DANISH NAGDA, MS IIIPERELMAN SCHOOL OF MEDICINE

SURGERY 200 PRESENTATION

Clinical Management of Hepatocellular Carcinoma

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.

Evolving Guidelines for Clinical Management of Hepatocellular Carcinoma

www.aasld.org

Radiological Diagnosis of Hepatocellular Carcinoma in Patients

With Cirrhosis: EASL/AASLD Guidelines

Imaging techniques contrast-enhanced US, contrast-enhanced spiral CT and gadolinium-enhanced MRI

Pathognomonic features wash-in followed by wash-out

< 2 cm node two concordant contrast imaging techniques

> 2 cm node one contrast imaging technique only

EASL, AASLD & JSH Conference, Barcelona 2005; AASLD Practice Guidelines 2007; *Forner et al 2008

Prospective validation* 89 patients with a 7-20 mm nodule

CE-US+MRI Sensitivity 33.3%

Specificity 100%

Abdominal tri-phasic spiral CTAbdominal tri-phasic spiral CT

Right lobe hepatic focal lesion 5 x 4.5 cm, with arterialRight lobe hepatic focal lesion 5 x 4.5 cm, with arterialenhancement and wash out in the porto-venous phase.enhancement and wash out in the porto-venous phase.

Ultrasound alone Ultrasound + AFP

Ultrasound Diagnosis of Early-stage HCC in Patients with Cirrhosis. Meta-analysis

Singal et al Aliment Pharmacol Ther 2009;30:37-47

Liver nodule

< 1 cm > 1 cm

Reapeat US at 3 months

Growing/changing character

Stable

Investigate according to size

4 – phase MDCT/dynamicContrast enhanced MRI

Arterial hypervascularity AND venous or delayed phase washout

Other contrast enhancedStudy (CT or MRI)

Arterial hypervascularity AND venous or delayed phase washout

Yes No

Yes No

HCC Biopsy

2010 AASLD Algorithm for Investigation of Small Nodules Found On Screening in Patients with Cirrhosis

Bruix J and Sherman M. AASLD Practice Guidelines 2010: Management of Hepatocellular Carcinoma; www.aasld.org

Staging Systems and Treatment Strategies in Hepatocellular Carcinoma

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

Variables Used in HCC Staging Systems

System Tumor Staging Liver Function Endorsement

Europe-US

GETCH/French

PVT; AFP < 35 or > 35 ug/L Bilirubin, alkaline phosphatase

-

CLIP Number of nodules, tumor > or < 50% area of liver, and PVT; AFP< 400 or ≥ 400 ng/mL

CTP AHPBA

BCLC Tumor size, number of nodules, and PVT CTP AASLD, EASL

TNM Number of nodules, tumor size, presence of PVT, and presence of metastasis

No AJCC

Asia

JIS TNM CTP -

Okuda/Tokyo

Tumor > or < 50% of cross-sectional area of liver

Ascites, albumin, and bilirubin

-

CUPI TNM; AFP< 500 or ≥ 500 ng/mL Bilirubin, ascites, alkaline phosphatase

-

Comparison of HCC Staging Systems

BCLC system uses key independent predictors of survival: Performance score, portal vein thrombosis, tumor

diameterCompared 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 survivalBCLC is the only staging system that stratifies

patients into treatment groupsMarrero JA, et al. Hepatology. 2005;41:707-716.

The Barcelona Clinic Liver Cancer (BCLC) Staging Classificationfor Hepatocellular Carcinoma Is Endorsed by EASL/AASLD

A Very Early/Early

B Intermediate

C Advanced

D End-stage

BCLC stage

0

0

1-2

3-4

Performance status

Single < 5 cm or 3 nodes

< 3 cm each

Large/multinodular

Vascular invasion and/or

extrahepatic spread

Any of the above

Tumor volume,numberand invasiveness

A & B

A & B

A & B

C

Child-PughExpectedsurvival

50-75% at 5 yr

16 months

6 months

< 3 months

Therapies used in the management of HCC

Surgery:- Resection- Liver transplantation

Locoregional therapy:- Percutaneous ethanol injection- Radiofrequancy thermal ablation- Trans-Arterial Chemo-Emobilisation (TACE)- Trans-Arterial Radio-Emobilisation (TACE)

Systemic therapy: - Targeted molecular therapy - Symptomatic treatment

Treatment of Very Early / Early Stage HCC

The Barcelona Clinic Liver Cancer (BCLC) Staging Classificationfor Hepatocellular Carcinoma Is Endorsed by EASL/AASLD

