1) Liver transplantation provides the best chance of cure for hepatocellular carcinoma (HCC) in cirrhotic livers, but is limited by organ availability. The Milan criteria, which select patients with very early HCC, have been expanded to include slightly larger tumors without reducing survival. 2) Patients with HCC can be prioritized for liver transplant by receiving exception MELD scores, but these are only granted if tumors can be downstaged within defined criteria through treatments like ablation. Successful downstaging selects less aggressive tumors and predicts good post-transplant survival. 3) While downstaging expands access to transplant for some patients with larger tumors, eligibility criteria remain unclear as very advanced disease carries a

1. Justin McWilliams, MD
Assistant Professor
Interventional Radiology
UCLA

2. Justin McWilliams, MD
Assistant Professor
Interventional Radiology
UCLA

3. Demographics
Carcinogenesis
Diagnosis
Staging

4.  4th
leading cause of
global cancer death
 Incidence has tripled in
the last 3 decades, and
continues to increase
in the Western world
Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

5.  In western world, cirrhosis precedes HCC
in 95% of cases
 Chronic liver injury -> regeneration ->
dysplasia -> malignancy
• Hepatitis C cirrhosis (3%/year)
• Hepatitis B cirrhosis (2.5%/year)
• Alcoholism (1.6%/year)
• Hemochromatosis (1.5%/year)
• Autoimmune hepatitis (1.1%/year)
• Hepatitis B infection (0.5%/year)
• Nonalcoholic steatohepatitis (unknown)
• Less commonly in Wilson’s disease, PBC, PSC
Bruno S, Silini E, Crosignani A, et al. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study. Hepatology.
1997;25:754–75.
Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis
type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology. 1995;21:77–8

6.  Screening at-risk patients saves lives
• HCC detected after onset of symptoms has
dismal prognosis (0-10% 5-year survival)
• Screening reduces HCC-related mortality by
37%, despite <60% adherence
 Ultrasound +/- AFP q6 months in
patients with cirrhosis and/or Hepatitis
B infection
• Ultrasound sensitivity for HCC is 65-80%
• AFP >20 is 60% sensitive, 40% specific for
HCC
 Ultrasound sensitivity is reduced
(<50%) in severely cirrhotic livers
• Multiphase CT or MRI should be considered
for screening
Kemp W, et al. Survival in hepatocellular carcinoma: impact of screening and etiology of liver disease. J Gastroenterol Hepatol 2005;20:873-881.

7.  Imaging has made biopsy unnecessary in
the vast majority of lesions
 Subcentimeter lesions, particularly if non-
enhancing, are unlikely to be HCC
• Q3 month surveillance for 2 years
 1-2 cm enhancing lesions in cirrhotic liver
have a high risk of HCC
• But if venous washout absent, ~25% are not HCC
 HCC biopsy carries ~2% risk of needle tract
seeding
Lencioni R. Evolving strategies in the diagnosis of hepatocellular carcinoma. J Hepatol 2011;54:184-186.
Shimizu A,, et al. Cirrhosis or chronic hepatitis: evaluation of small (<or= 2-cm) early-enhancing hepatic lesions. Radiology 2003;226(2):550–5.
Bartolozzi C, et al. HCC diagnosis with liver-specific MRI – close to histopathology. Dig Dis 2009;27:125-130.

8.  HCC patients are difficult to
stage prognostically
• These patients have two deadly
diseases
 Survival depends on
• Tumor stage
• Underlying liver function
• Physical condition of the patient
 An effective staging system
should consider all 3 variables

9.  TNM classification
• Does not consider
underlying liver function
• Recently revised,
requires validation
 Okuda and CLIP
• Consider tumor features
and hepatic function
• Rather inaccurate for
prognosis, especially in
patients with early HCC

10.  Barcelona Clinic Liver Cancer
(BCLC)
• Includes
 Tumor-related parameters (size, number,
vascular invasion)
 Patient’s clinical condition (ECOG)
 Liver function (Child class)
• Links stage of disease to treatment
strategy
• Greatest predictive power for survival
rates
 Most comprehensive and widely
accepted staging system for HCC

11. Liver transplantation
Surgical resection
Percutaneous ablation
Transarterial chemoembolization
Yttrium-90 radioembolization
Systemic chemotherapy

12. Liver transplantation
Indications and outcomes
MELD
Downstaging
Bridging
Surgical resection
Percutaneous ablation
Transarterial chemoembolization
Yttrium-90 radioembolization
Systemic chemotherapy

13.  OLT is the best available curative treatment
for HCC in cirrhotic livers
• Cures the cancer
• Cures the underlying cause
 Limited by disease extent, organ availability

14.  Originally,
OLT was reserved for
patients with contraindications
to resection
• Tumor too large
• Too many tumors
• Insufficient hepatic reserve
 5-year survival was 15-40%
• Much worse than OLT for benign
disease

15.  Transplant for early HCC yielded 4-
year survival of 85%
• Single lesion up to 5 cm
• 3 lesions up to 3 cm
• No vascular invasion / mets
 “Milan criteria”
• Similar to outcome of OLT in cirrhotics
without HCC
• Tumor recurrence rate ~10%
• Adopted by UNOS as selection criteria
Mazzaferro V. et al. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N
Engl J Med 1996.

