MANAGEMENT OF HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma: management
Presented By: Dr. Isha Jaiswal
Moderator: Prof. Kamal Sahni,Dr. Madhup Rastogi
Date: 22nd September 2015

Introduction
• aggressive tumor
• curative options :surgery only
• 70%–80% patients inoperable due to
advanced stage
 underlying liver disease

Management depends on following factors
Tumor related
•Size
•Stage
•Location
•Single vs. multiple
•vascular involvement
•Lymphatic spread
•Extra hepatic spread
Patient related
•Age
•Performance status
•Medical co morbidities
•Previous treatment
liver function
• Child-Pugh score
• Portal hypertension
• Cirrhosis
Treatment related factor
•Multimodality treatment
•High volume centres
•Transplant facility
•radiotherapy techniques
•cost

Treatment modalities
Surgery
 liver resection
 transplantation
Local ablative therapies
 Radiofrequency ablation
 Microwave ablation
 cryoablation
 Chemical ablation: ethanol, acetic acid
Regional therapies
 Tran arterial therapy
 Radiotherapy
Systemic therapies
 Chemotherapy
 Nonchemotherapy agents
 Targeted therapy
Supportive care

Grading System For Cirrhosis:
Child-Pugh Score
Barcelona Clinic Liver Cancer staging System
For Hepatocellular cancer

Llovet, J. M., Fuster, J., & Bruix, J. (2004). The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transplantation : Official
Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 10(2 Suppl 1), S115–S120.

SURGERY
Resection
Inclusion criteria
• AJCC Stage 1-2
• Preferable size ≤5 cm, solitary tumor
• No macro vascular, L.N, or distant metastases
• Non cirrhotic or compensated cirrhotic child Pugh A
• Adequate remnant liver
• medically fit
Exclusion criteria
• Advanced stage
• Multiple tumors
• portal hypertension
• Child Pugh B & C
Transplantation
Milan Criteria for inclusion
• Single tumours ≤ 5 cm or ≤3
nodules, each≤ 3 cm
• No vascular invasion or distant
metastases
• Medically fit
In patients with multiple nodules &
chronic liver disease or chirrhosis-
transplantation preferred

Types of Hepatic Resections
Non anatomic resection:
wedge resection
Anatomic resection
 segmentectomy
lobectomy (right and left)
trisegmentectomy (right and left)

Removal of a single segment - Segmentectomy
Small triangular-shaped portion of the liver along with tumor removed– Wedge
Resection.
Indicated for small superficial& peripheral lesions

Right lobe which consists of two segments – Right Lobectomy
Left lobe which consists of two segments – Left Lobectomy
Lobectomy: indications
• multiple lesions are located in different areas of one lobe.

Removal of the complete left lobe plus the medial segment of the right
lobe – Left Trisegmentectomy (also known as extended left hepatic
lobectomy)
Removal of the complete right lobe plus the medial segment of the left lobe
– Right Trisegmentectomy (also known as extended right hepatic
lobectomy

aim of surgery
complete resection with at least 1 cm margin
maximum preservation of normal hepatic parenchyma
Post resection liver volume:
at least 30% in non cirrhotic
At least 40-50% in cirrhotic
if potential remnant liver volume is less then following should be considered
 portal vein embolization
trans arterial chemoembolization
Liver resection

 ICG retention test
 ICG is delivered systemically and the hepatic retention is measured at 15 minutes.
 It determines the amount of liver resection for patients with impaired liver function
 When the retention rate is less than 10%, all resections are possible.
 If 10% to 20%, a bisegmentectomy is well tolerated;
 if 20% to 29%, a single segment can be excised safely;
 if 30% or more, the risk of liver failure with any form of resection is high.
Dynamic liver function test: to guide resection

Outcomes of Resection
• With improving patient selection and perioperative care, the outcome of hepatic resection has improved In
past 10 years
 perioperative mortality
rate of less than 7%,
 5yr overall survival rate
of 30% to 50%

