UNUSUAL PRESENTATION OF HCC

DR. RAJKUMAR, R.

III YR POST GRADUATE

DR. KALAICHELVI D.M. H.O.D. & PROF DEPT. OF MEDICAL ONCOLOGY MADRAS MEDICAL COLLEGE CHENNAI

MR . X 60/ M REFERRED FROM SGE IC/O SWELLING OVER THE ANT. CHEST WALL – 6 MONTHS .H/O PAIN FOR THE PAST- 2 WEEKS. NON ALCOHOLIC/ BEEDI SMOKER

10×7 CM MASS OVER THE ANT. CHEST WALLFIRM IN CONSISTENCYP/A- HEPATOMEGALY

INVESTIGATIONS• CBC- NORMAL• LFT- S. BILIRUBIN- 1.3 DIRECT- 0.9 ALK.POS- 80 T.PROT- 6.8 ALB- 3.7• RFT- NORMAL• HbSAG- NEGATIVE• ANTI HCV- NEGATIVE• HIV I & II- NEGATIVE• ALPHA-FETO PROTEIN- 1.62 IU/ml• USG ABDOMEN- HETEROECHOIC LESION

RIGHT LOBE OF LIVER-11.5×10.5 CM –• IMPRESSION- HCC Rt. LOBE OF LIVER

HCC – METASTATIC

• UNUSAL EXTRA HEPATIC METASTATIC SITE

• NON CIRRHOTIC BACKGROUND• GOOD P.S. STATUS• BCLC STAGE C• SORAFENIB – 200 MG B.I.D.• PALLIATIVE R.T. - STERNUM

LITERATURE REVIEW

HCC: COMMON AND INCREASING

• 694,000 deaths from liver cancer yearly worldwide[1]

• Age-adjusted US incidence has increased 2-fold from 1985-1998[2]

– Expected to continue to increase until 2015-2020[3]

• American Cancer Society statistics for liver cancer in 2010[4]

– Estimated new cases: 24,120– Estimated deaths: 18,910– 5th leading cause of cancer deaths in males

1. GLOBOCAN 2008. 2. SEER stat fact sheets: liver and intrahepatic bile duct. 3. Llovet JM. J Gastroenterol. 2005;40:225-235. 4. American Cancer Society. Cancer facts & figures 2010.

M.M.C. DATA

• 2010-2011• TOTAL NO. CASES- 88 ALCOHOLISM- 36% HEPATITIS B – 14.7% HEP B & ALCO -13.6% HEP C – 1.1%• MALE- 78.4%• FEMALE- 21.2%• BCLC D – 85.3%

HCC: RISK FACTORSThe most important risk factor is cirrhosis

from any cause:1. Hepatitis B (integrates in DNA)2. Hepatitis C3. Alcohol4. Aflatoxin5. Other

HCC: Metastases• Rest of the liver• Portal vein• Lymph nodes• Lung• Bone• Brain

Llovet JM, et al. Hepatology. 1999;29:62-67.

Natural History of Nonsurgical HCC

Study Design: Control Arm of 2 RCTs

• 102 untreated cirrhotic patients with unresectable HCC – Managed with symptomatic treatment

• Median survival of 17 months (range: 1-60 months)– 1-yr survival was 54%– 2-yr survival was 40%– 3-yr survival was 28%

Malignant Transformation:Multistep

Potential Targets

Oxidative stress and

inflammation

Viral oncogenes

Carcinogens

Growth factors Telomere shortening

Cancer stem cells

Loss of cell cycle

checkpoints

Antiapoptosis

Angiogenesis

Normal liver

Liver cirrhosis

Hepatitis CHepatitis B

EthanolNASH

Epigenetic alterationsGenetic alterations

HCC[2]

Dysplastic nodules[1]

1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.

Vascularity of HCC

CONTRAST WASHOUT IN HCC

Arterial Phase Portal Venous Phase

STAGING SYSTEMS IN HCC

Marrero JA, et al. Hepatology. 2005;41:707-716.

Staging System

Hepatic Function Alpha-fetoprotein

Performance Score

Tumor Staging

Okuda Ascites, albumin, and bilirubin

No No Tumor > or < 50% of cross-sectional area of liver

TNM No No No Number of nodules, tumor size, presence of portal vein thrombosis,

and presence of metastasis

CLIP CTP < 400 or ≥ 400 ng/mL

No Number of nodules, tumor > or < 50% area of liver, and portal vein

thrombosis

BCLC CTP No Yes Tumor size, number of nodules, and portal vein

thrombosis

CUPI Bilirubin, ascites, alkaline phosphatase

< 500 or ≥ 500 ng/mL

Presence of symptoms

TNM

JIS CTP No No TNM

GRETCH Bilirubin, alkaline, phosphatase

< 35 or ≥ 35 µg/L

Yes Portal vein thrombosis

Liver transplantation(CLT/LDLT) PEI/RFA Systemic

treatmentCurative treatments50% to 75% at 5 yrs

Randomized controlled trials 40% to 50% at 3 yrs vs 10% at 3 yrs

Chemoembolism

Single

Increased Associateddiseases

Normal No Yes

Terminalstage (D)

