Surgical Resection andAblative Therapies

for Hepatocellular Carcinoma

Kim M. Olthoff, MDAssociate Professor of Surgery

Liver Transplantation and Hepatobiliary SurgeryUniversity of Pennsylvania

Philadelphia, Pennsylvania, USA PennCancer Center

University of Pennsylvania Medical CenterPenn Transplant Center and Cancer

CenterFirst School of Medicine in United States

First Teaching Hospital in the US2nd Nationally in NIH grand dollars

Hepatobiliary Tumor ConferenceWeekly 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 surveillanceDefining high risk populations

• Cohort studies Male Advanced age HCV positivity/cirrhosis Functional impairment High AFP

• Other parameters 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 AFP <15 associated

with better outcome• Fong 1999

AFP > 400 associated with poorer outcome

• CLIP Investigators, 2000

• Prognosis of HCC Rx with OLT Pre-operative AFP not

independently associated with survival

• Iwatsuki 2000,• Shumihito 2001

AFP > 1000 RR=2.96, P=0.04

• Yao, 2001 AFP > 700

• Shetty, 2004

Tumor surveillance Defining high and low risk populations

Velazquez et al Hepatology March 2003

463 patientsAge 40-65Childs A or B

High risk:Males > 55HCVPT < 75%Plt < 75%

30%

2.3%

UTZ and AFP Q 3-6 mos

Treatment of HCC “Curative” Treatment Options

• Surgical resection is only proven curative treatment

• Spectrum of therapy• Surgical Options:

Resection OLT

• Nonsurgical “Curative” Options: Ablative therapies

• Percutaneous Ethanol Infusion

• Radiofrequency Ablation• Acetic acid Infusion

• Which is best? Surgery vs. ablation?

• Caveats 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 HCCPredictors of Recurrence

• 164 patients resected for HCC (99-2001) 55% developed recurrence with median f/u of 26

months• Median time to recurrence - 24 mos

5 yr survival 40%, 25% RF survival• Predictors of recurrence – Univariate

Tumor > 5 cm Multifocality Cirrhosis (40% of patient population) Vascular invasion Tumor satellites

• Predictors of recurrence – Multivariate Vascular invasion

Cha et al JACS 2003MSKCC

Treatment of HCC Surgical resection and HCC in cirrhosis

0102030405060708090

100

0 20 40 60 80

Months

Pro

babi

lity

(%

)

No Portal pressure, Bili <1

Portal pressure, Bili <1

Portal pressure, Bili 1

Llovet Hepatology 1999; 30:1434-40Patients selected by MazzaferoCriteria and Child’s A cirrhosis

Surgical Resection of HCCWho are candidates?

• Best candidates 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 HCCComparison 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

JapanFrance

Surgical Resection of HCCOperative Risks

• Potential complications Estimated 25-30% Bleeding from

coagulopathy and portal hypertension

Inadequate margins Liver failure Long LOS Hospital death Recurrent disease

• Strategies to decrease risk 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

X

12 mm - scope

X 12 mm - Stapler

5 mm - working

X5 mm - retractor

Unresectable385 pts (70%)

Transplant Ineligible74 pts (80% )

Transplant Eligible36 pts (20% )

Resected180 pts (30% )

HCC Pts Evaluated1990-2001

611 pts

Surgical Resection of HCCOutcome in US Cancer Center

Cha et al Ann Surg 2003, 238.315Memorial Sloan Kettering

78% with cirrhosis

Surgical Resection of HCCType of Resection in Transplant Eligible Patients

Trisegmentectomy

2 (6%)

Wedge/Single Segment

14 (39%)

Multiple Segments

12 (33%)

Lobectomy

8 (22%)

Cha et al Ann Surg 2003, 238.315Memorial Sloan Kettering

Surgical Resection of HCCOverall Survival After Resection (N=180)

100806040200

1.0

.8

.6

.4

.2

0.0

Months after Resection

Sur

viva

l

Transplant EligibleN=36

Transplant IneligibleN=144

p=.009

69%

31%

Cha et al Ann Surg 2003, 238.315Memorial Sloan Kettering

Surgical Resection of HCCRecurrence-Free Survival in Transplant Eligible Patients

Median follow-up of 35 mos

Recurrence in 20 of 36 pts

Months after Resection100806040200

Rec

urre

nce

Fre

e S

urvi

val

1.0

.8

.6

.4

.2

0.0

48%

Treatment of HCC Surgical Resection vs. OLT Three year recurrence rates

Wong LL. Amer. J Surgery. 2002;183:309-16

20-70% 0-43%

Treatment of HCC Surgical Resection vs. OLT

Five Year Survival

Wong LL. Amer. J Surgery. 2002;183:309-16

34-51% 60-69%

Treatment of HCCAblative 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 HCCGoals 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 HCCPatient Selection for RFA

• Unresectable lesions Good

• < 3 lesions• < 3 cm.