A Very Early/Early

BCLC stage

0

Performance status

Single < 5 cm or 3 nodes

< 3 cm each

Tumor volume,numberand invasiveness

A & B

Child-PughExpectedsurvival

50-75% at 5 yr

Early Stage Hepatocellular Carcinoma: Survival after Resection Is Influenced by Portal Hypertension and Bilirubin

Best candidates for resection : Solitary HCC ≤ 5 cmChild-Pugh A: Low portal hypertension

Normal bilirubin

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96

< 10 mmHg HVPG (n= 35)≥ 10 mmHg HVPG and normal bilirubin (n=15)≥ 10 mmHg HVPG and Bilirubin >1 mg/dL (n=27)

Log Rank 0.00001

Sur

viva

l (%

)

months

74%

50%

25%

Llovet JM et al, Hepatology 1999;30:1434-40

Liver Transplantation for HCC:Milan Criteria (Stage 1 and 2)

+Absence of macroscopic vascular invasion,

absence of extrahepatic spread

Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm

Ref: Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.

Strategy to expand criteria include use of locoregional therapy to downstage patients to Milan criteria

Treatment of Early Stage HCC: Liver Transplantation in Cirrhotic Patients Selected by

Milan Criteria

Milan

Barcelona

Paris

Berlin

Center

Single ≤ 5 cm≤ 3 nodes ≤ 3 cm

Single ≤ 5 cm

≤ 3 nodes ≤ 3 cm

Single ≤ 5 cm≤ 3 nodes ≤ 3 cm

HCC

48

79

45

120

Cases

Mazzaferro et al 1996

Llovet et al 1998

Bismuth et al 1999

Jonas et al 2001

Reference5-yr survival Recurrence

8%

4%

11%

16%

75%*

75%

74%

71%

Explanted livers: 35 (73%) Milan (+) with 95% survival 13 (27%) Milan () with 59% survival

*

* 4-yr survival

Patients with Cirrhosis and a HCC within Milan CriteriaLiver Resection or Transplantation

Poon RTP et al Ann Surg 2007;245:51-58

Survival predictors: HCV neg, ≤ 3 cm tumor, single tumor, no venous invasion.

Resection (n=204)

Transplantation(n=43)

p=0.017

Months after surgery

Cu

mu

lati

ve s

urv

ival

(%

)

0 12 24 36 48 60

0

20

40

60

80

100

Per-Protocol Analysis

Cu

mu

lati

ve s

urv

ival

(%

)

Resection (n=228)

Transplantation(n=85)

p=0.088

Months0 12 24 36 48 60

0

20

40

60

80

100

ITT Analysis

Hong-Kong, Queen Mary Hosp. Data-base: 1995-2004. Cirrhotics with HCC within Milan criteria

204 resected and 43 transplanted (30 LDLT). 218 (88%) HBsAg pos. 33 (13%) 2 or 3 nodules.

Treatment of Early HCC: the Initial Tumor Volume Predicts Survival After Percutaneous Ablation

Sala M et al Hepatology 2004;40:1352-1360

0 12 24 36 48 60 72

34 32 26 17 13 9 787 78 52 31 19 10 5

0

10

20

30

40

50

60

70

80

90

10097%

63%

32%

96%

56%

72%

Log-rank=.0075

Single ≤ 2 cm

Single 2.1-5 cm

Single ≤ 2 cmSingle 2.1-5 cm

months

Su

rviv

al (

%)

Patients at risk

A retrospective study of 282 consecutive patients with a HCC within Milan criteria treatedat BCLC, Barcelona during a 15-yr period.

Ablation of HCC

Percutaneous ethanol injection (PEI)CryotherapyRadiofrequency ablation (RFA)

Superiority of Resection vs Alcohol Injection in the Treatment of 2-5 cm HCC: A Nationwide Survey in

Japan

Arii S et al, Hepatology 2000;32:1224-1229

Clinical stage 1: solitary node 2-5 cm size

Resection n=2722

PEIT n=587

0 12 24 36 48 60 72 84 960

10

20

30

40

50

60

70

80

90

100

monthssu

rviv

al r

ate

(%)

800 hospitals, patients with < 5 cm tumors

8,010 treated by hepatic resection 4,037 treated by PEIT 841 treated by chemoembolization

Clinical stage 1: Ascites noneBilirubin < 2.0 mg/dlAlbumin > 3.5 g/dlICGR 15 < 15%Protime > 80%