Predictive factors determining outcome after liver resection
• TNM stage. 1
• Size
liver resection for >5 cm tumor --more recurrences.
Large HCC :propensity for vascular invasion, intraluminal & intrahepatic satellite mets
• surgical margins2,3,4
1-cm margin associated with 77% 3-year survival vs.21% with <1-cm margin.
• Type of liver resection 2,3,4
improved outcome for anatomic vs. nonanatomic resections 5-year :66% vs. 35%.
for small solitary tumors, anatomic resections less importance
1. Hasegawa K, Kokudo N, Imamura H, et al. Prognostic impact of anatomic resection for hepatocellular carcinoma. Ann Surg 2005;242:252–259
2. Shi M, Guo RP, Lin XJ, et al. Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial. Ann Surg2007;245:36–43
3. Ikai I, Arii S, Kojiro M, et al. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey.Cancer 2004;101:796–802.
4. Kang CM, Choi GH, Kim DH, et al. Revisiting the role of nonanatomic resection of small (< or = 4 cm) and single hepatocellular carcinoma in patients with well-preserved liver function. J Surg
Res 2010;160:81–89

Liver Transplantation: results
Milan Criteria
Single tumours ≤ 5 cm or no more than 3 nodules, each≤ 3 cm
No vascular invasion or distant metastases

excellent outcomes of Milan criteria led to explore more expansive criteria
.
Expanded Criteria for Liver Transplantation: UCSF Criteria
 Solitary lesion Within ≤ 6.5 cm
 Multiple:≤ 3 nodules,each ≤ 4.5 cm
 Total tumor diameter ≤ 8 cm

Milan criteria :5 yr survival of ≈ 70%
The UCSF criteria :5 years survival of ≈46%
Transplanted patients with tumours beyond the UCSF criteria had a survival 35%

Multimodality Management While Awaiting Transplant: bridge therapy
• major disadvantage with liver transplantation :long waiting time for donor organs.
• high risk of tumor progression
• To reduce tumor progression many local treatments are used such as
TACE
TART
RFA
PEI
• called as bridging therapies .
limits wait list dropout.
downstage HCC beyond transplant criteria.
decreases post transplant recurrence

Resection vs. Transplantation for small HCC≤ 2cm
comparable OS rates
patients with normal LFT
should be resected because
 No need of immunosuppression
 donor organ shortage
In patients with end-stage liver disease
transplant preferred
resection :used as bridging therapy for
transplant

Ablative Therapy
Indications: non surgical HCC
Contraindication: tumor near vital structure –major vessel, bile duct, diaphragm, viscera
 curative intent:
early stage solitary tumor ≤3 cm, child Pugh-A, PS-0
Neoadjuvant therapy: downstage tumor for resection
Bridge therapy : reduce tumor progression
Adjuvant therapy: after limited resection or in combination with TACE/TART
Palliative intent:
Large lesions
Old & frail patients: poor performance status
Child Pugh B-C

ABLATIVE THERAPY
Types:
• Radiofrequency ablation
• Microwave ablation
• Chemical ablation

Radiofrequency Ablation
• most widely used
• In this technique, the RF electrode placed into tumor (percutaneous or laparoscopic) with imaging
guidance.(CT,USG)
• The percutaneous approach may be limited by structures at risk such as major vessels, bile duct, diaphragm
and other intraabdominal organs
• These structures can be retracted free with a laparoscopic approach.

Radiofrequency Ablation
• thin probe (18 gauge) is inserted into middle of a tumor
• needle electrodes are deployed to adjustable distances.
• A.C current (400 to 500 kHz) is delivered through electrodes -agitation of particles of surrounding tissues,
• Generate frictional heat lead to sphere of necrosis.
• Size of the sphere depends on length of deployment of electrodes.
• Currently, the maximum size of probe arrays allows for 7-cm zone of necrosis, adequate for a 5-cm tumor..

Advantages:
 Well tolerated OPD procedure
 best suited to small tumors (3-5 cm) deep within hepatic parenchyma, away from hilum.
 repeated easily especially percutaneous approach
 Spares uninvolved hepatic parenchyma
 Less invasive then resection
Disadvantges
 difficulty of positioning probe
 Anatomic limitation: large blood vessels may act as heat sinks, preventing adequate cytodestruction
 tumors close to main portal pedicles -lead to bile duct injury
 local recurrence rate (at the site of ablation) : 5% and 20%.
 theoretical risk of needle tract tumor seeding:

RFA Vs. Liver Resection
RFA was as effective as surgical resection in the treatment of early HCC
four randomized trials comparing RFA and hepatic resection

no significant difference in 1-year overall survival between resection and radiofrequency ablation
long-term efficacy of surgery is better than that of RFA .

