Surgery; 137:403-410, 2005N=101
Months
2001751501251007550250
Pro
porti
on S
urv
ivin
g
1.0
.8
.6
.4
.2
0.0
No or minimal fibrosis
Moderate or severe fibrosis
P = 0.001
Resection: Major Vascular Invasion
Resection: Overall Survival for “All-
Comers”0.0
00.2
50.5
00.7
51.0
0
Perc
ent S
urv
ival
0 1 2 3 4 5Years
Resection Transplant
Survival by Surgery Type
Transplantation
Resection
66%
46%
79%
71%
P < 0.01
Bellavance , Pawlik. JOGS 2008.
65% 5-year survival
Resection Vs Transplantation
When is Resection “As Good” or Better
Normal Remnant Liver Parenchyma
• Child’s A Cirrhotic
– Total bilirubin (<1,5 mg/dl)
– Absence of portal HTN
• Platelets: >100000
• No varices
• Single Tumor
– Multiple Tumors often metastatic
– Hepatitis B Vs other
Ablation:
Small Lesions
Inoperable/Unresectable
Bridge
Resection:
All size HCC
Normal liver and early
fibrosis/cirrhosis
Transplantation:
Single 5 cm and
Multiple 3 cm up to 3
Advanced cirrhosis
Surgical Treatment Options
Hepatocellular Carcinoma: Transplantation
1. Only solid neoplasm for which transplantation
plays a role
2. Treats both the malignant disease and the
underlying hepatic parenchymal disease
3. Not restricted by liver function
4. Limited by:
• Disease extent (size and number: Milan criteria)
• Organ availability
Author N Recurrence 5-Year Survival
Ringe ’91 61 - 15%
Iwatsuki ’91 105 43% 36%
Pichlmayr ’92 87 - 20%
Bismuth ’93 60 54% 49% (3 yr)
Moreno ’95 38 32% 48%
Results of early series: broad selection criteria
Hepatocellular Carcinoma: Transplantation
Author N Recurrence 5-Year Survival
Mazzaferro ’96 48 8% 74% (4 yr)
Bismuth ’99 45 11% 74%
Llovet ’99 79 4% 75%
Jonas ’01 120 16% 71%
Hemming ’01 112 - 57%
Results of early series: restrictive criteria
Hepatocellular Carcinoma: Transplantation
Expanding the Criteria: UCSF
• Single tumor < 6.5 cm or up to 3 nodules each less
than 4.5 cm and a total diameter less than 8 cm
• 1 year survival 90% and 5 year survival was 75%
• 1 yr survival 50% in patients with tumors larger than
6.5 cm
• Size cutoffs were based on retrospective review of
explants, not preoperative imaging
Yao FY, et al. Hepatology 2001;33:1394-1403.
61 patients with disease exceeding UNOS T2
Solitary tumor: > 5 cm ≤ 8 cm
2 – 3 tumors: > 3 cm ≤ 5 cm
4 – 5 tumors: < 3cm
Down-staging protocol (≥ 3-month waiting period before transplantation)
Successful down-staging in 43 patients
Treatment failure in 18 patients
Tumor progression (15), death without OLT (3)
Yao et al. Hepatology 2008;48:819
Yao et al. Hepatology 2008;48:819
Follow-up (years)
Kap
lan
-Me
ier
Pro
ba
bilit
y
0 1 2 3 4
0.0
1.0
0.8
0.6
0.4
0.2
Intention-to-treat Survival (n = 61)
Treatment Failure (n = 61)
69%
32%
Survival (4-year)
Intention-to-treat = 69%
Post-transplant = 92%
No recurrent HCC after transplantation
Median follow-up = 25 months
Should LDLT Be Preformed for
Patients With HCC Exceeding the
Milan Criteria?• LDLT in pts outside Milan Criteria can be considered
justified since it involves the use of an individually available graft without penalizing other pt on the waiting list
• LDLT offers acceptable survival to pt who would otherwise die from liver failure following resection or
HCC / intrahepatic recurrence (SalvageTransplantation/… Ethical dilemmas..)