16.  Transplant
for slightly larger
HCC yielded similar survival
• Single lesion up to 6.5 cm
• 3 lesions up to 4.5 cm (max total
tumor size up to 8 cm)
• 5-year survival 75%
 “UCSF criteria”
• Prospectively validated
Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact
survival. Hepatology. 2001;33:1394–1403.
Yao FY, Xiao L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative
imaging. Am J Transplant. 2007;7:2587–2596

17.  Largest experience has been at
UCLA
• 22 years, 467 patients
 5-year survival after OLT
• Within Milan criteria: 86%
• Exceeds Milan, within UCSF: 81%
• Beyond UCSF: 32%
 Supports expansion of criteria
Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with
467 patients at UCLA. Ann Surg. 2007;246:502–509.

18.  Imaging-based selection of patients for OLT has
limitations
• Poor reproducibility of tumor measurements
• Weak correlation between tumor size/number and biologic
behavior
• High frequency of under- or over-staging (20-25%)
 Toronto criteria
• Any tumor size/number
• No systemic symptoms or vascular invasion
• Not poorly differentiated on biopsy
 189 patients within Milan: 5-year survival 72%
 105 patients beyond Milan: 5-year survival 70%
• Biopsy and aggressive bridging therapy improved survival (79%
vs 61% 5-year survival)
Dubay D, Sandroussi C, Sandhu L, et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an
exclusion criterion. Ann Surg 2011;253:166-172.

19.  Model for End-Stage Liver Disease
• Primary determinant of when you get a liver MELD =
3.78 [Ln T bili] + 11.2 [Ln INR] +
 Patients with HCC need to be prioritized for 9.57 [Ln creatinine] + 6.43
transplant (MELD exception points)
 T1 patients (single lesion <2 cm) get no MELD Typical observed 3-month
score condition mortality
bonus
• May be a benign lesion <10 Lead normal life 4%
10-19 Variable, normal to 27%
mildly disabled
 T2 patients (single lesion 2-5 cm, or 3 lesions
20-29 Unable to work, 76%
up to 3 cm) get a MELD score of 22 frequent medical care
• Score boosted by 10% q3 months 30-39 Variable, sick 83%
• This continues until patient is transplanted, dies, or >39 LOC, intubated, ICU 100%
drops out due to tumor progression
• Patients in most regions will get a transplant by ~1
year (or not…)

20.  Treatment with TACE or RFA can downstage
tumors into Milan criteria
 UCSF criteria for downstaging
• One lesion 5-8 cm
• 2-3 lesions up to 5 cm, total tumor diameter up to 8 cm
• 4-5 lesions up to 3 cm, total tumor diameter up to 8 cm
 3 months after tumor is downstaged, exception
points for OLT are granted
• “Ablate and wait” crudely assesses tumor biology
Yao FY, Kerlan RK, Jr, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an
intention-to-treat analysis Hepatology 2008

21.  Patients with tumors exceeding Milan do well with
transplant after downstaging
• Success of downstaging 24-90%
• If downstaging is successful, post-transplant 5-year survival
55-94%
 Successful downstaging selects less aggressive
tumors
• Able to be downstaged
• Remains downstaged over a waiting period of 3-6 months
• Infiltrative tumors and high AFP predict downstage failure
 Eligibility for downstaging is unclear
• Only tumors slightly beyond Milan?
• Any tumor without major vessel invasion or extrahepatic
disease?
Barakat O, et al. Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: an intention-to-
treat analysis. Liver Transplantation 2010;16:289-299.

22.  Systematic review of downstaging
for HCC beyond Milan criteria
 8 studies, 720 patients
 Successful downstaging 24-69%
 3-year survival 79-100%
 5-year survival
Barakat O, et al. Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: an intention-to-
treat analysis. Liver Transplantation 2010;16:289-299.

23.  “Downstaging with a subsequent interval
of observation to assess biologic
aggressiveness should be considered for
patients beyond Milan criteria.
Downstaged patients should be
considered for MELD exception points.”
Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

24.  Natural history of patients with
HCC within Milan criteria, at 1
year
• 70% will have tumor growth
• 20% will develop vascular invasion
• 9% will develop metastases
 Risk of drop-out is up to:
• 11% at 6 months
• 57% at 12 months
• 75% at 18 months
Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

25.  87 patients listed for OLT  52 patients listed for OLT
• 43 non-TACE and 22 TACE • Bridged with RFA
patients were comparable • Complete tumor necrosis in 85%
• TACE group had drop-off rate of • Drop-off rate of 6% at 1 year
3%
• Post-OLT survival of 76% at 3
• Non-TACE group had drop-off years, no HCC recurrence
rate of 15%

26.  “Bridgingtherapy with TACE and RFA
have low morbidity, favorable HCC
response, and probably reduce drop-out
for patients with wait times >6 months”
Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

27.  “OLT is the preferred treatment for patients
with cirrhosis and HCC meeting Milan
criteria”
 “OLTshould be considered on a highly
selective basis for patients beyond Milan
but within UCSF criteria”
Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

28. Liver transplantation
Surgical resection
Indications and outcomes
Portal vein embolization
Percutaneous ablation
Transarterial chemoembolization
Yttrium-90 radioembolization
Systemic chemotherapy

29.  Standard treatment for resectable HCC in
patients without cirrhosis
 Only~5% of HCC patients in the Western
world qualify
 Perioperative mortality rates
• Cirrhotic liver: 7-25%
• Non-cirrhotic liver: <3%
Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

