Hepatocellular carcinoma (HCC)

HEPATOCELLULAR
CARCINOMA
PRESENTOR: DR. SAOOD MALIK

EPIDEMIOLOGY
Hepatocellularcarcinoma (HCC) is one of the major causes of mortality among patients with
chronicliver disease
Hepatocellularcarcinoma (HCC) results in approximately 800,000deaths globally per annum.1
M:F :: 4:1
In adult men is the 5th most frequentlydiagnosed cancer and
In adult women, it is the 9th most commonly diagnosed cancer worldwide.2
1. Global Burden of Disease Liver Cancer Collaboration, Akinyemiju T, et al. JAMA Oncol 2017; 3:1683.
2. Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:E359.

INDIAN SCENARIO
According to data collectedby ICMR (Indian Council of Medical Research)
◦ Incidence among male ranges from 0.7 to 7.5 and for women 0.2 to 2.2 per 100,000 persons per year
Median age of presentationranges between 40 and 70 years and with increasing age, the
frequency of liver cancer increases
Majority of HCCs occur in patientswith chronicliver disease or cirrhosis

RISK FACTORS
Major Risk Factors
Chronic HBV infection
Chronic HCV infection
Cirrhosis
Dietary exposure to aflatoxin B1
Inherited Conditions Not Associated
with Liver Disease
Ataxia-telangiectasia
Hyper-citrullinemia
Other Factors
Cigarette smoking
Diabetes mellitus
Oral contraceptive steroid use
Other Liver Conditions
α1-Antitrypsin deficiency
Hemochromatosis
Nonalcoholic fatty liver disease
Type 1 and type 2 glycogen storage disease
Type 1 hereditary tyrosinemia
Wilson disease

HCC in Cirrhosis
Patients with chronicliver disease or cirrhosis from any cause have an increased risk of
developing HCC
Many patients(20 to 56 percent)with HCC have previously undiagnosed cirrhosis

HCC in Hepatitis B Virus
HCC can develop in patientswith chronicHBV, even in the absence of cirrhosis.
However, 70 to 90 percent of patientswith HBV who develop HCC will have cirrhosis
otherfactors-
◦ Viral load,
◦ Active viral replication- presence of hepatitis B e antigen (HBeAg),
◦ Genotype C and D are associated with high risk of developing HCC
Risk of HCC is not simply related to HBV exposure but require chronicinfection
Thus, infection acquired during birth (vertical transmission) or early childhood, are at high risk of
developing HCC early in life

HCC in Hepatitis C virus
•HCC in patientswith HCV occurs almost exclusively in patientswith advanced stages of hepatic
fibrosis or cirrhosis
•However, 10 percent of patients with HCV infection who undergo resection for HCC, only mild
degrees of fibrosis are found

CLINICAL FEATURES
Symptoms Frequency (%)
Abdominal pain 59-95
Weight loss 34-71
Weakness 22-53
Abdominal swelling 28-43
Nonspecific GI symptoms 25-28
Jaundice 5-26
Signs
Hepatomegaly 54-98
Ascites 35-61
Fever 11-54
Splenomegaly 27-42
Wasting 25-41
Jaundice 4-35
Hepatic bruit 6-25
Mark feldman, et al. (2010) sleisenger and fordtran's gastrointestinal and liver disease, 10th edn., : Elsevier.

Extrahepatic Metastases
•Common sites of metastases are lung > intra-abdominal lymph nodes > bone >
adrenal gland and Brain metastases (rare)
Uka K, et al. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J
Gastroenterol 2007; 13:414

Paraneoplastic Syndrome
•Carcinoid syndrome
•Hypercalcemia
•Hypertension
•Hypertrophic osteoarthropathy
•Hypoglycemia
•Neuropathy
•Osteoporosis

•Polycythemia (erythrocytosis)
•Polymyositis
•Porphyria
•Sexual changes—isosexual precocity, gynecomastia, feminization
•Thyrotoxicosis
•Thrombophlebitis migrans
•Watery diarrhea syndrome
•Cutaneous paraneoplastic manifestations-pityriasis rotunda

Serum Tumor Markers
◦ Alpha Fetoprotein-
◦ AFP is an α1-globulin normally present in high concentrations in fetal serum
but in only minute amounts thereafter.
◦ Reappearance of high serum levels of AFP strongly suggests the presence of
HCC especially in populations at risk for HCC.
◦ AFP is considered positive if its value is >20 ng/mL and negative if lower.
sensitivity of 60% and specificity of 90%
◦ The specificity and positive predictive value improve for higher cutoff value
of AFP(>400ng/ml), but decreases the sensitivity
Gupta S, et al. Test characteristics of α-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C.
Ann Intern Med 2003;139:46.