Symptomatic treatment

Stage A-C

Okuda 1-2, PST 0-2, Child-Pugh A-B

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Intermediate stage (B)Multinodular, PST 0

Okuda 3, PST > 2,Child-Pugh C

Stage D

Very early stage (0)Single < 2 cm

Carcinoma in situ

Early stage (A)Single or 3 nodules

< 3 cm, PST 0

Advanced stage (C)Portal invasion,N1, M1, PST 1-2

PST 0, Child-Pugh A

Stage 0

Resection

Barcelona Clinic Liver CancerStaging Classification

Llovet JM et al. Lancet. 2003;362:1907-1917.

COMPARISON OF HCC STAGING SYSTEMS

• BCLC system uses key independent predictors of survival– Performance score, portal vein thrombosis,

tumor diameter

• Compared with other staging systems in cohort study– BCLC had best stratification of survival across

all stages– BCLC was only system to have independent

predictive value on survival

• BCLC is the only staging system that stratifies patients into treatment groupsMarrero JA, et al. Hepatology. 2005;41:707-716.

LIVER TRANSPLANTATION FOR HCC:MILAN CRITERIA (STAGE 1 AND 2)

• 5-yr survival with transplantation: ~ 70%• 5-yr recurrent rates: < 15%

+Absence of macroscopic vascular invasion,

absence of extrahepatic spread

Single tumor, not > 5 cm

Up to 3tumors, none>3Cm

Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.

Candidates for RFA/PEI

• Includes individuals who are not candidates for surgery

• Radiofrequency ablation generally preferred over percutaneous ethanol injection– Necrotic effect more predictable across

tumor sizes– Meta-analyses suggest survival benefit

with radiofrequency ablation vs percutaneous ethanol injection

Bruix J, et al. AASLD HCC guidelines. July 2010.

CHEMOEMBOLIZATION

Image courtesy of www.hopkinscoloncancercenter.org.

Contraindications to TACE

• Extrahepatic tumor spread• Lack of portal blood flow

– Portal vein thrombosis, portosystemic anastomoses or hepatofugal flow

• Advanced liver disease (Child-Pugh Class B or C)

• Clinical symptoms of end-stage cancer

Bruix J, et al. AASLD HCC guidelines. July 2010.

Molecular Signaling Pathways in HCC

Wilhelm S, et al. Cancer Res. 2004;64:7099-7109.

Autocrine loop

Tumor Blood Vessels

Tumor Cell

Growth and

survival factors

(eg, VEGF, PDGF)

Sorafenib

PDGF

VEGF

EGF/HGF

ProliferationSurvival

Mitochondria

EGF/HGF

HIF-2

Nucleus

Apoptosis

ERK

RAS

MEK

RAF

Phase III SHARP Study: Sorafenib vs Placebo in Advanced HCC

Primary endpoints: OS, time to symptomatic progressionSecondary endpoint: TTP (independent review)

Llovet JM, et al. N Engl J Med. 2008;359:378-390.

Stratified by macroscopic vascular invasion and/or extrahepatic spread; ECOG PS; geographical region

Patients with advanced hepatocellular

carcinoma, ECOG PS ≤ 2, no

previous systemic treatment(N = 602)

Sorafenib 400 mg PO BID, continuous dosing

(n = 299)

Placebo 2 tablets PO BID, continuous dosing

(n = 303)

Sorafenib in Advanced HCC (SHARP): Survival

Surv

ival

Pro

babi

lity

Mos Since Randomization

1.00

0

0.75

0.50

0.25

Sorafenib median OS:46.3 wks (10.7 mos)(95% CI: 40.9-57.9)Placebo median OS: 34.4 wks (7.9 mos) (95% CI: 29.4-39.4)

HR (S/P): 0.69 (95% CI: 0.55-0.87; P < .001)

Llovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med. 2008;359:378-390.

0 1 2 3 4 5 6 8 9 10 11 12 13 14 15 167 17

Multidisciplinary HCC Management

• HCC is the intersection of 2 diseases– Liver disease and cancer

• Skilled pathologists needed for diagnosis• Specialists required to deliver treatment

options– Surgeons for resection or transplantation– Radiologists for ablation and

chemoembolization

• Hepatologists and oncologists follow treatment strategy and labs

• Midlevel providers bring support, particularly for oral therapy

Conclusions

• HCC occurs in cirrhotic patients and complicates diagnosis and treatment

• The Barcelona Clinic Liver Cancer staging system accounts for key prognostic factors: hepatic function, performance score, and tumor burden

• Chemoembolization is the best option in nonresectable patients without vascular involvement

• Sorafenib is the best option for advanced tumors

• Novel therapies are needed