Transcript Document

Surgical Resection and
Ablative Therapies
for Hepatocellular Carcinoma
Kim M. Olthoff, MD
Associate Professor of Surgery
Liver Transplantation and Hepatobiliary Surgery
University of Pennsylvania
Philadelphia, Pennsylvania, USA
Penn
Cancer Center
University of Pennsylvania Medical Center
Penn Transplant Center and Cancer Center
First School of Medicine in United States
First Teaching Hospital in the US
2nd Nationally in NIH grand dollars
Hepatobiliary Tumor Conference
Weekly multidisciplinary case presentations
• Weekly discussion of all
patients with possible
hepatobiliary tumors


Review history and
imaging
Determine options for
treatment
• Review of all pathology

Determine adjuvant
therapy
• Follow-up on cases
• Potential clinical trials
• Transplant and
Hepatobiliary surgeons
• Surgical oncology
• GI surgeons
• Oncologists
• Radiologists
• Interventional
radiologists
• Nuclear Medicine
• Hepatologists
Background:
Hepatocellular carcinoma (HCC)
• One of the most common fatal tumors worldwide

80-90% of primary malignant tumors
• Mostly associated with cirrhosis


Rising incidence in US due to Hepatitis C
Seen after 20 - 30 years after HCV infection
• In the year 2000 - an estimated 8,000-10,000 deaths in US
from HCV
• Mortality rate expected to double or triple by 2015

Much of this mortality due to development of HCC
• Younger population, increasing mortality
• 2-8% annual incidence of HCC in HCV cirrhosis
• 5 year cumulative incidence 15-20%
Background:
Natural history of HCC in cirrhosis
• Prognosis – not dependent only on
tumor stage

If “Resectable”
• may exceed 70% 5 yr

Untreated intermediate/advanced
• 10-50% 3 yr survival

Severity of disease determines outcome
• Child’s A - 82% at 2 years
• Child’s B/C - 36% at 2 yrs
• Child’s C, large tumors
• no survivors > 6 months
Tumor surveillance
Defining high risk populations
• Cohort studies

Male
 Advanced age
 HCV positivity/cirrhosis
 Functional impairment
 High AFP
• Other parameters
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Proliferation rate
Irregular regeneration
Dysplasia
Viral genotype
• Columbo et al NEJM 1991
• Tsukuma et al NEJM 1993
• Liver Cancer Study Group
Cancer 1994
• Bolondi et al Gut 2001
• Degos et al Gut 2000
• Chen et al Int J Cancer 2002
• Esnaola et al Ann Surg 2003
Tumor surveillance
HCC and Alpha Feto-protein (AFP)
• Prognosis of HCC with
treatment

• Prognosis of HCC Rx
with OLT

AFP <15 associated with
better outcome
• Iwatsuki 2000,
• Shumihito 2001
• Fong 1999

AFP > 400 associated
with poorer outcome
• CLIP Investigators,
2000
Pre-operative AFP not
independently associated
with survival

AFP > 1000 RR=2.96,
P=0.04
• Yao, 2001

AFP > 700
• Shetty, 2004
Tumor surveillance
Defining high and low risk populations
UTZ and AFP Q 3-6 mos
463 patients
Age 40-65
Childs A or B
High risk:
Males > 55
HCV
PT < 75%
Plt < 75%
30%
2.3%
Velazquez et al Hepatology March 2003
Treatment of HCC
“Curative” Treatment Options
• Surgical resection is only
proven curative treatment
• Spectrum of therapy
• Surgical Options:



Ablative therapies
• Percutaneous Ethanol
Infusion
• Radiofrequency Ablation
• Acetic acid Infusion
Surgery vs. ablation?
• Caveats

Resection
OLT
• Nonsurgical “Curative”
Options:

• Which is best?