Extended• < 4 lesions• < 5 cm.

Heroic!• > 4 lesions• > 5 cm.

• Treatable under 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 HCCAblative therapy: RFA Mechanism

CoagulationNecrosis

Energy

Deposited

Local TissueInteractions

Heat Loss

= x

-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 HCCRFA: 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 HCCRFA: 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 HCCRFA 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 HCCRFA 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 HCCRFA 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 HCCRFA 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 mos post-RFA scan

Stable RFA site, NED

6 months s/p Lap. RFA HCC

OLTx 9 mos post-RFA, no viable tumor at RFA site, incidental 1 cm left lobe HCC

Ablative Therapies of HCCComplications 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 HCCFollow-up of RFA

• Imaging must be “functional”

• Dynamic CT• Gad-enhanced

MRI Early arterial

enhancement Bright on T2

Ablative Therapies of HCCFollow-up of RFA: Results

• “Complete” necrosis in 70-75%. HCC 80%-90%

• Local recurrence in 13%-60%.• Disease-free survival

1 year 56% 2 years 29% 3 years 14%

• 65% new/distant lesionsDodd GD III; Solbiati L; RSNA 2000

Ablative Therapies of HCCFollow-up of RFA vs. PEI: HCC 5 cm

PEI RF• N 50 52

# lesions 73 69 # sessions 5.4 1.1

• 1,2 yr survival 77%,43% 86%,64%• Local failure 26% 6%• Complications 0 0

Lencioni et al. Radiology 2003; 228: 235-240

Treatment of HCCExplant 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

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 HCCExplant pathology post RFA: Methods

• 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 HCCExplant pathology post RFA: Results

• 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.

Treatment of HCCExplant pathology post RFA: Conclusions

Ablative Therapy of HCCChemoembolization

• Liver has a dual blood supply

• Portal vein: 75-80%

• Hepatic artery: 20-25%

• HCC and Metastases have ~ 90% of blood supply from HA

Breedis and Young, Am J Pathol 1954; 30: 969-985.

Ablative Therapy of HCCChemoembolization

• 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 HCCChemoembolization: Eligibity at Penn

• Tissue diagnosis unless AFP>400

• Unresectable disease

• No active extrahepatic disease

• No biliary obstruction

• No contraindication to angiography

• No contraindication to HA embolization hepatic failure risk >50% tumor LDH>425 AST>100 AND bili>2

ChemoembolizationCAM-Oil-Particle

100 mg Cisplatin

50 mg Adriamycin in 8.5 cc Contrast

10 mg Mitomycin-C 1.5 cc H2O

emulsified with

0.1 cc/kg Ethiodol plus 150-250 µ PVA

Ablative Therapy of HCCChemoembolization 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 HCCChemoembolization 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 HCCOther 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 HCCOther 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 HCCSurgery 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• Resection

Survival 74-96% 25-72%

• Liver Transplantation Survival 84-90% 69-75%

• Ablation (PEI) Survival 87-98% 29-54%

Recent citations 1995-2001Bruix and Llovett Hepatology 2002

Treatment of HCCSurgery 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 neededDaniele et al, CLIP, J Clinical Gastro 2003

Ablative Therapy for HCCConclusions

• 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 HCCCombined Modalities

• TACE and surgery• TACE and PEI, RFA• RFA and surgery• Portal vein embolization and

surgery• Laparoscopic techniques

Diagnosis Determine resectability Biopsy RFA Resection

HCC < 5 cm3 HCC < 3 cm

Child B/CChild A

Single lesionLimited resection

No medical problems

“Bridge” therapy,

CE, RFA, PEIPercutaneous

Or laparoscopic

Resect? Combine withOther therapy

Ablation,Chemoembo,CombinationPercutaneousor surgical

Surgical Candidate?

No

Yes

TransplantCandidate?

No

Yes

AlgorithmSmall HCC

Consider Laparoscopy

HCC > 5 cm> 3 HCC

RadioemboSupportive

Therapy

Chemoembo - Possibly combinewith RFA

Adequateliver function,performance

Inadequateliver function

Bili<2 Bili>2

AlgorithmLarge HCC

SurgicalTherapy?

Tumorshrinkage

Treatment options for HCCBasic principles

• Assess tumor burden Up to date imaging

• Vascular invasion• Focality• AFP

• Assess liver function Cirrhosis Portal hypertension Child’s score

• Assess patient status Surgical

candidate? Transplant

candidate? Chemotherapy

candidate?

• Develop multidisciplinary approach