• The proportion of HCC pts not fulfilling the Milan Criteria that could be cured by LT ranges from 25-50%
Ablation:
Small Lesions
Inoperable/Unresectable
Bridge
Resection:
All size HCC
Normal liver and early
fibrosis/cirrhosis
Transplantation:
Single 5 cm and
Multiple 3 cm up to 3
Advanced cirrhosis
Surgical Treatment Options
Hepatocellular Carcinoma: Ablation
Ablation: radiofrequency ablation (RFA), microwave
Efficacy limited by several factors:
Size (> 5 cm)
Location (major vascular structures)
Tumor burden (multifocal disease)
Short follow-up, inadequate assessment of response
Associated morbidity and mortality
Analysis of ˜ 4000 procedures in Japan
♦Morbidity = 8%
♦Mortality = 0.3%
Kasugai et al Oncology 2007;72 (suppl 1):72
Radiofrequency Ablation
Ideal Tumors for RFA are:
•Preferably <3cm but up to 5cm in diameter
•<4 in number
•Completely surrounded by hepatic parenchyma
• 1cm deep tp the liver capsule
•2cm from large hepatic or portal veins
•Not immediately adjacent to the diaphragm,
gallbladder or bowel.
Thermal Ablation:
HCC vs. Colorectal Liver Metastasis
Soft Tumor + Hard Liver Hard Tumor + Soft Liver
Resection vs. ablation for small HCC
Petrowsky et al J Hepatol 2008;49:502Hasegawa et al J Hepatol 2008:49;589
Hepatocellular Carcinoma: Ablation
HCC: Resection vs RFA (single < 4cm Lesion)
148 Patients (Hep B/C)
Refuse Surgery Resection (93)
RFA (55)
No difference in 1 and 3yr recurrence free and overall survival
Hong et al, J. Clin.
Gastroenterology 2005; 39(3): 247
NO DIFFERENCE
FACTOR CATEGORY # CASES % RECURRENCE
Size
> 5 cm 31 58
3 – 5 cm 106 25
≤ 3cm 1680 14
Pathology
HCC/Met Colorectal 3132 15
Other Metastatic 1046 10
Met Neuroendocrine 330 3
SubcapsularYes 13 62
No 57 16
Vascular
Proximity
Yes 104 37
No 271 3
Approach
Percutaneous 3002 16
Laparoscopic 515 6
Open 907 4Mulier et al Ann Surg 2005;242:158
Local recurrence after RFA: 5224 treated tumors
Hepatocellular Carcinoma: Ablation
Hepatology 2008;47:89
218 patients with HCC
Solitary
≤ 2 cm
1995 – 2006
5 Centers
One or two sessions
Follow-up = 31 months
Major morbidity = 2%
6 Treatment failures (2.7%)
Survival (5-year)
Disease-free = 20%
Overall = 55%
Operable = 68%
291 patients 2001 – 2004
≤ 3 tumors
> 3 cm but < 7.5 cm
Free of major vasculature
Child’ A or B
Randomized: TACE, RFA, both
1378 patients screened
1087 excluded
Results:
45% solitary tumors
75% ≤ 2
3 – 4 courses of therapy
Median survival
TACE 24 months
RFA 22 months
TACE + RFA 37 months
TACE
RFA 2nd RFA
Pre-RFA Post-RFA
Management of Hepatoma
When Surgical Options are not Available
Perc RFA
TACE
Y-90
Sorafenib
Summary: Locoregional Therapy
What we know:
• Effective Palliation in non
transplant/surgical pt.
What we think we know:
• Bridging to Transplant
• Downstaging
Y-90RFA
TACE
Summary
• In patients with ‘small’ HCC: good results can be
obtained with all modalities
• Resection
• Best alternative for advanced tumors with well
preserved liver function
• Transplantation
• Best alternative for advanced cirrhosis or multifocal
disease
• Ablation
• Reasonable as 1st line therapy in patients with small
(2 - 3cm) tumors
RESECTIONTRANSPLANTATION
Individualize Therapy NOT Dogmatic Approaches
• Underlying liver disease
• Tumor size, number, vascular invasion
• Location of lesion
• Performance status
• Local expertise
• ? Other factors: hepatitis status, wait time, etc.
ABLATION