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Only 30% of patients
referred are surgical
candidates
No good randomized
controlled trials
Apples and oranges
Limitation of center
expertise and treatment
availability
Treatment of HCC
Limitations of Resection
• Majority of HCC associated
with cirrhosis

Reduced hepatic reserve
• No accurate way to measure

Increased morbidity and mortality
• Mortality now 3-10%

Surgical margins may be
compromised
• Multifocal tumors common

20 to 60% of small HCC
• Frequently underestimated
• Recurrence rates high

70-90% by 5 years
Surgical Resection of HCC
Predictors of Recurrence
• 164 patients resected for HCC (99-2001)
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55% developed recurrence with median f/u of 26 months
• Median time to recurrence - 24 mos
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5 yr survival 40%, 25% RF survival
• Predictors of recurrence – Univariate
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Tumor > 5 cm
Multifocality
Cirrhosis (40% of patient population)
Vascular invasion
Tumor satellites
• Predictors of recurrence – Multivariate

Vascular invasion
Cha et al JACS 2003
MSKCC
Treatment of HCC
Probability (%)
Surgical resection and HCC in cirrhosis
100
90
80
70
60
50
40
30
20
10
0
No Portal pressure, Bili <1
 Portal pressure, Bili <1
 Portal pressure, Bili  1
0
20
40
60
80
Months
Llovet Hepatology 1999; 30:1434-40
Patients selected by Mazzafero
Criteria and Child’s A cirrhosis
Surgical Resection of HCC
Who are candidates?
• Best candidates
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Well-compensated liver disease
 Asymptomatic
 Single lesion
 Normal bilirubin
 No evidence of portal hypertension
 No medical comorbidities
 Limited resection
 Minimize operative time
Surgical Resection of HCC
Comparison between USA, France and Japan
• Similar outcomes

31-41% 5 yr survival
• Larger tumors resected
in US than in France or
Japan

8 cm vs. 6 and 3.5 cm
• Less HCV in resection
patients in US

20% vs. 38 and 74%
• Less cirrhotics resected
in US

23% vs. 52 and 65%
US
France
Japan
Surgical Resection of HCC
Operative Risks
• Potential complications
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

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
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Estimated 25-30%
Bleeding from
coagulopathy and portal
hypertension
Inadequate margins
Liver failure
Long LOS
Hospital death
Recurrent disease
• Strategies to decrease
risk
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
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Liver anesthesiologist
Minimize crystalloid
Transfuse FFP/plts early
Keep CVP low
Minimize OR time
Minimize blood loss
• Pringle if necessary

Careful post-op
management
Port Placement for Lap. left lateral segmentectomy
lesion
X 5 mm - working
X 12 mm - Stapler
5 mm - retractor X
X
12 mm - scope
Surgical Resection of HCC
Outcome in US Cancer Center
HCC Pts Evaluated
1990-2001
611 pts
Unresectable
385 pts (70%)
Resected
180 pts (30%)
Transplant Ineligible Transplant Eligible
74 pts (80%)
36 pts (20%)
78% with cirrhosis
Cha et al Ann Surg 2003, 238.315
Memorial Sloan Kettering
Surgical Resection of HCC
Type of Resection in Transplant Eligible Patients
Trisegmentectomy
2 (6%)
Lobectomy
Wedge/Single
Segment
8 (22%)
14 (39%)
Multiple Segments
Cha et al Ann Surg 2003, 238.315
Memorial Sloan Kettering
12 (33%)
Surgical Resection of HCC
Overall Survival After Resection (N=180)
Cha et al Ann Surg 2003, 238.315
Memorial Sloan Kettering
1.0
Survival
.8
69%
Transplant Eligible
N=36
.6
.4
31%
Transplant Ineligible
N=144
.2
p=.009
0.0
0
20
40
60
80
Months after Resection
100
Surgical Resection of HCC
Recurrence-Free Survival in Transplant Eligible Patients
1.0
Recurrence Free Survival
Median follow-up of 35 mos
Recurrence in 20 of 36 pts
.8
.6
48%
.4
.2
0.0
0
20
40
60
80
Months after Resection
100
Treatment of HCC
Surgical Resection vs. OLT
Three year recurrence rates
20-70%
0-43%
Wong LL. Amer. J Surgery. 2002;183:309-16
Treatment of HCC
Surgical Resection vs. OLT
Five Year Survival
34-51% 60-69%
Wong LL. Amer. J Surgery. 2002;183:309-16
Treatment of HCC
Ablative therapies
• Direct tissue ablation

Thermal
•
•
•
•

Radiofrequency Ablation (RFA)
Cryoablation
Microwave coagulation therapy (MCT)
Laser Induced Thermotherapy (LITT)
Chemical
• EtOH
• Acetic acid
• Chemoembolization
• Radioembolization
Ablative Therapy of HCC
Goals of Ablation
• Equivalent to surgical resection in survival
and local recurrence
• Bridge therapy to stabilize disease while
awaiting transplant
• Palliation of unresectable, nontransplantable
disease
• Conversion from unresectable to resectable
Ablative Therapy of HCC
Patient Selection for RFA
• Unresectable lesions • Treatable under

Good
• < 3 lesions
• < 3 cm.
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Extended
• < 4 lesions
• < 5 cm.

Heroic!
• > 4 lesions
• > 5 cm.
US/CT/MR guidance:


Can you see it?
Can you reach it?
• Adequate clotting
function:


Platelets >50K
INR <1.5
• Adjacent structures

Bowel, gallbladder,
diaphragm, vessels, bile
ducts
Treatment of HCC
Ablative therapy: RFA Mechanism
Coagulation
Necrosis
=
Energy
Deposited
-
x
Local Tissue
Interactions
Heat Loss
Limitations for RFA:
• Lesions close to heat sink make treatment less effective
• Charring and impedance can limit size
• Proximity of bowel or diaphragm
Ablative Therapy of HCC
RFA: Technique
• Percutaneous, laparoscopic, or open

Benefits and limitations of all approaches
• Multiple overlapping burns to cover entire
tumor volume plus “surgical margin”
Ablative Therapy of HCC
RFA: Percutaneous Technique
• IV access for
sedation/analgesia.
• No abx
• 4 grounding pads
• Localize lesion
• Prep and local
anesthetic through
capsule
• Puncture with RF probe
to 5 mm from back wall
of lesion
Ablative Therapy of HCC
RFA Modality Selection:Ultrasound
• Real-time guidance
• Allows complex angled
approach
• Visualization of probe
can be difficult
• Steam obscures
margins and probe
• Imaging is inadequate
endpoint for therapy
Ablative Therapy of HCC
RFA Modality Selection:CT
• Lesions must be conspicuous
on non-contrast scans
• Access limited by gantry and
axial imaging
• Not real-time imaging
• Excellent visualization of probe
location
• Not obscured by steam
• Can do dynamic enhanced
scan to assess completion of
ablation
Ablative Therapy of HCC
RFA Device Selection:RITA
• Radial array up to 7 cm
• Measures temperature
and impedance at
multiple tines.
• Endpoint is target
temperature for a
specified time.
• Rise in impedance
prevented by reducing
power to allow
complete burn time.
Ablative Therapy of HCC
RFA Device Selection:Radiotherapeutics
• Radial array up to 4 cm
• Only measures
impedance
• Burn endpoint is
“rolloff” of current due
to rising impedance in
the coagulated tissue.
OR procedure: s/p Lap. RFA R. lobe HCC
Pre-Op CT Scan 3/02
3 mos post-RFA
scan
6 months s/p Lap. RFA HCC
Stable RFA site, NED
OLTx 9 mos post-RFA, no viable
tumor at RFA site, incidental 1 cm
left lobe HCC
6 mos post-RFA
scan
Ablative Therapies of HCC
Complications of RFA
•
•
•
•
•
•
•
Pain
Fever
Vasovagal/Hypotension
Oversedation
Pleural Effusion (0.6%)
Pneumothorax
Hemorrhage (0.5%)
•
•
•
•
•
•
Ascites
Cholangitis Abscess
Hepatic Infarct
Biliary Stricture
Tract Tumor Seeding
Skin burns
Ablative Therapies of HCC
Follow-up of RFA
• Imaging must be
“functional”
• Dynamic CT
• Gad-enhanced MRI


Early arterial
enhancement
Bright on T2
Ablative Therapies of HCC
Follow-up of RFA: Results
• “Complete” necrosis in 70-75%.

