Hepatocellular Carcinoma

HCC: Incidence

• The most common primary liver cancer

• Increasing all the world

HCC: Risk Factors

The most important risk factor is cirrhosis from any cause:

1. Hepatitis B

2. Hepatitis C

3. Alcohol

4. Aflatoxin

5. Other

HCC: Clinical Features

• Wt loss and RUQ pain (most common)

• Asymptomatic

• Worsening of pre-existing chronic liver dis

• Acute liver failure

PE:

• Signs of cirrhosis

• Hard enlarged RUQ mass

• Liver bruit (rare)

HCC: Metastases

• Rest of the liver

• Portal vein

• Lung

• Bone

• Adrenal

• Brain

• Lymph nodes

HCC: labs

• Labs of liver cirrhosis

AFP (Alpha feto protein)

• Is an HCC tumor marker

• Values more than 200ng/ml are highly suggestive of HCC

• Elevation seen in more than 70% of pt

HCC: Diagnosis

• Clinical presentation

• Elevated AFP

• US

• Triphasic CT scan: early enhancement in arterial phase, wash out in portovenous phase

• MRI with hepatobiliary-specific contrast

• Biopsy

US: HCC

Hepatology, vol 53, no. 3, 2011

HCC: Prognosis

• Tumor size

• Extrahepatic spread

• Underlying liver disease

• Pt performance status

Treatment/Management

• Surgical resection • Liver transplantation

• Percutaneous ablation – Alcohol injection – Radiofrequency ablation

• Transarterial embolization and chemoembolization

• Chemotherapy

“Radical”

“Potentially Curative”

“ Palliative ”

Very early stage (0)

Early stage (A)

Intermediate stage (B)

Advanced stage (C)

Terminalstage (D)

Liver transplantation Chemoembolisation SorafenibResection PEI/RF

Symptomatictreatment

Curative treatments Palliative treatments

Associated diseases

YesNo

Increased

Normal

Single HCC

Portal pressure/

bilirubin

HCC

3 nodules ≤3cm

Hepatology, vol 53, no. 3, 2011

Extrahepatic metastasisMain portal vein tumor thrombus

Solitary or multifocal tumor in noncirrhotic liver or Child A cirrhosis

Sorafenib or systemic therapy trial

Resection /

RFA (for

< 3 cm HCC)

Solitary tumor 5 cm 3 tumors 3 cm

No venous invasion

Child A Child B Child C Child A / B Child’s C

Transplantation TACE Supportive careRFA

HCC

Confined to the liverMain portal vein patent

APASL Consensus on Treatment Algorithm

Tumor 5 cm 3 tumors

Invasion of hepatic / portal vein branches

Yes No

Child A / B Child C

Asia-Pacific Association for Study of Liver Annual Congress, 2009

Tokyo Approach

Ascites

>2.0

Not indicated for hepatectomy

Not Controlled

Total Bilirubin

None or Controlled

1.1-1.5

Limited resection

1.6-1.9

Enucleation

Left hepatectomyRight sectorectomy

Normal

ICG-R15

TrisectorectomyBisectorectomy

Normal 10-19%

Segmentectomy

20-29%

Limited resection

30-39%

Enucleation

>40%

Imamura. J Hepatobiliary Pancreat Surg 2005; 12:16–22

HCC : Resection Surgery is the mainstay of HCC treatment and achieve the

best outcomes in well-selected candidates.

Factors affecting resectability: Size<5cm

number of tumors

involvement of major structures

hepatic function

no extra-hepatic spread

no portal hypertension

5 year survival 60%-70%

3 year recurrence 45 - 60%

Llovet JM. Hepatology 1999; 30: 1434–40.

Mazzaferro V, et al. N Engl J Med 1996; 334: 693–9.

HCC: Liver Transplantation

• Best available treatment

• Removes tumor and cirrhotic liver

• Recurrence rate is low

• Not widely available

• Only if single tumor less than 5cm, or less than 3 tumors less than 3 cm each ( Milan’s criteria )

N Engl J Med 1996; 334:693-700

HCC: Local Ablation

• For non-resectable pt• For pt with advanced liver cirrhosis• Alcohol injection• Radiofrequency ablation• Complete responses in more than 80% of tumors

smaller than 3 cm in diameter, but in 50% of tumors of 3-5 cm in size.

• 5-year survival rates of 40%-60%. reported in patients with small single tumors, commonly <2 cm in diameter.

Sala M, et al. Hepatology 2004; 40: 1352–60. Lencioni R, et al. Radiology 2005; 234: 961–7.

Omata M, et al. Gastroenterology 2004; 127: S159–66.

Radiofrequency Ablation

BEFORE RFA AFTER RFA

Ethanol Injection

HCC: Chemoembolization• Primary treatment for unresectable HCC.• Embolization agents usually gelatin or

microspheres may be administered together with selective intra-arterial chemotherapy mixed with lipiodol (chemoembolization).

• Doxorubicin, mitomycin and cisplatin are the commonly used antitumoral drugs.