30.  Advantages
• No restrictions on tumor size or number (within a lobe)
• Macrovascular invasion acceptable
• No obligatory waiting time
• Allows complete pathologic evaluation
 Disadvantages
• Only feasible in non-cirrhotic or mildly cirrhotic livers without portal
hypertension
• Precancerous cirrhotic liver remains
• Perioperative mortality about 5%
• Significant post-operative morbidity
Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

31.  Overall 5-year survival for hepatic resection in HCC is 25-50%
• If solitary tumor and non-cirrhotic liver, 5-year survival is 41-74%
• If HCC is multifocal or has vascular invasion, 5-year survival is <25%
 Liver function and portal hypertension are important predictors of
post-operative liver failure and 5-year survival
• Normal serum bilirubin and no portal HTN: 70%
• Normal serum bilirubin and portal HTN: 50%
• Elevated serum bilirubin and portal HTN: 30%
 Post-resection recurrence rates are high
• 70% at 5 years
• >80% intrahepatic; usually due to dissemination from primary tumor
• Associated with high AFP, larger/more numerous tumors, and vascular invasion
Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure.
Gastroenterology 1996;111(4):1018–22..

32.  Liver resection is often limited due to inadequate
volume of the future liver remnant
• Normal patients can survive if 20% of liver volume
remains
• Post-chemotherapy patients need 30% of liver
• Patients with fibrosis/early cirrhosis need 40% of liver
 Portal vein embolization can pre-operatively
enlarge the future liver remnant
• Redirection of nutrient-rich portal vein blood enlarges the
FLR
• May enable resection in patients who would otherwise not
be candidates
De Baere T, et al. Preoperative portal vein embolization: indications and technical considerations. Tech Vasc Interv Radiol 2007;10:67-78.
Memorial Sloan-Kettering Cancer Center. “Portal vein embolization.” Patient brochure, 2005.

33.  Technical considerations
• Access ipsilateral (into tumor bearing lobe)
• 5F sheath and pigtail portogram; consider pressures
• Kumpe catheter and microcatheter for segment IV (if needed)
• Simmons-2 or Sos-2 catheter for right portal branches
• 100-700 micron Embospheres followed by coils; or NBCA
• Final portogram
• Embolize access tract with coils or gelfoam
 Results at 4 weeks post-PVE
• 53-90% hypertrophy of FLR in normal liver
• 28-42% hypertrophy of FLR in cirrhotic liver
 Complications
• Well-tolerated
• Occasional transient liver insufficiency in cirrhotics
• Poor technique can occlude entire PV
• If tumor is present in FLR, its growth may be more rapid
Madoff D, et al. Portal vein embolization with polyvinyl alcohol particles and coils in preparation for major liver resection for
hepatobiliary malignancy: safety and effectiveness- study in 26 patients. Radiology 2003;227:251-260.
De Baere T, et al. Preoperative portal vein embolization: indications and technical considerations. Tech Vasc Interv Radiol
2007;10:67-78.

34.  “Resection with wide margins is the treatment of
choice for HCC in patients without cirrhosis”
 “Resection is acceptable for cirrhotic patients
(Childs A without portal hypertension) with single
HCC, regardless of size.”
 “Highly selected patients with multifocal HCC or
major vascular invasion may be resected, but
recurrence rates are high.”
Jarnagin W, et al. Surgical treatment of hepatocellular carcinoma: expert consensus statement. HPB 2010;12:302-310.

35. Liver transplantation
Surgical resection
Percutaneous ablation
PEI
Radiofrequency ablation
Microwave ablation
Transarterial chemoembolization
Yttrum-90 radioembolization
Systemic chemotherapy

36.  Ethanol injection causes vessel
thrombosis and protein denaturation
• Complete necrosis of small (<2 cm) HCC
can be achieved
• Tumors near sensitive organs can be
treated; no heat sink effect
 5-year survival of 32-38%
 Disadvantages
• Multiple treatment sessions needed
• Uncertain ablation zone
• High local recurrence rate (17-38%)

37.  RF current induces thermal
coagulation necrosis around an
electrode
• Complete ablation rates >80% for small
to medium HCC
• Local recurrence uncommon (1-12%)
 5-year survival of 40-58%
 Disadvantages
• Relies on thermal conduction (limited
ablation size)
• Heat sink effect
• Slow
McWilliams J, et al. Percutaneous ablation of hepatocellular carcinoma: current status. J Vasc Interv Radiol 2010;21:S204-S213.
Hinshaw J. The role of image-guided tumor ablation in the management of liver cancer. Cancer News review article.

38.  Three RCTs and two meta-
analyses confirm superiority of
RFA over PEI for small HCC
• 5-year survival about 15% better for PEI: 5-year RFA: 5-year
RFA versus PEI survival 35% survival 50%
• Less local tumor recurrence for RFA
• 3x fewer treatment sessions for RFA
 PEI still useful for tumors in
sensitive locations
Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma.
Gastroenterology 2005; 129:122–130.
Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular
carcinoma or 4 cm. Gastroenterology 2004; 127:1714–1723.
Lencioni RA, Allgaler HP, Cloni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation
versus percutaneous ethanol injection. Radiology 2003; 228:235–240.

39.  Next-generation RF ablation
electrodes are available
• Internal cooling
• Saline injection
• Expandable tines
 Ablation zones of 4-7 cm are
achievable
McWilliams J, et al. Percutaneous ablation of hepatocellular carcinoma: current
status. J Vasc Interv Radiol 2010;21:S204-S213.