Microwave Ablation
• Like RFA, microwave ablation (MWA) uses electromagnetic waves to produce heating.
• Unlike RFA, the MW energy is much higher frequency range 300 MHz to 300 GHz.
• Similar safety and efficacy results *
• perceived advantages of MW over RF energy include
broader deposition of MW energy
much larger zone of active heating.
less severe heat sink effects.
larger resultant ablative volume
faster treatment time
• Still not tested in clinical trials
*Wright AS, Lee FT Jr, Mahvi DM. Hepatic microwave ablation with multiple antennae results in synergistically larger zones of coagulation necrosis. Ann
Surg Oncol2003;10:275–283.
*Martin RC, Scoggins CR, McMasters KM. Safety and efficacy of microwave ablation of hepatic tumors: a prospective review of a 5-year experience. Ann
Surg Oncol2010;17:171–178.

Chemical Ablation
chemicals such as ethanol or acetic acid injected into tumor
destroy tumor tissue by dehydration, protein denaturation, coagulation necrosis & vascular thrombosis
 advantages:
Inexpensive
Minimally invasive
Favourable at some anatomic location where RFA not suitable due to heat sink
Disadvantages:
Non selective for tumor cell & normal parenchyma
Multiple applications required
15% risk of recurrence at site of injection
RFA is superior to chemical ablation* for early stage
Tsai WL, Cheng JS, Lai KH, et al. Clinical trial: percutaneous acetic acid injection vs. percutaneous ethanol injection for small hepatocellular carcinoma—a long-term follow-up
study. Aliment Pharmacol Ther 2008;28:304–311

Lin, S.-M., Lin, C.-J., Lin, C.-C., Hsu, C.-W., & Chen, Y.-C. (2005). Randomised controlled trial comparing percutaneous radiofrequency thermal
ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut, 54(8),
187 patients with HCCs of 3 cm or less
randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63).
Tumour recurrence and survival rates were assessed
P valueRFAPEIPAI
NS96.1 %88.1 %92.4Complete Necrosis
RFTA v PEI, p = 0.012;
RFTA v PAI, p = 0.017
14%34%31%3yr local recurrence rate
RFTA v PEI, p = 0.031;
RFTA v PAI, p = 0.038
74%51%53%3yr survival rate
RFTA vs. PAI/PEI
p = 0.035
4.8%nonenoneMajor complications

Radiofrequency ablation vs. chemical ablation
RFA : more effective more complication, more expensive,
PEI/PAI: less effective more Sessions, minimally invasive, inexpensive
Lin SM, Lin CJ, Lin CC, et al. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid
injection to treat hepatocellular carcinoma of 3 cm or less. Gut 2005;54:1151–1156

Embolic Therapies
Indications:
• Non surgical HCC
• intermediate stage patients
• multifocal liver-disease
• not candidates for resection, transplantation,
ablation
• no vascular invasion; no shunting; no extra
hepatic disease
Contraindications
Absolute
• Child’s C cirrhosis
• Total bilirubin > 3mg/dl
• Main PV thrombosis
Relative
• Bilirubin ≥2mg/dl
• Cardiac & renal insufficiency
• variceal bleed,thrombocytopenia

Arterial directed Embolic Therapies: Principal
• rely on the dual blood supply of the liver: arterial and portal venous.
• portal vein provides 75-80% of the blood to hepatic parenchyma,
• hepatic artery is primary supply of tumor.
• Selectively delivering agents trans arterially into hepatic artery targets the tumor while
sparing the liver.
• portal blood flow protect the noncancerous liver from the treatment agents and
ischemia.

Trans arterial embolic therapy: procedure
• interventional radiology
• performed by angiography
• gaining percutaneous access to hepatic artery
• passing catheter into branch supplying tumor.
• selective angiogram performed
• distal most branches supplying the tumor(s) identified
• embolic particles gel foam/microspheres are injected
• At completion catheter and removed & bleeding from
punctured artery controlled by applying pressure to the entry
site

Trans-arterial Therapy Types:
bland hepatic artery embolization (HAE)
Chemoembolization (CE)
Conventional TACE
DEB DOX-TACE
Trans-arterial radiotherapy(TART)
 Yttrium-90 microspheres
 Iodine-131 lipiodol
 Rhenium-188,
 Holmium-166

Three types of trans arterial therapies
1. bland hepatic artery embolization (HAE)
 tumor killing due to ischemia
not very effective
2. Chemoembolization (CE)
kills tumor with ischemia & chemotherapy
mitomycin C, doxorubicin, cisplatin loaded in gelatin ,pvc microspheres most commonly used
DEB: allow more distal occlusion of small vessels and delivery of high-dose chemotherapy to tumor with
low systemic circulation
3. radio embolization (RAE)/TART/internal radiotherapy
involves the administration of radioactive source loaded in glass or resin microspheres intra-arterially.
.

Internal radiotherapy
delivery of radioisotopes by
1. direct intra-tumour implantation via percutaneous route
2. injecting radioisotope through the hepatic artery directly into the
tumour or trans-arterial radioisotope therapy (TART).
3. parenteral injection of radiolabelled antibodies specific to HCC
antigens (radio immunotherapy)

TART: trans arterial radiotherapy
• Indication
inoperable HCC
Small HCC close to vital structure: ablation contraindicated
as a neoadjuvant therapy before surgery
as an adjuvant therapy, after limited surgery or ablative therapy to
reduce the risk of recurrence
HCC with portal vein thrombosis
Palliative

Systemic therapy
large number of clinical trials performed with chemotherapy,
given as single agent or in combination
 no proven benefits on survival
Most promising results with gemcitabine1 as single agent & gemcitabine +
oxaliplatin2 or cisplatin, doxorubicin, 5-fluorouracil3 in combination.
Many other non- chemotherapeutic agents tried including LHRH agonists, tamoxifen,
IFN, statin, megestrol, vitamin K, thalidomide, interleukin-2, without any definitive
success,
1.Yang TS, Lin YC, Chen JS, et al. Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2000;89:750–756.
2. Leung TW, Patt YZ, Lau WY, et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable
hepatocellular carcinoma. Clin Cancer Res 1999;5:1676–1681
3. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma
(HCC). Cancer2007;109:1384

MOLECULAR THERAPY
• vascular endothelial growth factor (VEGF) promotes HCC development and
metastasis,
• Hence antiangiogenic agents studied extensively
• sorafenib is the only molecular agent approved.
• Sorafenib is a multikinase inhibitor that targets VEGF,PDGF receptor, RAF
inhibitor

• Phase III, multicentre RCT ,602 patients with advanced HCC Child-Pugh Class A
randomized to either sorafenib 400 mg b.d or placebo.
• primary outcomes: O.S & time to symptomatic progression.
• study was stopped, after 2nd prespecified interim analysis( 321pts.were dead)
• Median OS 10.7 vs.7.9 months in sorafinib vs. placebo (HR=0.69; 95% C.I, 0.55 to 0.87; P<0.001)
• N.S difference in median time to symptomatic progression (4.1 months vs. 4.9 months,
respectively, P=0.77).
• 7pts. in sorafenib (2%) and 2 in placebo (1%) had PR ;no patients had CR
• Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent
in sorafenib gp.
Llovet et al. (2008)
SHARP-Sorafenib HCC Assessment Randomized Protocol

 Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the
sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001
 There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs.
4.9 months, respectively, P=0.77).
 The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group
(P<0.001

Why RT is not the initial choice in HCC
 Late presentation: large tumour-underlying chirrhosis: ONLY palliative care
 HCC considered ‘radio-resistant’. Liver is relative radiosensitive; low tolerance
 EBRT dose of 30 Gy@ 2Gy/# whole liver considered threshold for RILD: far less than
standard tumoradical doses. Even 25 Gy in 10 # or 32 Gy in 1.5 Gy/# bid was associated
with >5% risk of RILD, particularly with cirrhosis and chronic liver ds.
 Difficult to deliver high dose
 Difficult to spare liver: moves with respiration: large margin
 Technology not available to deliver precise RT

RILD: limit dose of RT
RILD can be categorized as classic and non-classic.
Classic RILD :
• anicteric ascites, hepatomegaly, and elevated liver enzymes (particularly alkaline
phosphatase)
• typically occurs within 4 months of therapy
• veno-occlusive disease
Nonclassic RILD:
• in patients with hepatitis and cirrhosis,
• jaundice and markedly elevated serum transaminases (>5 times the upper limit of normal)
• within 3 months of completion of therapy.
• direct hepatocyte rather than endothelial injury

Radiotherapy For Unresectable HCC
Dose Response Relationship
higher the radiation doses
given, the higher the tumor
response seen

Sem Rad Onc-Dawson L 2013,21; 241-246
portal vein thrombosis
obstructive jaundice
recurrent HCC

Klein, J., & Dawson, L. a. (2013). HCC radiation therapy: Review of evidence and future opportunities. IJROBP87(1), 22–32.

Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities.
International Journal of Radiation Oncology Biology Physics, 87(1), 22–32.
SBRT has comparable
effectiveness in treating
HCC compared with
other local therapies

Klein, J., & Dawson, L. a. (2013).HCC therapy: Review of evidence and future opportunities. IJROBP 87(1), 22–32.

Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future
opportunities. International Journal of Radiation Oncology Biology Physics, 87(1), 22–32.
SBRT as bridge to transplant
RT has been delivered safely as a bridge to liver transplant, especially if other bridging therapies are
contraindicated.

Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future
opportunities. International Journal of Radiation Oncology Biology Physics, 87(1), 22–32.

Combination TACE & RT In Unresectable HCC

International Journal of Radiation Oncology Biology Physics, 87(1), 22–32.

Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy:
Review of evidence and future opportunities. International Journal of Radiation Oncology Biology Physics, 87(1), 22–32.

International Journal of Radiation Oncology Biology Physics, 87(1), 22–32

Soliman, H.,Dawson, L. a. (2012). Phase II Trial of Palliative Radiation Therapy for Symptomatic Hepatocellular Carcinoma and Liver Metastases.
International Journal of Radiation Oncology*Biology*Physics, 84(3), S10.
 N=40 (21 HCC)
 tumors unsuitable for resection, transplantation, RFA, systemic therapy, conformal RT, or SBRT
 Eligible patients had ≥ 1 of following symptoms attributed to liver cancer: pain, abdominal
discomfort, nausea, or fatigue.
 ECOG 0 to 2, expected survival > 3 months,Child Pugh A-B
 8Gy SFRT
 The Brief Pain Inventory (BPI), EORTC QoL completed
by patients at baseline & each follow-up
 At 1 month,
 48% had an improvement in symptom (primary end point)
 25% had improvement of QoL (sec. end point)

Radiotherapy techniques
• Internal radiotherapy
• 3D-conformal radiation therapy
• intensity-modulated radiation therapy [IMRT]
• stereotactic body radiation therapy [SBRT]
• Proton beam therapy (PBT)

EBRT TECHNIQUES
Simulation And Field Design
CT-based treatment planning recommended
Position: Supine with arms above head
Immobilization: wing board, alpha cradle
Contrast: oral and I.V
The CT scan taken 3- to 5-mm-thick slices from the level of the carina to L5-S1.
Treatment plans individualized
multiple fields used to precisely irradiate the tumor and spare normal tissues

Treatment volumes
Whole Liver (palliation only).
• AP/PA, chose borders based on CT scan
• 3DCRT reasonable because permits generation of DVHs
Partial Liver (definitive option).
• For 3DCRT/IMRT treatment planning
• GTV: defined by a arterial phase CT scan & MRI scan , fusion preferred
• CTV = GTV+ 1 cm in all directions
• PTV = CTV + 0.5 cm for setup error + margin for organ motion error

SBRT
Indications
 One to three lesions, Maximum tumor diameter ≤ 6 cm
 no extra hepatic disease.
 Child-Pugh A or selective B liver disease
Comprehensive, N., & Network, C. (2015). Hepatobiliary Cancers. NCCN Clinical Practice Guidelines in Oncology, I, 1–94.

For SBRT treatment planning
• breathing motion should be less than 5 mm or controlled with external compression or an
ABC device.
• The CTV for SBRT should include the GTV + 0.5–1 cm.
• The PTV should include the CTV + 0.5 cm for set-up uncertainty and an additional
margin for breathing motion.
• fiducials such as gold seeds placed in the tumor by CT or US guidance can sometimes be
used to track tumor motion during respiration
• Normal tissues to be delineated include bilateral kidneys, normal and diseased liver,
spinal cord, stomach, and small bowel.
• Dose volume histograms should be used to outline dose to these structures.

No extra hepatic, L.N vascular invasion
Non surgical HCC
intermediate stage patients
multifocal liver-disease
no vascular invasion; no shunting; no extra hepatic disease
Not suitable for lesion > 10cm
Contraindicated in shunting
Same as TACE
Portal vein thrombosis
RESECTION
RF ABLATION
TACE
Y-90 TART
SBRT
TRANSPLANT

Acute and Late Complications of RT
• The dose-limiting tissue injuries include the liver, stomach, duodenum,
bowels, and kidneys.
• Acute complications include general fatigue, transient elevation of
LFT, nausea, fever, and pancytopenia.
• Sub acute and late complications include hepatic failure, radiation
pneumonitis, and G.I bleeding
• Hepatic failure can be avoided by an appropriate selection of patients
and careful treatment planning.

MANAGEMENT OF HEPATOCELLULAR CARCINOMA

MANAGEMENT OF HEPATOCELLULAR CARCINOMA

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