HCC 80%-90%
• Local recurrence in 13%-60%.
• Disease-free survival
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

1 year 56%
2 years 29%
3 years 14%
• 65% new/distant lesions
Dodd GD III; Solbiati L; RSNA 2000
Ablative Therapies of HCC
Follow-up of RFA vs. PEI: HCC  5 cm
PEI
RF
• N
50
52

73
5.4
69
1.1
# lesions
 # sessions
• 1,2 yr survival
• Local failure
• Complications
77%,43% 86%,64%
26%
6%
0
0
Lencioni et al. Radiology 2003; 228: 235-240
Treatment of HCC
Explant pathology post RFA: Methods
• Patients listed for OLT at Penn


Retrospective study, between 1996-2004
28 patients (40 HCC) had neoadjuvant image-guided
therapy 1-392 days prior to OLT
• Solitary lesions: (19 pts) 2.2-5.0 cm
• Multifocal HCC (9 pts) 1.1-6.0 cm diameter
• Exemption to UNOS criteria: 4 patients
Soulen et al 2004
Treatment of HCC
Explant pathology post RFA: Methods
Pathology
• Viable tumor was seen in 35/40 treated
nodules, but only 1 patient is completely free
of tumor
• 11 of the treated HCC’s had either satellite
nodules or microvascular invasion
• 3 patients had macroscopic extrahepatic
extension or portal vein tumor thrombus, from
2 treated HCC’s and from 1 new lesion
Treatment of HCC
Explant pathology post RFA: Results
• 35 of the 40 treated HCC had residual viable
tumor (87.5%)
• 27/28 patients had viable tumor anywhere in
the explanted liver at the moment of OLT (total
of 55 nodules)
• In 6/18 patients, imaging studies were false
negative for treated and occult tumors
• Recurrence-free post transplant survival is 85%
with a follow-up of 1-61 months (mean 15 mos)
Treatment of HCC
Explant pathology post RFA: Conclusions
• Although image-guided therapy is proven to
be effective to provide local control of HCC,
viable local or remote tumor is identified on
explanted liver in the majority of patients
• Contrast enhanced follow-up CT and MRI
tend to underestimate the amount of viable
tumor in the treated lesions and miss
additional sites of disease.
Ablative Therapy of HCC
Chemoembolization
• Liver has a dual
blood supply
• Portal vein: 75-80%
• Hepatic artery: 2025%
• HCC and
Metastases have ~
90% of blood supply
from HA
Breedis and Young, Am J Pathol 1954; 30: 969-985.
Ablative Therapy of HCC
Chemoembolization
• No standards:

Patient selection
 Number and type of embolics
 Number and type of drugs
 Volume of liver treated
 Frequency and end-point of treatment
 Measurement of response
Ablative Therapy of HCC
Chemoembolization: Eligibity at Penn
• Tissue diagnosis

unless AFP>400
• Unresectable
disease
• No contraindication
to angiography
• No contraindication
to HA embolization
• No active
extrahepatic disease

hepatic failure risk

>50% tumor
• No biliary
obstruction

LDH>425

AST>100 AND

bili>2
Chemoembolization
CAM-Oil-Particle
100 mg Cisplatin
in
50 mg Adriamycin
10 mg Mitomycin-C
8.5 cc Contrast
1.5 cc H2O
emulsified with
0.1 cc/kg Ethiodol plus 150-250 µ PVA
Ablative Therapy of HCC
Chemoembolization RCTs: Barcelona Study
• 112 Patients with HCC
• Majority had Hepatitis C
• Stratified by tumor
burden and Okuda
stage
• Patients randomized to
CE, bland embolization,
or supportive care
• CE had 2 year
survival of 63% vs.
50% with bland
embo and 27% with
no therapy
Llovet et al. Lancet 2002; 359: 1734-39.
Ablative Therapy of HCC
Chemoembolization RCTs: Hong Kong Study
• 80 Patients with HCC
• 80% HBSAg positive
• Equal proportions of
Okuda I/II
• Randomized to CE or
supportive care
• CE performed with
cisplatin/lipiodol/Gelfoam
sponge
• 2 year survival 31%
vs. 11%
Lo, Hepatology 2002; 35: 1164-71.
Ablative Therapy of HCC
Other Ablative Techniques
• Laser-induced
thermotherapy (LITT)
• Microwave coagulation
therapy (MCT)
• Chemical