False-positiveAFP results (for HCC) also may occur in patients with tumors of endodermal
origin, non-seminomatousgerm cell tumors, and pregnancy
A progressively rising serumAFP concentrationis highly suggestive of HCC.
With improvement in imaging technology and ability to detect smaller tumors, AFP is largely
used as an adjunctive therapyin patient with liver masses
Used in treated patientsto check for recurrence after normalization

Fucosylated Alpha Fetoprotein- AFP
◦ Lens culinaris agglutinin reactive fraction (AFPL3), has been suggested to
improve the specificity of AFP, particularly AFP serum levels from 10 to 200
ng/mL
◦ recommended cutoff value for AFP-L3 to diagnose HCC is higher than 10% of
total AFP,
◦ specificity varies depending on the absolute level of AFP

Des-γ-Carboxy Prothrombin- (also known as prothrombin produced by
vitamin K absence or antagonist II)
◦ raised in most patients with HCC
◦ DCP has been suggested to be a better marker than, or at least complementary to,
AFP
◦ the precise role of DCP in the diagnosis of HCC still requires validation

IMAGING
ULRASONOGRAPHY (US)
◦ US detects most HCCs but may did not distinguish this tumor from other solid
lesions in the liver.
◦ it is more effective as a tool for screening than for diagnosis.
◦ As with all imaging methods, the sensitivity increases with increasing size of
the lesion.
◦ The diagnostic accuracy when used as surveillance test, sensitivity range from
58% – 89% and specificity of greater than 90%.
Bolondi L, et al. Screening for hepatocellular carcinoma in cirrhosis. J Hepatol 2003;39:1076–1084.

Advantages-
◦ safety,
◦ availability, and
◦ cost effectiveness
Drawbacks-
◦ lack of standardization,
◦ examiner dependence, and
◦ limited sensitivity particularly obesity, and with fatty infiltration of the liver

Multiphase/Dynamic Computed Tomography
Most popularimaging techniquefor the diagnosis of HCC.
Dynamic contrast-enhancedCT can includenon-contrast,arterial, portal venous, and delayed phases
Classic and most diagnostic pattern for HCC is a combination of
◦ enhancement in the arterial phase (with the uninvolved liver lacking enhancement),
◦ loss of central nodule enhancement compared with the enhancing uninvolved liver (washout), and
◦ capsular enhancement in the portal-venous and delayed phases.
When the lesion is larger than 2 cm in diameter, this pattern has almost 100%specificity for HCC.

Dynamic Magnetic Resonance Imaging
Dynamic MRI using gadoliniumcontrast agents provides anotherway of distinguishing HCC
from normal liver tissue
Hyperintensity of a noduleon T2-weighted images is specific for HCC
MRI compared to CT, with specificity ranging between 85% and 100%.
Results vary according to HCC size, with MRI performing betterthan CT particularlyin small
lesions
◦ tumours smaller than 20 mm sensitivity of 48% and 62% for CT and MRI, respectively,
◦ tumours equal or larger than 20 mm sensitivity of 92% and 95% for CT and MRI, respectively.
• Chou R, et al. Imaging techniques for the diagnosis of hepatocellular carcinoma. Ann Intern Med 2015;162:697.
• Lee YJ, et al. Hepatocellular carcinoma: diagnostic performance of multidetector CT and MR imaging-a systematic review and meta-
analysis. Radiology 2015;275:97–109.

Other modalities helpful in detecting HCC
HepaticAngiography
Laparoscopy
18-FDG-PET-CT-Usefull in looking for extra hepaticmetastasis that would change the treatment
plan.
Sensitivityand specificityof dynamic CT and MRI are superiorto these modalities.

PATHOLOGICAL DIAGNOSIS
Pathological diagnosis is required in two scenarios:
a) in patients without cirrhosis, and
b) if radiology is not typical in at least one of two imaging techniques (CT and MRI).
not an ideal gold standard, becauseof variation introducedby sampling and complications.
Sensitivity ranges between 70 and 90% for all tumor sizes, and decrease to <50% in tumors 1–2 cm
in size.
The risk of complicationssuch as tumor seeding and bleedingafter liver biopsy is ~3%.
Biopsies should be assessed by an expert hepatopathologist.