40.  Next-generation ethanol injection
needles now available
• Expandable tines
• Multiple sideholes
 Tumors up to 5 cm can be
ablated
• 88% complete ablation rate
• 12% local recurrence rate (56% in
tumors 3-5 cm)
• 2% major complication rate
Kuang M, et al. Ethanol ablation of hepatocellular carcinoma up to 5.0 cm by using a
multipronged injectino needle with high-dose strategy. Radiology 2009;253:552-561.

41.  Microwave creates a field of electromagnetic
energy and thermal coagulation around an
antenna
• Active heating not reliant on conduction (faster, larger
ablation zones)
• Less heat-sink effect
• Multiple antennae can be activated simultaneously
 5-year survival of ????
 Next-generation 2450 MHz MW ablation devices
now available
• 17-gauge antennae
• CO2 based internal cooling
• High power (140 watts)
• Large ablation zones (3.5 x 5 cm)
McWilliams J, et al. Percutaneous ablation of hepatocellular carcinoma: current status. J Vasc Interv Radiol 2010;21:S204-S213.

42.  “Local ablation is safe and effective therapy
for patients who cannot undergo resection,
or as a bridge to transplantation.”
American Association for Study of Liver Diseases (AASLD) and European Association for the Study of the Liver
(EASL).

43. Liver transplantation
Surgical resection
Percutaneous ablation
Transarterial chemoembolization
Conventional TACE (cTACE)
Drug-eluting beads (DEB-TACE)
Pushing the envelope
Yttrium-90 radioembolization
Systemic chemotherapy

44.  HCC takes its blood supply almost
exclusively from the hepatic artery
 Surrounding normal liver has dual
blood supply (with portal vein)
 Chemotherapy + embolic agent
administered into hepatic artery
should selectively kill tumor while
sparing normal liver

45. 1. Celiac and SMA arteriography with late-phase
portal vein imaging
• Determine arterial supply to tumor
• Detect hepatic arterial variations
• Identify non-target arteries (right gastric, etc)
• Determine patency of portal vein and hepatopetal flow
2. Subselection of tumor-bearing artery
3. Embolize to near-stasis or stasis
• Chemotherapy (doxorubicin, cisplatin, mitomycin C)
• Lipiodol vehicle; selectively retained by HCC
 Causes ischemia
 Extends contact of chemotherapy with tumor
• Finish embolization with gelfoam or particles

46.  6 randomized trials in 1990s showed no
benefit of TACE for unresectable HCC
• Selection criteria not stringent
 Prognosis related to functional status of underlying
liver
• Many patients not aggressively re-treated
 Objective responses to TACE are not maintained
with time
• Nonselective embolization often used

47.  RCT of TACE vs. symptomatic
treatment for unresectable HCC
 112 patients
• Mostly Hepatitis C
• 75% had multinodular tumor
• Mean diameter of main nodule was ~5
cm
• About 75% Child A, 25% Child B
• ~80% ECOG 0, max ECOG 2

48.  Exclusion criteria:
 Treatment schedule:
• Age >75
• Baseline, 2 months, 6
• Child class C months, then q6 months
• Active GI bleeding, encephalopathy, refractory ascites thereafter
• Vascular invasion (including segmental portal obstruction) • Mean treatment sessions ~3
• Extrahepatic spread
• Portosystemic shunt
 Doxorubicin used
• 25-75 mg depending on liver
• Hepatofugal blood flow
function
• Platelets <50 Only 38% of • All received 10 cc Ethiodol
patients with
• PT activity <50%
intermediate
• Renal failure HCC (target  Embolization completed
• Severe atheromatosis
population) were with gelfoam
enrolled!
• Bilirubin >5.0
• WBC <3.0
• EF <50%
• End-stage tumor

49.  Survival at 3 years:
• TACE: 29%
• Symptomatic: 17%
 TACE improves survival!
• Selective recruitment needed to obtain survival
advantage

50.  RCT of TACE vs. symptomatic
treatment for unresectable HCC
 80 patients
• Mostly Hepatitis B
• 60% had multifocal tumor
• Mean diameter of main nodule was ~7 cm
• ~25% had right or left PV obstruction
• ~50% ECOG 0, max ECOG 3

51.  Exclusion criteria:  Embolization performed at
baseline, and every 2-3 months
• Active or recent GI bleeding, thereafter
encephalopathy, refractory ascites
• Median treatment sessions ~4.5
• Serum bilirubin >2.9
 Relatively nonselective
• Right or left hepatic artery injection for unilobar
• Albumin <2.8 mg/dL tumors
• Proper hepatic artery injection for bilobar
• PT >4 seconds over control tumors
• Creatinine >2.0  Cisplatin was chemotherapeutic
• Median 10 mg, depending on tumor size
• Extrahepatic metastasis • Median 10 cc Ethiodol
• Main PV thrombosis  Embolization completed with
gelfoam
• Arteriovenous shunting
• ECOG grade 4

52.  Survival at 3 years:
• TACE: 26%
• Symptomatic: 3%
 TACE improves survival!
• Even in less selected patient population

53.  Meta analysis of cTACE
• Meta-analysis of 5 RCTs of TACE versus symptomatic treatment;
and 13 RCTs of different transarterial modes of therapy
 TACE reduced 2-year mortality (OR 0.54) compared to
symptomatic treatment
 TACE does not appear superior to TAE
Camma C, et al. Transarterial chemoembolization for unresectable
hepatocellular carcinoma: meta-analysis of randomized controlled trials.
Radiology 2002.