58%

39%

The Liver Cancer Study Group: 1988-1996

Radiofrequency vs Percutaneous Ethanol Injection Therapy for Hepatocellular Carcinoma: a Meta-analysis

Germani G et al J Hepatol 2010;52:380-388

Mortality rates

Treatment of Intermediate Stage HCC

The Barcelona Clinic Liver Cancer (BCLC) Staging Classificationfor Hepatocellular Carcinoma Is Endorsed by EASL/AASLD

A Very Early/Early

B Intermediate

BCLC stage

0

0

Performance status

Single < 5 cm or 3 nodes

< 3 cm each

Large/multinodular

Tumor volume,numberand invasiveness

A & B

A & B

Child-PughExpectedsurvival

50-75% at 5 yr

16 months

Treatment of HCC: Chemoembolization

Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery

Tumor receives most of its blood supply from the hepatic artery

Injection into the hepatic artery spares most of the normal liver

Embolization of the hepatic artery induces ischemic necrosis of tumor

Tumor

Liver

Portal vein

Hepaticartery

Catheter placement forchemoembolization

Selective arterial radiotherapy with Y90 microspheres

Intermediate HCC: The Outcome of ChemoembolizationA Meta-analysis

Bruix J et al, Gastroenterology 2004;127:S179-88

Lin , Gastroenterology 1988 63

GRETCH, NEJM 1995 96

Llovet, Lancet 2002 112

Pelletier, J Hepatol 1998 70

Bruix , Hepatology 1998 80

Overall 503

Heterogeneity: Q:7.73 P=0.14

Author,Journal year Patients

Lo, Hepatology 2002 79

Favors treatment Favors control

1010.10.01 1000.5 2

p=0.017

Random effects model (DerSimonian & Laird).

OR (95% IC)

Improved survival: from 16 to 20 months

Treatment of Advanced Stage HCC

The Barcelona Clinic Liver Cancer (BCLC) Staging Classificationfor Hepatocellular Carcinoma Is Endorsed by EASL/AASLD

A Very Early/Early

B Intermediate

C Advanced

BCLC stage

0

0

1-2

Performance status

Single < 5 cm or 3 nodes

< 3 cm each

Large/multinodular

Vascular invasion and/or

extrahepatic spread

Tumor volume,numberand invasiveness

A & B

A & B

A & B

Child-PughExpectedsurvival

50-75% at 5 yr

16 months

6 months

Systemic treatment Benefit Evidence

Sorafenib Increased survival 1iA

Tamoxifen No benefit 1iA

Systemic chemotherapy No benefit 1iiA

Interferon No benefit 1iiA

Levels of Evidence in the Assessment of Benefits in the Treatment of “Advanced” HCC

LLovet JM et al JNCI 2008;100:698-711

Randomized Controlled Trials of Sorafenib in Advanced Hepatocellular Carcinoma

Study characteristics SHARP Study1 Asia Study2

Median age 65 yrs 51 yrs

BCLC-B stage 18% 4%

Previous treatments 67% na

HBV etiology of cirrhosis 19% 71%

TTP (control) 5.5 mo. (2.8 mo.) 2.8 mo. (1.4 mo.)

Median survival (control) 10.7 mo. (7.9 mo.) 6.5 mo. (4.2 mo.)

Grade 3/4 toxicity 30% 24%

1 Llovet JM et al NEJM 2008;359:378-390; 2 Cheng A et al Lancet Oncol 2009;10:25-34

Treatment of Terminal Stage HCC

The Barcelona Clinic Liver Cancer (BCLC) Staging Classificationfor Hepatocellular Carcinoma Is Endorsed by EASL/AASLD

A Very Early/Early

B Intermediate

C Advanced

D End-stage

BCLC stage

0

0

1-2

3-4

Performance status

Single < 5 cm or 3 nodes

< 3 cm each

Large/multinodular

Vascular invasion and/or

extrahepatic spread

Any of the above

Tumor volume,numberand invasiveness

A & B

A & B

A & B

C

Child-PughExpectedsurvival

50-75% at 5 yr

16 months

6 months

< 3 months

Tailoring Treatment According to the Clinical Stage of HCC

Very early stage (0)

Early stage (A)

Intermediate stage (B)

Advanced stage (C)

Terminalstage (D)

HCC

PEI/RFLiver transplantationResection Chemoembolization Sorafenib

RCTs (50-60%) Median survival untreated: 6-16 months

Symptomatictreatment (10%)

Survival <3 months

Curative treatments (30%)5-year survival: 50–70%

3 nodules ