Prepared by:

DR. Yasar Albushra

Primary liver tumors that develop in the setting of chronic liver disease.

World wide, it is the 5th most common cancer and the 2nd cause of cancer related death with about 600,000 annual death

ETIOLOGYLIVER CIRRHOSIS OF VARIOUS CAUSES (VIRAL

HEPATITIS, METABOLIC, ALCOHOL ABUSE, PRIMARY BILLIARY CIRRHOSIS, NON-ALCOHOLIC STEATOHEPATITIS, AFLATOXIN EXPOSURE).

30%-50% OF HB CARRIERS WITH HCC ARE NOT CIRRHOTIC.

ANNUAL RATE OF HCC IN HB CLD IN USA IS 0.5% IN PATIENT WITHOUT CIRRHOSIS, 2.5% IN PATIENT WITH CIRRHOSIS.

INCREASING HB DNA VIRAL LOAD, ASIAN MALE >40 YEARS, ASIAN FEMALE >50, AFRICAN AND NORTH AMERICAN BLACKS ARE RISK FACTORS FOR HCC IN HB CLD

INCIDENCE IS HIGHER IN MALE THAN FEMALE.

Relation between hepatocellular carcinoma rate and aflatoxin intake

Location HCC rate, per 100,000/yr* Aflatoxin B intake, ng/kg per day

Kenya, high altitude 1.2 3.5

Kenya, low altitude 4.0 10

Thailand 6.0 45

Mozambique 17.7 131.4

* Based on hospitalized patients.

Adapted from: Van Rensburg SJ, Cook-Mozaffari P, van Schalkwyk DJ, et al. Br J Cancer 1985; 51:713.

CLINICAL MANIFESTATIONS OF HCC

NON-SPECIFIC, INCLUDING SYMPTOMS OF CHRONIC LIVER DISEASE, DECOMPENSATE LIVER CIRRHOSIS, ABDOMINAL DISTENTION DUE TO ASCITES.

PARANEOPLASTIC MANIFESTATIONS (HYPOGLYCEMIA, HYPERCALCEMIA, ERYTHROCYTOSIS).

TUMOR RUPTURE MANIFESTED BY SUDDEN SEVERE ABDOMINAL PAIN.

LABORATORY: ABNORMAL LFT, ANEMIA THROMBOCYTOPENIA, RISING ALPHA FETO PROTEIN (AFP)

SCREENING FOR HCC

SYMPTOMATIC DISEASE IS FREQUENTLY ASSOCIATED WITH ADVANCED STAGE AND POOR PROGNOSIS.

TO IMPROVE THE PROGNOSIS, REGULAR SURVEILLANCE EVERY 6 MONTHS WITH LIVER ULTRASOUND AND AFP FOR AT RISK PATIENT IS RECOMMENDED.

A CHINESE STUDY OF 18816 PATIENTS WITH HB CLD FOUND THAT SCREENING WITH AFP AND LIVER ULTRASOUND EVERY 6 MONTHS RESULTED IN 37% DECREASE IN HCC MORTALITY.

DIAGNOSIS OF HCC

IMAGING: - HCC IS CHARACTERIZED BY ARTERIAL HYPERVASCULARITY AND DERIVES ITS BLOOD SUPPLY FROM THE HEPATIC ARTERY WHILE NORMAL LIVER BLOOD SUPPLY IS FROM THE PORTAL VEIN.

IMAGING MODALITIES INCLUDE HELICAL CT, 4 PHASE DYNAMIC CONTRAST ENHANCING MRI AND CONTRAST ENHANCED LIVER ULTRASOUND.

CLASSIC ARTERIAL ENHANCEMENT USING A SINGLE MODALITY IS CONSIDERED DIAGNOSTIC FOR HCC IN PATIENTS AT RISK WITH LIVER NODULE - 1 CM (USE 2ND

MODALITY IF NO ENHANCEMENT).BIOPSY IS REQUIRED FOR LIVER NODULE 2 CM WITHOUT

CLASSIC ENHANCEMENT. EITHER BIOPSY OR FOLLOW UP EVERY 3-6 MONTHS WITH REPEAT IMAGING AND AFP IS RECOMMENDED BY NCCN GUIDELINES FOR LESIONS 1-2 CM WITHOUT CLASSIC ENHANCEMENT.

REGULAR FOLLOW UP IF BIOPSY IS NEGATIVE.

Algorithm for investigation of small nodules found on screening in patients at risk for hepatocellular carcinoma

CT: computed tomography; HCC: hepatocellular carcinoma; MDCT: multidetector CT scan; MRI: magnetic resonance imaging; US: ultrasound.

Reproduced with permission from: Bruix J, Sherman M. Management of Hepatocellular Carcinoma: An Update. Hepatology 2010. Copyright © 2010 John

Wiley & Sons.

ALPHA FETO PROTEIN

A GLYCOPROTEIN THAT IS PRODUCED BY FETAL LIVER AND YOLK SAC DURING PREGNANCY.

AFP LEVEL MAY RISES IN PATIENTS WITH HCC, GERM CELL TUMORS, OTHER MALIGNANCY INCLUDING CHOLANGIOCARCINOMA, CA OF STOMACH, METASTATIC CA COLON TO LIVER, CLD WITHOUT HCC.

LEVEL OF 400 MG/ML – 500 MG/ML IS CONSIDERED DIAGNOSTIC FOR HCC, HOWEVER, AFP AS TUMOR MARKER IS NOT SENSITIVE AND NOT SPECIFIC FOR DIAGNOSIS OF HCC.

IN A SERIES OF 1158 PATIENTS WITH HCC ONLY 18% HAD VALUE >400 MG/ML AND THE LEVEL WAS NORMAL IN 46%.

HIGH AFP IS ASSOCIATED WITH POOR PROGNOSIS.

STAGING AND INITIAL EVALUATION

EVIDENCE OF PORTAL HTN

ROUTINE LAB WITH CBC, LFT, PT, PTT. AFP, HEPATITIS VIRAL PROFILE, HEPATITIS VIRAL LOAD .

EXTRAHEPATIC METASTASIS ARE UNCOMMON IN SMALL SIZE TUMOR< 5 CM. THE MOST COMMON SITES OF MTASTASES INCLUDE LUNGS, INTRA ABDOMINAL LYMPH NODES, AND BONE.

IMAGING STUDIES TO INCLUDE HELICAL CT OF LIVER OR MRI, TO DETERMINE THE EXTENT OF DISEASE, PRESENCE OF VASCULAR INVASION AND PRESENCE OF PORTAL HYPERTENSION. CHEST IMAGING ,BONE SCAN IF SYMPTOMATIC

ENLARGED ABDOMINAL LYMPH NODE IS COMMON IN PATIENT WITH CIRRHOSIS AND MAY NOT REPRESENT METASTASIS

ASSESSMENT OF LIVER RESERVE USING VARIOUS SCORING SYSTEM I.E. CHILD-PUGH, OKUDA, THE CANCER OF THE LIVER ITALIAN PROGRAM (CLIP) AND BARCELONA CLINIC.

PROGNOSTIC FACTORS IN HCC

CLINICAL STAGE (TUMOR SIZE, VASCULAR INVASION, EXTRA

HEPATIC DISEASE)

GROWTH RATE OF THE TUMOR

LIVER RESERVE – PERFORMANCE STATUS

GRAPHICS

Parameter

Points assigned

1 2 3

Ascites Absent Slight Moderate

Bilirubin <2 mg/dL (<34.2

micromol/liter

2-3 mg/dL (34.2 to 51.3

micromol/liter)

>3 mg/dL (>51.3

micromol/liter

Albumin >3.5 g/dL (35 g/liter) 2.8-3.5 g/dL (28 to 35 g/liter) <2.8 g/dL (<28 g/liter)

Prothrombin time

Seconds over

Control

<4 4-6 >6

INR <1.7 1.7-2.3 >2.3

Encephalopathy None Grade 1-2 Grade 3-4

Modified Child-Pugh classification of the severity of liver disease according to the degree of ascites, the plasma concentrations of bilirubin and albumin, the prothrombin time, and the degree of encephalopathy. A total score of 5-6 is considered grade A (well-compensated) disease); 7-9 is grade B (significant functional compromise); and 10-15 is grade C (decompensated disease). These grades correlate with one- and two-year patient survival: grade A – 100 and 85 percent; grade B – 80 and 60 percent; and grade C – 45 and 35 percent.

Child-Pugh classification of severity of liver disease

CLIP (Cancer of the Liver Italian Program) scoring system for hepatocellular cancer

Variable Score

Child-Pugh stage

A 0

B 1

C 2

Tumor morphology

Uninodular and extension ≤50 percent 0

Multinodular and extension ≤50 percent 1

Massive or extension >50 percent 2

Alpha-fetoprotein

<400 0

≥400 1

Portal vein thrombosis

No 0

Yes 1

The Cancer of the Liver Italian Program (CLIP) score has been used to predict survival in patients with hepatocellular carcinoma. The total score is derived by adding each of the subscores. In one study, median survival was 36, 22, 9, 7, and 3 months for patients in CLIP categories 0, 1, 2, 3, and 4 to 6, respectively. Prospective validation of the CLIP score: A new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 2000; 31:840.

TUMOR CATEGORIES FOLLOWING INITIAL WORK UP

POTENTIALLY RESECTABLE OR TRANSPLANTABLE, OPERABLE BY

PERFORMANCE STATUS AND COMORBIDITIES

UNRESECTABLE DISEASE

INOPERABLE BY PERFORMANCE STATUS OR COMORBIDITY

WITH LOCAL DISEASE ONLY

METASTATIC DISEASE

SURGERY FOR HCCSURGICAL CANDIDATES INCLUDE:

PATIENT MUST BE MEDICALLY FIT FOR MAJOR SURGERY.

EARLY STAGE DISEASE (SOLITARY TUMOR 5 CM OR 3 TUMER NODULES, NON MORE THAN 3 CM WITH NO EXTRAHEPATIC DISEASE).

NO MAJOR VASCULAR INVASION.

ADEQUATE LIVER RESERVE (CHILD-PUGH A, SELECTED CASE OF B).

NO PORTAL HYPERTENSION.

ADEQUATE FUTURE LIVER REMNANT (FLR 20% IN PATIENT WITHOUT CIRRHOSIS AND AT LEAST 30% - 40% IN CHILD A).

PREOPERATIVE PORTAL VEIN EMBOLIZATION IS USEFUL IN PATIENT WITHOUT ADEQUATE POSTOPERATIVE LIVER REMNANT BUT OTHERWISE ARE OPERABLE.

LARGE RETROSPECTIVE STUDIES HAVE SHOWN 5 YEARS SURVIVAL RATE OVER 50% FOLLOWING HEPATOCTOMY, HOWEVER, RECURRENCE RATE IS HIGH >70%.

HEPATIC RESECTION IS CONTROVERSIAL IN PATIENTS WITH LIMITED AND RESECTABLE MULTIFOCAL DISEASE AND IN THE PRESENCE OF MAJOR VASCULAR INVASION.

LIVER TRANSPLANTATION

PATIENTS WITH PORTAL HYPERTENSION OR INADEQUATE POSTOPERATIVE LIVER REMNANT ARE CANDIDATE FOR TRANSPLANT IF THEY MEET OTHER CRITERIA.

MILAN CRITERIA (ADOPTED BY UNOS) INCLUDE:- SINGLE TUMOR 5 CM OR 2-3 TUMORS NON > 3 CM.- NO MAJOR VASCULAR INVASION.- NO EXTRA HEPATIC DISEASE.

A STUDY OF LIVER TRANSPLANT PATIENTS WHO MET MILAN CRITERIA SHOWED 4 YEARS DISEASE FREE SURVIVAL AND OVERALL SURVIVAL OF 85% AND 92%

UCSF CRITERION (EXPANSION OF MILAN) INCLUDES A SINGLE HCC TUMOR 6.5 CM, MAXIMUM OF 3 TUMORS WITH NO TUMOR > 4.5 CM (CUMULATIVE TUMOR SIZE 8 CM).

TRANSPLANTABLE PATIENTS WHO MET USCF CRITERIA HAD 5 YEARS SURVIVAL OF 38% - 93%.

BRIDGE THERAPY (RFA, TACE, SORAFENIB) IS BEING INCREASINGLY USED FOR LIVER TRANSPLANT CANDIDATE ON THE WAITING LIST.

DOWNSTAGING FOR PATIENTS WITH LOCOREGIONAL DISEASE WHO DON’T MEET TRANSPLANT CRITERIA HAVE RESULTED IN IMPROVE DFS IN SOME RECENT STUDIES.

PRINCIPLES OF LOCOREGIONAL THERAPY

ALL HCC PATIENTS SHOULD BE EVALUATED FOR POTENTIAL

CURATIVE THERAPIES (RESECTION, TRANSPLANTATION). THOSE

PATIENTS NOT CANDIDATES FOR CURATIVE TREATMENTS MAY BE

TREATED WITH LOCO-REGIONAL APPROACHES. THESE ARE BROADLY

CATEGORIZED INTO ABLATION AND TRANS-ARTERIAL

EMBOLIZATION.

LOCAL REGIONAL THERAPY

INVOLVES INDUCTION OF TUMOR NECROSIS BY- LOCAL ABLATION- EMBOLIZATION

THE EXTENT OF TUMOR NECROSIS IS ASSESSED BY A FOLLOW UP DYNAMIC CT/MRI AT CERTAIN TIME AFTER THE PROCEDURE.

THE ABSENCE OF CONTRAST UPTAKE WITHIN THE TUMOR AS COMPARED TO IMAGING FINDINGS PRIOR TO TREATMENT IS AN INDICATIVE OF NO RESIDUAL TUMOR ACTIVITY AND COMPLETE TUMOR NECROSIS.

EUROPEAN ASSOCIATION FOR THE STUDY OF LIVER DISEASE RESPONSE CRITERIA USING DYNAMIC IMAGING STUDIES IN PATIENTS WITH HCC TREATED WITH LOCOREGIONAL

THERAPY

CR: ABSENCE OF ENHANCED TUMOR AREA

PR: > 50% DECREASE IN ENHANCED AREA

PD: > 25% INCREASE IN THE SIZE OF ≥ 1

MEASURABLE LESION OR APPEARANCE OF

NEW LESION

STABLE DISEASE: BETWEEN PR AND PD

ABLATION THERAPY

TUMOR NECROSIS CAN BE INDUCED BY EITHER PERCUTANEOUS ETHANOL INJECTION (PEI), RADIOFREQUENCY ABLATION (RFA), CRYOABLATION OR MICROWAVE.

RFA IS GENERALLY MORE EFFECTIVE THAN PEI.

HEPATECTOMY FOR PATIENTS WHO MEET RESECTION CRITERIA RESULTS IN BETTER 5 YEARS SURVIVAL AND RECURRENCE FREE SURVIVAL IN COMPARISON TO RFA.

TUMOR SIZE IS A MAJOR FACTOR IN DETERMINING THE EFFECTIVENESS OF ABLATION THERAPY FOR HCC WITH RECOMMENDATION TO RESTRICT ABLATION TO TUMOR SIZE ≤ 3 CM.

PRINCIPLES OF ABLATION (RADIOFREQUENCY, CRYOABLATION, PERCUTANEOUS ALCOHOL INJECTION, MICROWAVE):

ALL TUMORS SHOULD BE AMENABLE TO ABLATION SUCH THAT THE TUMOR AND MARGIN OF NORMAL TISSUE IS TREATED.

TUMORS SHOULD BE IN A LOCATION ACCESSIBLE FOR PERCUTANEOUS/LAPAROSCOPIC/OPEN APPROACHES FOR ABLATION.

TUMORS 3 CM ARE OPTIMALLY TREATED WITH ABLATION. LESIONS BETWEEN 3-5 CM MAY BE TREATED USING COMBINATION EMBOLIZATION AND ABLATION AS LONG AS TUMOR LOCATION IS FAVORABLE. UNRESECTABLE/INOPERABLE LESIONS >5 CM SHOULD BE CONSIDERED FOR TREATMENT USING ARTERIAL EMBOLIC APPROACHES OR SYSTEMIC THERAPY. 1-2

CAUTION SHOULD BE EXERCISED WHEN ABLATING LESIONS NEAR MAJOR VESSELS, MAJOR BILE DUCTS, DIAPHRAGM, AND OTHER INTRA-ABDOMINAL ORGANS.

SORAFENIB IS APPROPRIATE FOR POST ABLATION THERAPY IN PATIENTS WITH ADEQUATE LIVER FUNCTION ONCE BILIRUBIN RETURNS TO BASELINE IF THERE IS EVIDENCE OF RESIDUAL/RECURRENT TUMOR NOT AMENABLE TO ADDITIONAL LOCAL THERAPIES. THE SAFETY AND EFFICACY OF THE USE OF SORAFENIB CONCOMITTANTLY WITH ABLATIVE PROCEDURES IS BEING INVESTIGATED IN ONGOING CLINICAL TRIALS.

EMBOLIZATION

INCLUDE: CHEMOEMBOLIZATION, BLAND EMBOLIZATION AND

RADIOEMBOLIZATION.

FEASIBILITY IS BASED ON THE TUMOR BLOOD SUPPLY IS DERIVED

MAINLY FROM THE HEPATIC ARTERY AND THE FACT THAT HCC IS

USUALLY HYPERVASCULAR.

GENERAL SELECTION CRITERIA FOR EMBOLIZATION INCLUDE

UNRESECTABLE (INOPERABLE DISEASE WITH TUMOR NOT

AMENABLE FOR ABLATION-THERAPY)

ABSENCE OF SIGNIFICANT EXTRAHEPATIC DISEASE.

PRINCIPLES OF EMBOLIZATIONALL TUMORS IRRESPECTIVE OF LOCATION MAY BE AMENABLE TO

EMBOLIZATION (CHEMOEMBOLIZATION, BLAND EMBOLIZATION, RADIOEMBOLIZATION) PROVIDED THAT THE ARTERIAL BLOOD SUPPLY TO THE TUMOR MAY BE ISOLATED WITHOUT NON-TARGET EMBOLIZATION. 3-5

CHEMOEMBOLIZATION/BLAND EMBOLIZATION ARE RELATIVELY CONTRAINDICATED IN PATIENTS WITH BILIRUBIN > 3 MG/DL UNLESS SEGMENTAL INJECTIONS CAN BE PERFORMED. 6

CHEMOEMBOLIZATION IS RELATIVELY CONTRAINDICATED IN CASES OF MAIN PORTAL VEIN THROMBOSIS AND ABSOLUTELY CONTRAINDICATED FOR CHILD-PUGH CLASS C.

THE ANGIOGRAPHIC ENDPOINT MAY BE CHOSEN BY THE TREATING PHYSICIAN AND IS DEPENDENT ON SIZE OF HEPATIC VESSELS, FLOW DYNAMICS, TUMOR VASCULARITY, PATENCY OF THE PORTAL VEIN AND NUMBER OF PREVIOUS ARTERIAL TREATMENTS.

SORAFENIB IS APPROPRIATE FOR POST TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION (TACE) IN PATIENTS WITH ADEQUATE LIVER FUNCTION ONCE BILIRUBIN RETURNS TO BASELINE IF THERE IS EVIDENCE OF RESIDUAL/RECURRENT TUMOR NOT AMENABLE TO ADDITIONAL LOCAL THERAPIES. THE SAFETY AND EFFICACY OF THE USE OF SORAFENIB CONCOMITTANTLY WITH TACE IS BEING INVESTIGATED IN ONGOING CLINICAL TRIALS.

BLAND EMBOLIZATION (TAE) AND CHEMOEMBOLIZATION (TACE)

RANDOMIZED TRIALS OF TAE OR TACE VERSUS BEST SUPPORTIVE CARE SHOWED SURVIVAL ADVANTAGE FOR TACE OVER CONSERVATIVE CARE.

NO SIGNIFICANT SURVIVAL ADVANTAGE FOR TACE OVER TAE, ALTHOUGH THE 1 AND 2 YEARS SURVIVAL RATE WERE HIGHER FOR TACE COMPARED TO TAE IN ONE TRIAL.

PREDICTORS OF POOR OUTCOME FOLLOWING TAE IN ONE TRIAL WERE TUMOR SIZE >5 CM, 5 OR MORE TUMORS AND EXTRAHEPATIC DISEASE. OTHER PREDICTORS OF POOR OUTCOME INCLUDE CHILD-PUGH CLASS C, S. BILIRUBIN ≥3 MG/DL AND PORTAL VEIN THROMBOSIS (ABSOLUTE CONTRAINDICATION TO TACE & TAE).

COMPLICATIONS OF TAE AND TACE INCLUDE PORTAL VEIN THROMBOSIS, CHOLYCYSTITIS AND BONE MARROW SUPPRESSION AND POST EMBOLIZATION SYNDROME (ABDOMINAL PAIN, FEVER, AND INTESTINAL ILEUS).

TAE AND TACE RELATED MORTALITY IS <5%.

LLOVET JM ET AL LANCET 2002; 359. 1734-1739

DHANASEKRAN R ET AL J SURG ONCOL 2010; 101:476-480

COMBINATION THERAPY

A RECENT META-ANALYSIS OF 10 RCT COMPARING ABLATION WITH

THOSE OF TACE ALONE AND COMBINATION OF BOTH SUGGEST

THAT THERE IS A SIGNIFICANT SURVIVAL ADVANTAGE FOR THE

COMBINATION OF TACE AND PEI IN LARGE SIZE TUMOR, HOWEVER

THERE WAS NO ADVANTAGE FOR THE COMBINATION OF TACE AND

PEI OVER RFA ALONE FOR THE TREATMENT OF SMALL SIZE HCC.

Wang W et al Liver Int 2010;30:741-749

RADIOEMBOLIZATION (TARE)

TARE IS ACCOMPLISHED THROUGH CATHETER BASED ADMINISTRATION OF MICROSPHERES IN WHICH YTTRIUM 90, AN EMITTER OF BETA RADIATION, IS EMBEDDED.

A RECENT COMPARATIVE EFFECTIVE ANALYSIS OF HCC TREATED WITH TARE OR TACE HAD SIMILAR SURVIVAL TIMES. HOWEVER, TARE RESULTED IN LONGER TIME TO PROGRESSION AND LESS TOXICITY.

COMPLICATIONS INCLUDE CHOLECYSTITIS AND ABSCESS FORMATION.

Salem R Gastroenterology 2011;140:497-507

NCCN RECOMMENDATION FOR LOCOREGIONAL THERAPIES

PATIENTS WHO MEET RESECTION CRITERIA HEPATOTECTOMY IS RECOMMENDED.

PERCUTANEOUS ABLATION IS RECOMMENDED FOR PATIENTS WHO ARE NOT SURGICAL CANDIDATE AND TUMOR ≤ 3 CM.

PATIENTS WITH UNRESECTABLE/INOPERABLE HCC AND TUMOR SIZE 3-5 CM MAY BE TREATED WITH COMBINATION OF EMBOLIZATION AND ABLATION. EMBOLIZATION IS RECOMMENDED FOR PATIENTS WITH TUMORS > 5 CM.

SYSTEMIC THERAPY

SORAFENIB: MULTI-TYROSINE

KINASE INHIBITOR THAT INHIBIT

RAF AND VEGFR RESULTING IN

SUPPRESSION OF ANGIOGENESIS

AND CELL PROLIFERATION.

RANDOMIZED PHASE III TRIALS COMPARING SORAFENIB WITH BEST SUPPORTIVE CARE IN

ADVANCED HCC

Median Survival in Months

Sorafenib Best Supportive Care P

* SHARP(602 patients)

10.7 7.9 <0.001

** Asian Pan Pacific

(226 patients)

6.5 4.2 0.014

* > 90% of patients in both trials were in Child-Pugh A** 70% of case in the Asian trial were HB related HCC

Llovet et al N Engl J Med 2008;359:378Cheng AL Lancet Oncol 2009;10:25

SORAFENIB IN CHILD PUGH B PATIENTS

A PHASE II TRIAL OF SORAFENIB IN 137 PATIENTS, 28% WERE CHILD-PUGH CLASS B SHOWED MEDIAN SURVIVAL OF 3.2 MONTHS AND 10.5 MONTHS IN CLASS B AND A RESPECTIVELY.

A REPORT OF 1586 PATIENTS TREATED WITH SORAFENIB AND REGISTERED IN THE INTERNATIONAL GIDEON (GLOBAL INVESTIGATION OF THERAPEUTIC DECISION IN HCC AND ITS TREATMENT WITH SORAFENIB) THE SAFETY PROFILE WAS SIMILAR BETWEEN CHILD A & B CIRRHOSIS BUT A GREATER PERCENTAGE OF PATIENTS WITH CHILD B DISCONTINUED TREATMENT DUE TO ADVERSE EFFECTS AND THEY ALSO HAD HIGHER DEATH RATE DURING TREATMENT UP TO 30 DAYS FROM THE LAST SORAFENIB DOSE.

SIDE EFFECTS OF SORAFENIB

INCLUDE HAND AND FOOT SYNDROME, DIARRHEA, HYPERTENSION, THYROID DYSFUNCTION, RARELY FATAL LIVER TOXICITY.

A SUBGROUP ANALYSIS OF DATA FROM THE SHARP TRIAL SHOWED THAT PATIENTS WITH MILD TO MODERATE LIVER DYSFUNCTION (≥ 1.8 TIMES THE UPPER LIMIT OF NORMAL DIDN’T EXPERIENCE INCREASED HEPATIC OR OTHER TOXICITY.

A PHASE I TRIAL SUGGEST DOSE REDUCTION TO 200MG B.I.D. IN PATIENTS WITH S. BILIRUBIN 1.5-3 TIMES THE UPPER LIMIT OF NORMAL AND THE DRUG CAN’T BE TOLERATED IN MORE SEVERE HYPERBILIRUBINEMIA.

NCCN RECOMMENDATION FOR SORAFENIB

RECOMMENDED FOR PATIENTS WITH

EXTENSIVE UNRESECTABLE/INOPERABLE

OR METASTATIC HCC IF PATIENTS ARE

NOT CANDIDATE FOR LIVER TRANSPLANT.

CATEGORY I FOR CHILD-PUGH A AND 2A

FOR SELECTED PATIENTS WITH CLASS B

Barcelona clinic liver cancer staging classification and treatment algorithm

HCC: hepatocellular carcinoma; N: nodules; M: metastases; PST: performance status test.* Cadaveric liver transplantation or living donor liver transplantation.Modified with permission from: Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma. J Natl Cancer Inst 2008: 100:698.

PRINCIPLES OF STEREOTACTIC BODY RADIOTHERAPY (SBRT) AND EXTERNAL-BEAM RADIOTHERAPY

THERE IS GROWING EVIDENCE FOR THE USEFULNESS OF RADIOTHERAPY IN THE MANAGEMENT OF HCC. 7,8 ALL TUMORS IRRESPECTIVE OF LOCATION MAY BE AMENABLE TO SBRT OR EXTERNAL-BEAM CONFORMAL RADIATION. SBRT IS OFTEN USED FOR 1-3 TUMORS WITH A CUMULATIVE DIAMETER UNDER 6 CM. SBRT COULD BE CONSIDERED FOR LARGER LESIONS, IF THERE IS AT LEAST 800 CC OF UNINVOLVED LIVER AND LIVER RADIATION TOLERANCE CAN BE RESPECTED. THERE SHOULD BE NO EXTRA-HEPATIC DISEASE OR IT SHOULD BE MINIMAL AND ADDRESSED IN A COMPREHENSIVE MANAGEMENT PLAN. MOST PATIENTS TREATED TODAY WERE IN THE CHILD-PUGH A CATEGORY. RADIOTHERAPY CAN BE CONSIDERED AS AN ALTERNATIVE TO THE ABLATION/EMBOLIZATION TECHNIQUES MENTIONED ABOVE OR WHEN THESE THERAPIES HAVE FAILED.

Kaplan-Meier estimated survival curves based on the CLIP score (log rank test)

Data from: Farinati F, Rinaldi M, Gianni S, Naccarato R. How should patients with hepatocellular carcinoma be staged? Validation of a new prognostic system. Cancer 2000; 89:2266.

Cumulative incidence of hepatocellular carcinoma

Cumulative incidence of hepatocellular carcinoma by:(A) Group of long-term HBV DNA change.(B) Long-term pattern of ALT.Both P values for log-rank tests were <0.001. * Data were not available for 326 participants because of <2 measurements of ALT level.• ALT level ≥45 U/L in ≥50 percent of sequential ALT measurements.Δ At least one ALT level ≥45 U/L but <50 percent of sequential ALT measurements ≥45 U/L.◊ All sequential ALT measurements <45 U/L and at least one ALT level >30 U/L.§ All sequential ALT measurements ≤30 U/L.Reproduced from: Chen CF, Lee WC, Yang HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology 2011; 141:1240. Illustration used with the permission of Elsevier Inc. All rights reserved.

Guidelines for liver transplantation in HCC from the European Association for the Study of the Liver and European Organisation for Research and Treatment of Cancer

Liver transplantation is considered to be the first-line treatment option for patients with single tumors less than 5 cm or ≤3 nodules ≤3 cm (Milan criteria) not suitable for resection(evidence 2A; recommendation 1A)

Perioperative mortality and one-year mortality are expected to be approximately 3 percent and ≤10 percent, respectivelyExtension of tumor limit criteria for liver transplantation for HCC has not been established. Modest expansion of Milan criteria applying the "up-to-seven" in patients without microvascular invasion achieves competitive outcomes, and thus this indication requires prospective validation(evidence 2B; recommendation 2B)

Neoadjuvant treatment can be considered for locoregional therapies if the waiting list exceeds six months due to good cost-effectiveness data and tumor response rates, even though impact on long-term outcome is uncertain(evidence 2D; recommendation 2B)

Down-staging policies for HCCs exceeding conventional criteria cannot be recommended and should be explored in the context of prospective studies aimed at survival and disease progression end-points(evidence 2D; recommendation 2C)

Assessment of downstaging should follow modified RECIST criteriaLiving donor liver transplantation is an alternative option in patients with a waiting list exceeding six to seven months, and offers a suitable setting to explore extended indications within research programs(evidence 2A; recommendation 2B)

HCC: hepatocellular carcinoma.Reproduced from: EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012; 56:908. Table used with the permission of Elsevier Inc. All rights reserved

Groups for whom HCC surveillance is recommended or in whom the risk of HCC is increased, but in whom efficacy of surveillance has not been demonstrated

Population groupAnnual incidence (percent per year) for which

surveillance is considered to be cost-effectiveIncidence of HCC

Surveillance recommended

Asian male hepatitis B carriers over age 40

0.2 0.4-0.6 percent per year

Asian female hepatitis B carriers over age 50

0.2 0.3-0.6 percent per year

Hepatitis B carrier with family history of HCC

0.2Incidence higher than

without family history

African/North American blacks with hepatitis B

0.2HCC occurs at a younger

age

Cirrhotic hepatitis B carriers 0.2-1.5 3-8 percent per year

Hepatitis C cirrhosis 1.5 3-5 percent per year

Stage 4 primary biliary cirrhosis 1.5 3-5 percent per year

Genetic hemachromatosis and cirrhosis

1.5Unknown, but probably

>1.5 percent per year

Alpha 1-antitrypsin deficiency and cirrhosis

1.5Unknown, but probably

>1.5 percent per year

Other cirrhosis 1.5 Unknown

Surveillance benefit uncertain

Hepatitis B carriers younger than 40 (males) or 50 (females)

0.2 <0.2 percent per year

Hepatitis C and stage 3 fibrosis 1.5 <1.5 percent per year

Non-cirrhotic NAFLD 1.5 <1.5 percent per year

HCC: hepatocellular carcinoma; NAFLD: nonalcoholic fatty liver disease.

Reproduced with permission from: Bruix J, Sherman M. Management of Hepatocellular Carcinoma: An Update. Hepatology 2010. Copyright © 2010 John Wiley & Sons.