PEI
• Safe, inexpensive, easy to
perform. Minimal side effects

Acetic acid
• Diffuses into liver better
• Must be small lesions < 3 cm
• One study showing superior
survival to PEI
Ablative Therapy of HCC
Other Embolization Techniques
• Radioembolization

Theraspheres, SIR-Spheres
• Yttrium-90 microspheres

Uses hypervascularity of HCC
to deliver high dose local
radiation via  source
• Small series (27 pts) showed
reduction in size in 90%,
complete tumor destruction in
8 on histology
• Concern for radiation hazards
Treatment of HCC
Surgery vs. Percutaneous local ablation therapy
• Comparison of surgery vs. PLAT
• Surgical resection (5 studies)

Recurrence free survival
• 3 yr 38-64%
5 yr 23-58%
• PLAT (7 studies – 4 PEI, 3 RFA)


Recurrence free survival
• 2 yr 41-64%
4 yr 18-39%
RFA superior to PEI
Lau et al, Annals of Surgery 2003
Treatment of HCC
Surgical Resection vs. OLT vs. ablation
1 yr
5 yr
74-96%
25-72%
• Resection

Survival
• Liver Transplantation

Survival
84-90%
69-75%
• Ablation (PEI)

Survival
87-98%
29-54%
Recent citations 1995-2001
Bruix and Llovett Hepatology 2002
Treatment of HCC
Surgery vs. Percutaneous Ethanol Injection
• Compared resection vs. PEI for small single
nodule HCC


197 eligible, 82 matched
Matched for age, CTP, date of diagnosis
• 1 and 3 yr survival



PEI
91% 65%
Resection
82% 63%
Concluded no significant difference
• Higher cost and morbidity with resection
• Randomized trial needed
Daniele et al, CLIP, J Clinical Gastro 2003
Ablative Therapy for HCC
Conclusions
• Thermal ablation, chemoembolization,
radioembolization part of multimodality
approach to HCC
• Paucity of randomized trials
• Unstable and evolving technology
• Combination of therapies likely to be of most
benefit
• Multidisciplinary approach essential
Chemoembolization + RFA
Therapy of HCC
Combined Modalities
•
•
•
•
•
TACE and surgery
TACE and PEI, RFA
RFA and surgery
Portal vein embolization and surgery
Laparoscopic techniques

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
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
Diagnosis
Determine resectability
Biopsy
RFA
Resection
Algorithm
Small HCC
HCC < 5 cm
3 HCC < 3 cm
Surgical Candidate?
No
Percutaneous
or surgical
Consider Laparoscopy
Child B/C
No
Ablation,
Chemoembo,
Combination
Yes
Transplant
Candidate?
Child A
Single lesion
Limited resection
No medical problems
Yes
“Bridge”
therapy,
CE, RFA, PEI
Percutaneous
Or laparoscopic
Resect
? Combine with
Other therapy
Algorithm
Large HCC
Surgical
Therapy?
HCC > 5 cm
> 3 HCC
Adequate
liver function,
performance
Inadequate
liver function
Bili<2
Tumor
shrinkage
Chemoembo Possibly combine
with RFA
Radioembo
Bili>2
Supportive
Therapy
Treatment options for HCC
Basic principles
• Assess tumor
burden

Up to date imaging

• Vascular invasion
• Focality
• AFP

• Assess liver function



• Assess patient
status
Cirrhosis
Portal hypertension
Child’s score

Surgical candidate?
Transplant
candidate?
Chemotherapy
candidate?
• Develop
multidisciplinary
approach