• Arterial embolization achieves partial responses in 15-55% of patients, and significantly delays tumour progression and vascular invasion.

Bruix J, et al. Gastroenterology 2004; 127: S179–88.Llovet JM, et al. Lancet 2002; 359: 1734–9.

Lo CM, et al. Hepatology 2002; 35: 1164–71.

Chemoembolization

HCC : Transarterial Chemoembolization

Meta-analysis of 7 randomized controlled trials

• 2 yr survival: 41% (19-63%)

• Treatment response: 35% (16-61%)

• Average no. of sessions: 1-4.5

• Risks: – Infection

– Tumor lysis syndrome

– Hepatic failure

Llovet J HepatoI 2003"37:429

Phase III Trials of Sorafenib for Advanced HCC

Llovet JM, et al. N Engl J Med 2008; 359; 378-90Cheng AL, et al. Lancet Oncol 2009; 10: 25-34

p < 0.001 p < 0.001

p < 0.001p = 0.014

Treatment Patient ObjectiveMedian Survival (m)

Level of

No. responseOS TTP

evidence

Llovet

et al

Sorafenib 299 RR : 2.3%

SD : 71%10.7 5.5 1b

Placebo 303 RR : 0.7%

SD: 67%7.9 2.8

Cheng

et al

Sorafenib 150 RR: 3.3%

SD : 54.0%6.5 2.8 1b

Placebo 76 RR 1.3%

SD: 27.6%4.2 1.4

Cholangiocarcinoma

Cholangiocarcinoma

• Incidence in Thailand

– North East 85 / 100,000 person/yr (ASR)

– North 14.6

– Central 14.4

– South 5.7

Khon Kaen 118.8

Sriamporn S, et al. Trop Med Int Health 9: 588-594.

Cholangiocarcinoma (CCA)

Intrahepatic (Peripheral) (IHC) 6-10%

Extrahepatic (Bile duct CA) (EHC) Upper third or Hilar (Klatskin

tumor) 40-60% Middle third

17-20% Lower third or Distal

18-27%

Ronald S, et al. Ann Surg Oncol 2000; 7,1:55-66

CCA : Risk Factors

Primary sclerosing cholangitis (5-15%) Congenital biliary cystic dz, choledochal cyst,

Caroli’s dz (5-7%) Parasitic biliary tract infection: Opisthorchis

viverrini, Clonorchis sinensis Cholelithiasis, hepatolithiasis, oriental

cholangiohepatitis (10%) Chronic typhoid carrier (X6) Exposure to chemical carcinogens: asbestos,

thorium dioxide, nitrosamines

Incidence of CCA and OV in Thailand

Sriamporn S, et al. Trop Med Int Health 9: 588-594.

Characteristics of CCA

CCA

Mass forming type

Periductal infiltrating type

Intraductal growing type

CCA : Clinical Presentation

• Jaundice (90-98% of EHC)

• Weight loss (29%)

• Abdominal pain (20%)

• Fever (9%)

• Pruritus (30%)

• Unresectable pts usually die within 6-12 m.

CCA : Treatment

• Surgery– Resection: the only curative treatment– Liver transplantation: currently contraindicated

• Chemotherapy– No demonstrable survival benefit– Partial response 10-50% (5-FU, gemcitabine, cisplatin)

• Radiotherapy– No survival benefit– Palliative for painful localisable metastasis, uncontrol bleeding

• Palliation– Surgical bypass– Biliary stent or PTBD

Liver Metastases

Liver Metastases

• The most common site for blood born metastases

• Common primaries : colon, breast, lung, stomach, pancreases, and melanoma

• Dx imaging or FNA

• Treatment depends on the primary cancer

• In some cases resection or chemoembolization is possible

Colorectal Liver Metastases

• Develop in 50%

• Responsible for 2/3 of deaths

• 5-yr survival following liver resection: 25-58% compared with 0-5% for patients who cannot be operated

Faivre J, et al. Bull Acad Natl Med 2003

Wagner JS, et al. Ann Surg 1984Abdalla EK, et al. Ann Surg 2004

Rougier P, et al. Br J Surg 1995

Results of nonsurgically treated colorectal cancer metastasis

McLoughlin JM, et al. Cancer Control 2006

Results of colorectal liver metastasis resection

McLoughlin JM, et al. Cancer Control 2006

Contraindication for resection of CRLM

• When the clearance of all hepatic metastases is impossible

• Celiac LN involvement

• Non-resectable extrahepatic disease

• Inadequate future liver remnant volume

Van den Eynde M, et al. Reviews on Recent Clinical Trials 2009

Unresectable liver metastasesMethods to improve resectability

• Downsizing chemotherapy

• Portal vein embolization

• Hepatic resection + RFA

• 2-stage hepatectomy

Adam R, et al. Surg Clin N Am 2004

Neoadjuvant chemotherapyfor initially unresectable liver metastases

Fig.1. Initially unresectable, centrally located colorectal liver metastasis before chemotherapy.Fig.2. Downstaging after chemotherapy in the case of Fig.1. enabled further hepatectomy.

Adam R, et al. Surg Clin N Am 2004