Positive staining in two of four markers is highly specific for HCC.
◦ Glypican 3 (GPC3),
◦ Glutamine synthetase,
◦ Heat shock protein 70 (HSP70), and
◦ Clathrin heavy chain
Negative biopsy does not eliminate the diagnosis of HCC.
Second biopsy is recommended in case of
◦ inconclusive findings, or
◦ growth or change in enhancement patternidentified during follow up.

SURVEILLANCE
Goal of HCC surveillance is to reducemortality, and groups at risk for HCC
Ultrasonography
◦ Acceptable diagnostic accuracy,
◦ absence of risks,
◦ non-invasiveness,
◦ good acceptance by patients and relatively moderate cost
Multidetector CT or dynamic MR imaging are not cost-effective for surveillance
AFP can be used as surveillance in association with USG but never alone

According to AASLD and EASLD surveillance is done in the following patients
o Patients with cirrhosis, Child-Pugh class A and B
o Patients with cirrhosis, Child-Pugh class C, only if awaiting liver transplantation
o Patients with chronic hepatitis C virus and advanced liver fibrosis (stage F3)
o Non-cirrhotic patients with hepatitis B virus (HBV) infection with any of the following
characteristics:
• Active hepatitis (elevated serum alanine aminotransferase [ALT] and/or high viral load)
• Family history of HCC
• Africans and AfricanAmericans
• Asian males over 40 years of age
• Asian females over 50 years of age

Algorithm used for surveillance in HCC

Several staging systems have been proposed, including the Barcelona Clinic Liver
Cancer (BCLC), Okuda, Cancer of the Liver Italian Program (CLIP), ALBI (albumin-
bilirubin) grade, Chinese University Prognostic Index, among others.
BCLC offer the most prognostic information, it includes
◦ extent of the primary lesion,
◦ performance status,
◦ vascular invasion, and
◦ extra-hepatic spread.

HCC
Child-Pugh A,
Single<2cm
ECOG PS 0-1
Child-Pugh A-B Child-Pugh C
Very early
Stage 0
Single or 2-3
nodules <3cm,
ECOG PS 0-1
Multi-nodular,
ECOG PS 0-1
Portal Vein
invasion,
N1,M1,
ECOG PS 0-2
Any T,N OR M,
ECOG PS >2
Early
Stage A
Intermediate
Stage B
Advanced
Stage C
Terminal
Stage D
BCLC (Barcelona Clinic Liver Cancer) Satging for HCC
ECOG PS – Eastern CooperativeOncologyGroup Performance Status

OUTCOME PREDICTION AND TREATMENT
ALLOCATION
Patients with HCC are classified into five stages (0, A, B, C and D) accordingto BarcelonaClinic
Liver Cancer staging
Treatment allocationincorporatestreatment dependentvariables, which have been shown to
influence therapeuticoutcome, such as bilirubin, portal hypertension or presence of symptoms-
ECOG PS

• Preserved liver function-Child–Pugh A without ascites

Available therapeuticoptionscan be divided into curative and non-curative interventions.
Curative therapies include - long-term response and improved survival
◦ surgical resection,
◦ orthotropic Liver Transplantation, and
◦ ablative techniques such as thermal ablation.
Non-curative therapies - attempt to prolongsurvival by slowing tumor progression,
◦ transarterial chemoembolization (TACE),
◦ transarterial radioembolization (TARE),
◦ stereotactic body radiation therapy (SBRT), and
◦ systemic therapy.

Surgical therapy, whether by tumor resection or liver transplantation, offers the best chance of
cure for HCC.
5-year survival of 60%
Liver resection and transplantationis first option with early tumours
◦ Extended to otherstages after non-surgical tumour downstaging
Surgical resection is a viable option, particularlyfor child-pugh class A patientswithout portal
hypertensionand with a MELD score of 9 or less
Peri-resection mortality in cirrhoticpatients should be <3%
Recurrencerate after resection is 70% at 5 years.
Ishizawa T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma.
Gastroenterology 2008; 134: 1908-16

Liver Transplantation
Milan criteria are the benchmark for selecting patientsfor LT
◦ a single lesion up to 5 cm in size or
◦ 2 to 3 lesions each up to 3 cm,
◦ with no large-vessel vascular invasion or
◦ Metastasis
Survival of 60 to 80% at 5 years and 50% at 10 years, respectively
Post-transplantation tumorrecurrencelower than 15%
If estimated time to transplantationis greater than 6 months,
◦ bridging therapy with RFA or trans-arterial chemoembolization can often be performed to prevent tumor
growth beyond Milan criteria
Mazzaferro V, et al. Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma.
Gastroenterology 2018; 154: 128-39

Ablation is recommended in patientswith BCLC stage 0 or A tumors who are not candidatesfor
surgery
In patientswith very early stage HCC (BCLC-0) radiofrequencyablation in favourable locations
can be adopted as first-line therapy even in surgical patients
Types of ablationtherapies
◦ Percutaneousethanol injection (PEI),
◦ Hyper-thermic treatments (heating of tissue at 60◦–100 ◦ C) – including
◦ Radiofrequency ablation (RFA),
◦ Microwave ablation (MWA), and
◦ Laser ablation
◦ Cryo-ablation (freezing of tissue at -20◦C and -60◦C)

Most proceduresare performed using a percutaneousapproach, although in some instances ablation
with laparoscopyis recommended.
Percutaneousethanolinjection (PEI) - induces coagulative necrosis of the lesion as a result of cellular
dehydration, protein denaturation, and chemical occlusion of small tumour vessels
PEI in < 2cm lesion - 90% of completetumor necrosis
PEI in >2cm lesion – high recurrencerate of 49%
RFA is favored over PEI as it shows betteroverall survival (OS), disease-free survival, and recurrence.
• Sala M, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 2004;40:1352–1360.
• Pompili M, et al. Single hepatocellular carcinoma smaller than 2 cm: are ethanol injection and radiofrequency ablation equally effective? Anticancer Res 2015;35:325–332,.

Patients with intermediate-stagetumors (BCLC stageB) should be considered for transarterial
therapies.
It can be considered if the waiting time for transplantation is more than 6 months (bridging therapy)
It can be used to reduce the size of the tumor to make resection or transplantation possible
(downstaging)or to allow a more conservative resection
TACE should not be used in patients with:
◦ Decompensatedliver disease
◦ Advancedliver and/orkidney dysfunction
◦ Macroscopic vascularinvasion
◦ Extra hepatic spread

Trans arterial
chemoembolisatoion
Conventional Drug eluting beads
• Sustained release of drug
• Lower toxicity profile

Selective Internal Radiation Therapy (SIRT)
Infusion of radioactive substancessuch as 131-iodine-labelledlipiodolor microspheres
containingyttrium-90 (Y90) agents into the hepatic artery.
The hypervascularity of HCC, intra-arterial injected microspheres are preferentiallydelivered to
the tumour-bearingarea and selectively emit high-energy, low penetrationradiation to the tumour.
Median survival time
◦ 16.9 months to 17.2 months for patients at intermediate stages and
◦ 10 months to 12 months for patients at advanced stages with portal vein invasion.
Around 20% of patients present liver-related toxicity and 3% treatment-relateddeath
• Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres:
a comprehensive report of long-term outcomes. Gastroenterology 2010;138:52–64.

Targeted chemotherapy
First-line therapies
◦ Sorafenib
◦ Lenvatinib
Second line therapies
◦ Regorafenib
◦ Cabozantinib
◦ Ramucirumab

SORAFENIB
It is an Inhibitor of the serine–threonine kinases Raf-1 and B-Raf and the receptor tyrosine
kinase activity of vascular endothelial growth factor receptors [VEGFRs] and platelet-derived
growth factor receptor β [PDGFR-β]
Thus it inhibits cell proliferation, tumor angiogenesis, and increases the rate of apoptosis
First drug approved by FDA for the use in HCC in 2007

Sorafenib Hepatocellular Carcinoma Assessment
Randomized Protocol (SHARP) trial
A large double-blinded placebo-controlled phase III trial, shows positive survival results.
Overall survival (OS) of patients in the sorafenib (400mg BD) group was 10.7 months compared
to 7.9 months in the placebo group (HR, 0.69;95%, p = 0.00058),
Representing a 31% decrease in the relative risk of death.
Most common grade 3 drug-related adverse events observed are diarrhoea and hand-foot skin
reaction, which occurred in 8–9%, and 8–16% of patients, respectively
The magnitude of survival benefit was similar to that demonstrated in a parallel phase iii trial
conducted in the asian-pacific population, in which hepatitis b was the main cause of HCC.

Lenvatinib
Lenvatinib received FDA approval for the treatment of HCC in 2018.
Lenvatinib was investigated in an open-label,phase III, multicentre, non-inferioritytrial involving
patientswith advanced HCC vs sorafenib
Dose - Body weight ≥60 kg: 12 mg/day; <60 kg: 8 mg/day
Median overall survival: lenvatinib, 13.6 months vs. Sorafenib, 12.3 months, hazard ratio [HR]:
0.92; 95% ci 0.79–1.06),
Lenvatinib also improved progression-free survival (7.4 months vs. 3.7 months on sorafenib) and
time to progression (8.9 months vs. 3.7 months on sorafenib).
most common grade 3/4 treatment-relatedAEs were hypertension, diarrhoea and palmar-plantar
erythrodysesthesia.

Regorafenib
Oral multi-kinase inhibitor ( VEGFR2, TIE-2)
FDA have approved Regorafenib in patients with HCC who have been previously treated with
sorafenib.
RESORCE (Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma) trial
◦ Regorafenib (160 mg p.o. once daily 3 weeks on / 1 week off) showed survival benefits compared to
placebo who progressed on sorafenib.
◦ Regorafenib improvedthe median OS from 7.8 months on placebo to 10.6 months (HR 0.63; p <0.0001)
◦ Radiographicobjectiveresponse was 10.6% and
◦ disease control rate 65.2%.
◦ leading AEs were hand-foot-skin-reaction, fatigue and hypertension

Cabozantinib - CELESTIAL trial
MET, VEGFR2 and RET inhibitor.
The phase III celestial trial comparing cabozantinib (60 mg daily) with placebo in second line
treatment of advanced HCC (Child-Pugh A, ECOG PS 0/1) shown to reduce the risk of death, as
compared with placebo (hazard ratio, 0.76).
Improved overall survival from 8.0 months on placebo to 10.2 months
grade 3 or 4 adverse events, mostlyhypertension and palmar-plantar erythrodysesthesia

Ramucirumab – REACH trial
A monoclonalantibodytargeting VEGFR-2 was compared to placeboin a randomised doubleblind
phase III trial includingpatientsprogressing on sorafenib.
The study did not meet the primary endpoint.
A pre-specified subgroup analysis of patientswith high baseline alpha-fetoprotein(> 400 ng/ml),
showed a significantly bettersurvival with ramucirumab than placebo(7.8 months vs. 4.2 months;
HR 0.67; 95% CI 0.51–0.90).
Anotherphase III trial (REACH-2) is currentlyongoing for this specific population.

Other agents
Other treatment approaches subsequently tested in phase 3 trials failed to improve on or
parallel the efficacy of sorafenib as frontline treatment;
They also did not increase survival, as compared with placebo, for second-line treatment.
These agents and treatments include
◦ Erlotinib,
◦ Brivanib,
◦ Sunitinib,
◦ Linifanib,
◦ Everolimus,
◦ Doxorubicin,
◦ FOLFOX (fluorouracil,leucovorin[folinic acid], and oxaliplatin),
◦ Tivanitinib.

IMMUNOTHERAPY
Tremelimumab - a cytotoxicT-lymphocyte-associatedprotein 4 (CTLA-4) inhibitor, a phase II
trial showed a partial response rate of 17.6%.
Nivolumab –
◦ A programmed cell death 1 (PD-1) immune checkpoint inhibitor,
◦ In patients who had disease progression or unacceptable adverse effects with sorafenib, treatment with
the nivolumab achieved a median survival of 15.6 months in a single-group phase 2 trial.
◦ The overall response was 14.3% according to response evaluation criteria in solid tumors (RECIST), and
in 55% of the patients with a response, the duration of the response was more than 12 months.
◦ These response data prompted FDA approval under the accelerated program.

Pembrolizumab -
◦ another PD-1 inhibitor,
◦ A phase 2 trial showed a similar response (17%) but shorter survival (median, 12.9 months);
◦ the associated phase 3 trial of pembrolizumab for second-line treatment did not show longer overall
survival or progression-free survival than placebo.

TREATMENT RESPONSE EVALUATION AND FOLLOW UP IN HCC
The treatment response evaluation should be done by dynamic CT or MRI studies using the modified-
RECIST (modified-Response Evaluation Criteria in Solid Tumors) criteria.
The timing of initial treatment response evaluation should depend on treatment used as follows:
Resection—4 weeks
Liver transplantation—3 months
Percutaneousablation—4 weeks
TACE—4 weeks

The follow-up of patientswho underwentcurative treatmentsevery 3 months for the first 2 years
and routinesurveillance every 6 months thereafter.
More advanced stages of HCC who were treated with TACE or systemic agents follow up should
be doneevery 2 months.

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