54.  Cohort study of 8510 patients having cTACE
• Initial treatment
• Unresectable HCC
• No extrahepatic disease
• 5-year survival 26%
Takayasu K, et al. Prospective Cohort Study of Transarterial
Chemoembolization for Unresectable Hepatocellular Carcinoma in 8510
Patients. Gastroenterology 2006.

55.  AFP  Child class  Max tumor size
• <20 = 34% • A = 33% • <=2 cm = 39%
• 21-200 = 27% • B = 21% • 2.1-3 cm = 28%
• 201-1000 = 19% • C = 8% • 3.1 – 5 cm = 23%
• >1000 = 15% • >5 cm = 16%
 # of lesions  PV invasion
• 1 = 33% • None = 28%
• 2-3 = 24% • Peripheral branch = 12%
• 4 or more = 16% • Left or right = 11%
• Main = 0%
Takayasu K, et al. Prospective Cohort Study of Transarterial
Chemoembolization for Unresectable Hepatocellular Carcinoma in 8510
Patients. Gastroenterology 2006.

56.  “TACE is first-line non-
curative therapy for non-
surgical patients with large
or multifocal HCC who do
not have vascular invasion
or extrahepatic spread
(level I evidence).”
American Association for Study of Liver Diseases (AASLD) and European Association for the Study of the Liver
(EASL).

57.  Chemotherapy in lipiodol washes out
of tumor quickly
• Less effective tumor kill
• More systemic side effects
 Chemotherapy loaded onto a particle
can be eluted slowly
• LC beads: Size-calibrated spherical hydrogel
particle which can be loaded with doxorubicin
• Chemotherapeutic elutes gradually over
weeks, though tumor necrosis greatest at 7-
14 days

58.  RCT vs. bland embo
 Mid-term survival data
• 41 DEB-TACE vs. 43 bland embo • 71 patients
• Child A and B, ECOG 0 or 1 • Child A and B, ECOG 0 or 1
• Procedures q2 months up to 3; 100-300 and • Exclusion criteria: Creatinine >2, Portosystemic
300-500 micron LC beads shunt, Hepatofugal blood flow, Main portal vein
thrombus, extrahepatic disease
 DEB-TACE: • 1-4 procedures, q3 months as needed. 100-
• Higher complete response rate at 6 months 300 and 300-500 micron LC beads with 150
(27 vs 18%) mg doxorubicin per treatment.
• Lower recurrence rate at 12 months (46% vs
78%)  88% survival at 30 months (better
• Longer time to progression (42 vs 36 weeks) than historical cTACE)

59.  212 patients randomized to DEB-TACE with LC beads
vs. cTACE with doxorubicin
• Child A and B, ECOG 0 or 1
• Exclusion criteria: Bili >3, Vascular invasion, >50% tumor, extrahepatic
spread, AST or ALT >5x normal
• 1 vial 300-500, 1 vial 500-700 micron LC beads, 75 mg doxo/vial
vs. 150 mg doxo in Ethiodol with operator choice embolic
• Treatments q2 months up to 3 treatments; tumor response
evaluated at 6 months
 Tendency toward better response with DEB-TACE (52
vs. 44%)
 Significant reduction in liver toxicity and side effects with
DEB-TACE
 Survival was not an endpoint (too short f/u)

60.  Expandable microspheres made of
sodium acrylate/vinyl alcohol
copolymer
 Ionically binds doxorubicin
 Arrive dehydrated; when placed in
saline or contrast, they increase in
volume (50-100 micron goes to
150-300 micron)
 Soft and deformable, conform to
vessel wall

61.  Single-arm trial of 50 patients
• Child A
• Exclusion criteria
 Tumor size >10 cm, Portal vein invasion, Extrahepatic
disease
• 50 mg doxo or epirubicin per treatment,
repeated “on demand” ? Survival ?
• 6-month results: ? Durable effect ?
 CR in 52%
 PR in 26%
 PD in 23% ? Comparison to LC
 Only 31/50 followed up beads or cTACE ?
 “Safe, well-tolerated and efficient
agent to produce tumor necrosis”

62.  164 patients with segmental or  125 patients with main PV
 281 consecutive patients major PV invasion invasion
with PV invasion studied • 84 treated with TACE vs. 80 with • 83 treated with superselective
retrospectively supportive care TACE vs. 42 with supportive
• 1-year survival 31% vs. 4% care
• Repeated TACE showed
• 2-year survival 9% vs. 0%
 Aggressive repeated TACE survival benefit (5.6 vs. 2.2
• Significant advantage for TACE in months)
was well tolerated and both segmental and major PV
• 29% morbidity rate (similar to
showed significant survival invasion
supportive care), no mortality
benefits (median survival • No procedure-related mortality
• Selection bias?
10 vs 2 months)

63.  Retrospective study of >1000
patients
• 843 patients <70 compared to 197
patients >70
• Elderly patients had more comorbid
disease (64 vs 33%) but had earlier
stage of HCC
• Overall survival better for the old people
 14 vs. 8 months
 TACE tolerated equally well
 TACE is good for young and old
alike

64.  114 patients who underwent
TACE for post-surgical
recurrence
• 50% of recurrences were single
nodular
• Mean size of recurrent tumor = 2.1
cm
• Overall survival was 32% at 5
years
 TACE is safe and effective for
HCC recurrence after surgery

65. Liver transplantation
Surgical resection
Percutaneous ablation
Transarterial chemoembolization
Yttrium-90 radioembolization
Systemic chemotherapy

66.  Transarterial administration of radioactive
microspheres (Yttrium-90)
• Half-life 64 hours; decays into stable zirconium-90
• Beta-emitter with path length of 2.5 mm
• Particles lodge in the tumor, producing very high local
radiation dose (100-1000 Gy or more)
• Not dependent on flow occlusion
 TheraSpheres
• FDA approved under Humanitarian Device Exemption
for use in treatment of HCC
• Glass particle, 15-35 micron diameter
• 1.2-8 million spheres per vial (3GBq)
• Minimally embolic
 Two scenarios must be avoided with Y90
• Shunting into lung (radiation pneumonitis)
• Nontarget embolization of GI tract (ulceration)

67.  Liver-only or liver-dominant tumor, not suitable
for radical therapy
• Resection
• Liver transplantation
• Ablation
 Preserved functional status
• ECOG 0-2
 Preserved hepatic function
• Total bili <= 2.0
• Albumin >= 3.0
• No ascites or other clinical signs of liver failure
 Low risk of pulmonary effects
• <20% hepatopulmonary shunt
• <30 Gy expected dose delivery to lungs (<50 Gy for
multiple infusions)

68. 1. Superior mesenteric angiogram
• Detect hepatic arterial variations
• Determine patency of portal vein and hepatopetal flow
2. Complete celiac angiography
• Map arterial anatomy
• Detect extrahepatic supply to tumor
• Det
3. Prophylactic embolization of any vessel in the
treatment zone which does not lead to liver
• GDA
• Right gastric
• Accessory left gastric
• Falciform
• Supraduodenal
• Cystic
4. Place microcatheter at site of expected Y90 treatment
and administer 4 mCi Tc-99m MAA
• Similar size particles to TheraSpheres
• Perform MAA scan to see distribution of particles
• Measure lung-shunt fraction (must be <20%)
• Detect any mesenteric flow

69. 1. 2 weeks after mesenteric mapping,
patient returns for Y90 administration
2. Repeat celiac/hepatic angiography
• Ensure continued occlusion of embolized
vessels
3. Position microcatheter in lobar artery
supplying the most tumor and infuse Y90
4. If bilobar disease, patient will return in 1
month for Y90 treatment of opposite lobe

71.  108 patients with unresectable  291 patients with unresectable intermediate
intermediate or advanced HCC or advanced HCC
• No extrahepatic disease • PVT and limited extrahepatic disease allowed
• 17% BCLC A; 28% B; 52% C; 3% D
 159 sessions of TheraSphere Y-90
• 40% response rate (almost all partial)  526 sessions of TheraSphere Y-90
• Time to progression 10 months • 42% response rate
• Overall median survival 16 months • Time to progression 8 months
• Transient fatigue syndrome and • Survival: 17 months Child A; 8 months Child B
abldominal pain • Fatigue, pain, nausea, elevated LFTs (all 20-50%)

72.  8-center study of 325 patients with
unresectable intermediate or advanced
HCC
• 82% Child A, 18% Child B
• 24% solitary, 76% multifocal
• 9% extrahepatic metastases
• 14% branch PV occlusion, 10% main
 Overall median survival 12.8 months
 Predictors of poor survival:
• ECOG status
• >5 nodules
• INR >1.2
• Extrahepatic disease

73.  Y90 expected to be better tolerated than TACE
in patients with PV invasion
• Y-90 is less embolic; therefore less risk of hepatic
infarction
• Median overall survival 7-10 months
 4 months in main PV invasion
• Mostly grade 1 and 2 toxicities
 Abdominal pain (38%)
 Nausea (28%)
 Fatigue (22%)
 Ascites (13%)
 Encephalopathy (13%)
 Y90 is safe and shows tumor response in
patients with branch or lobar PV invasion.

74.  Minimal data on use of Y90 as
bridging or downstaging therapy
 One retrospective study, cohorts not
very well matched, included tumors
>8 cm (especially in TACE group)
• 43 patients with conventional TACE, 43
patients with Y90
• Downstaging achieved in 31% of TACE vs.
58% of Y90 patients
• Overall median survival favored Y90 (19
vs. 36 months), perhaps because more
Y90 patients got transplant
 Y90 seems effective as a
bridging/downstaging therapy

75.  Parasitized extrahepatic arteries
• Usually R phrenic or R intercostal arteries supplying
tumor
• Contraindicated to deliver Y90 to these arteries
• Instead, occlude them with large particles (500-700 or
700-900 micron Embospheres) followed by coils
• There should be immediate redistribution of flow from
the hepatic circulation (96%)
• This redistribution can be confirmed by DSA or C-arm
CT of the hepatic artery

76.  Accessory hepatic arteries
• Presence of accessory/replaced hepatic
arteries may increase the number of
injection points and could increase risk
(especially with embolic SIR-spheres)
• Instead of treating these
accessory/replaced arteries, consider coil-
embolizing them proximally
• There is rapid redistribution of arterial
supply from the non-embolized hepatic
artery branches
• Tumor response in the redistributed
segments was similar in 96% of patients
and worse in 4% (but excluded those who
had diffuse progression…)

77. Liver transplantation
Surgical resection
Percutaneous ablation
Transarterial chemoembolization
Yttrium-90 radioembolization
Systemic chemotherapy

78.  Traditional chemotherapy regimens
had high toxicity and low efficacy
 Targeted agents show promise
• Sorafenib
• Sunitinib
• Brivanib
• Avastin
• mTOR inhibitors (sirolimus, everolimus)
• Others

79.  SHARP trial
• Phase III, double-blind, placebo-controlled trial
• 602 patients
• Not eligible for, or had progression with locoregional therapies
• ECOG 2 or less; Child A; adequate hematologic, liver and renal
function
• 36% with vascular invasion; 53% with extrahepatic spread
• Median survival extended 3 months with sorafenib (10.7
vs 7.9 months)
• 0% CR; 2% PR; 71% SD; 18% PD
• Major adverse events: 8% diarrhea, 8% hand-foot skin
reaction
• Asian SHARP trial
• Similar study design, 271 patients
• Median survival extended 2 months with sorafenib (6.5
vs 4.2 months)
• Major adverse events: 11% HFSR, 6% diarrhea, 3%
fatigue

80. Resection vs. TACE
Resection vs. ablation
Ablation vs. TACE
TACE vs. Y90

81.  185 patients with resectable early-  419 patients with resectable HCC
stage HCC and Child A cirrhosis • 46 had TACE
• 73 had superselective TACE • 311 had resection
• 112 had resection • 62 refused treatment (supportive
care)
 5-year survival
 5-year survival
• TACE: 52% (ns)
• TACE: 34% (ns)
• Resection: 57% (ns)
• Resection: 43% (ns)
• Supportive care: 7% (p = 0.0001)

82.  3225 patients with HCC  87 patients with resectable HCC
retrospectively grouped by clinical • 20 had TACE
prognosis and tumor burden • 67 had resection
 Compensated patients with 3 or fewer  5-year survival
tumors, any size • TACE: 18%
• Surgery: 45-55% 5-year survival • Resection: 55% (p<0.05)
• TACE: 17-20% 5-year survival

83.  115 RFA vs. 115 surgery  180 patients with solitary HCC <5 cm
• HCC within Milan criteria • Half had HCC <3 cm, half had HCC 3-5 cm
 Survival at 5 years:  Survival at 4 years:
• RFA 55% • RFA 68%
• Surgery 76% (p<0.05) • Surgery 64%
 DFS at 4 years:
 DFS at 5 years:
• RFA 46%
• RFA 29%
• Surgery 52%
• Surgery 51% (p<0.05)
 RFA had fewer adverse events (55% vs 4%)
 RFA had fewer adverse events (32 vs. 5)

84.  5317 American patients with HCC
 7185 patients with HCC (3 tumors up to 3 • Median tumor size 6 cm
cm) and Child A/B liver function • 52% solitary; 28% multiple; 20% extrahepatic
• 30-day mortality was 8% resection; 3% OLT; 3%
 3022 RFA patients ablation; 31% no or incomplete local therapy
• 55% tumor recurrence in 2 years • 5-year survival 67% OLT; 35% resection; 20% ablation;
• 1.6% death rate at median 10 months 3% no or incomplete local therapy
 2857 resection patients  Prognostic factors
• 35% tumor recurrence in 2 years • Disease extent
• 1.9% death rate at median 10 months • Tumor grade
• Tumor size
 Relative risk or recurrence was 0.62 in • Vascular invasion
resection group; no difference in survival • Age
 Selection bias is likely

85.  91 patients with unresectable HCC (up to 3 nodules, each up to
5 cm)
 258 patients with hypervascular HCC (1 nodule
 40 TACE patients
<5 cm or up to 3 nodules <3 cm)
• Mean 6 sessions
• 58% survival at 2 years • Mean tumor size 1.7 cm in both groups
• TACE group had more multifocal tumors, more
 51 RFA patients peripheral tumors, more previously treated tumors
• Mean 1 session
• 72% survival at 2 years (ns)
 133 TACE patients
 Morbidity higher for RFA (28% vs. 10%) • Local recurrence 51% at 2 years
 No treatment-related mortality
 105 RFA patients
 Similar time to progression • Local recurrence 40% at 2 years (p<0.05)

86.  790 patients with unresectable
intermediate-stage HCC +/- PVT
 245 comparable patients with
unresectable intermediate-stage
 99 had TheraSphere Y-90 vs. 691 had
HCC and no PVT
repetitive cTACE
• Overall median survival 11.5 vs. 8.5 months
 123 underwent TheraSphere Y-90 (p<0.05)
vs. 122 had TACE • But, TACE group had more severe liver disease
• 72% vs. 69% response rate (ns) • No difference in survival after controlling for
• Time to progression 13 vs. 8 months underlying disease
(p=.046) • Y-90 (outpatient, 1 or 2 treatments) is compelling
• Overall median survival 20 vs. 17 months as a palliative treatment option compared to
(ns) TACE (inpatient stay, multiple treatments)
• Less abdominal pain and LFT increase
with Y90

87.  73 comparable patients with unresectable HCC,
~35% with vascular invasion
• Segmental PV occlusion could have TACE or Y90
• Extensive PV occlusion favored Y90
 38 underwent TheraSphere Y-90 vs. 35 had
TACE
• 7 Y90 patients and 2 TACE patients crossed over
• Median survival 8.0 vs. 10.3 months (ns)
• Mean total hospitalization (initial + re-hospitalization)
days 0.5 vs. 3.5 (p<0.001)
• Complication rate higher for TACE, mostly due to
more severe PES

88. TACE + ablation
TACE + sorafenib

89.  83 patients treated with
TACE/RFA compared with 231
patients treated with RFA alone
• Small HCC (2-3 cm)
• Median follow-up 37 months
• 5-year survival 63% vs 53% (ns)
• Local tumor progression 16% vs.
41% (p<0.001)
• Rate of major complications ~1% for
both groups

90.  37 patients with solitary HCC 3.1-5.0
cm
 89 patients with 93 HCC <3 cm
• TACE-RFA same day vs. RFA alone
• TACE then RFA 1 week later vs. RFA
• Slightly larger ablation size with TACE-RFA
alone
(5.0 vs. 4.1 cm)
• Local tumor progression 18% vs. 14% at 4
• Local tumor progression 6% vs. 39% at 3
years (ns)
years (p=.012)
• Overall survival 73% vs. 74% at 4 years
• Overall survival 93% vs. 80% (ns) (ns)
• Rate of major complications ~1% for both
• Rate of major complications ~2% in both
groups
groups

91.  14 patients
• Sorafenib 200-400 mg daily starting 7 days prior to TACE
• cTACE with doxorubicin (median 2 per patient)
• Sorafenib continued median 8 months
 Adverse effects were comparable to sorafenib monotherapy
 No increases in circulating VEGF levels after TACE while
patients were on sorafenib
 Phase II/III trials pending

92. What have we learned?

93.  Interventional radiology plays a key role (maybe the
key role!) in liver cancer treatment
• Percutaneous ablation
• Early HCC
• TACE •
•
Preserved liver function: Resection or ablation
Compromised liver function: Transplantation
• Bridge to transplant with ablation or TACE
• Y-90
• Intermediate HCC:
• Preserved liver function: TACE, Y90 and/or ablation
• Portal vein embolization • Downstage to transplant if possible
• Compromised liver function: Supportive care
• Consider extended criteria OLT or LDLT
• Downstaging to transplant
• Advanced HCC:
• Bridging to transplant •
•
Preserved liver function: Sorafenib or Y90
Compromised liver function: Supportive care
• Percutaneous biopsy
• Transjugular pressure measurements
• Salvaging operative mishaps

95. TS
65 y/o female
Hepatitis B cirrhosis
Routine screening US and CT demonstrated
two adjacent 4-cm HCCs
Not a surgical candidate TACE 1/26/2010: 75 mg
doxorubicin on LC beads
Outside Milan criteria for OLT
Referred for locoregional therapy and possible
down-staging

96. MRI 2/25/2010: No residual tumor.
Patient downstaged, exception points
awarded for OLT
TACE #2 6/8/2010
22.5 mg doxorubicin on
LC beads to R hepatic
Awaiting OLT artery
CT 4/24/2010:
Intrahepatic recurrence

97. TACE #3 11/18/2010
75 mg doxorubicin on
LC beads to R phrenic
and R hepatic arteries
MRI 10/25/2010:
Intrahepatic recurrence

98. MRI 12/20/2010: Minimal residual tumor
Successful OLT 1/22/2011 (1 year after first
intervention)
Now almost 1 year s/p OLT, doing well
without recurrence

99. YO
58 y/o male
Hepatitis B and C and HIV
Abdominal pain prompted CT
7 cm biopsy-proven HCC
Not a surgical or transplant candidate
Referred for locoregional therapy

100. MRI 1 month later –
100 mg doxorubicin on mass mostly
LC beads devascularized

101. Follow-up MRI –
Percutaneous complete necrosis, no
microwave ablation recurrence at 4 mos

102. TG
39 y/o female
Fibrolamellar HCC diagnosed in 2001
Left lobe resection of 9 x 11 cm mass in 2001
Recurrence 2007 with partial right lobe
resection
CT 4/9/2010: At least
Presents with multifocal recurrence 2/2010 10 hypervascular liver
masses
Not a surgical or transplant candidate
Presented at tumor board and referred for
locoregional therapy

103. TACE 5/3/2010 100 mg doxorubicin on
LC beads
2 weeks later, returns
with fevers, RUQ pain

104. CT 5/19/2010: near- complete
tumor necrosis
Prolonged CT 8/6/2010: Biloma
Percutaneous biloma catheter resolved, but
drainage drainage intrahepatic recurrence
and new lung nodule.
To study drug

105. August 2009 –
present 100 patients with HCC referred for
locoregional treatment
3 contraindicated for treatment
(bilirubin too high, extrehepatic
disease, hepatofugal flow)
3 insurance denials
13 did not receive 2 decided against treatment
1 awaiting treatment
locoregional treatment 1 direct to OLT
87 patients treated 1 referred for surgery
1 referred for Y-90
152 total procedures, mean 10 mo 1 died prior to treatment
follow-up
19 patients treated 66 patients treated 2 patients had
initially with RFA initially with TACE combo TACE/RFA
2 free of disease
12 2 2 3 8 15 7 10 18 8
Alive, Alive, Alive, with Dead Alive, Down- Alive, Alive, Progressive Awaiting
disease-free bridged to recurrence disease- staged under bridged to disease follow up
OLT free treatment OLT
1 TACE 1 ALL
1 trial drug 1 asp PNA
1 OLT 2 13 4 6 8
rejection
Surgery RFA Extrahepatic Intrahepatic Dead
progression progression
1 awaiting 7 alive, 1 Nexavar 3 Y-90 7 liver cancer
surgery disease-free 3 Unknown 3 Nexavar 1 unknown
1 alive, 1 alive, OLT cause
disease-free 2 dead
3 alive with
recurrence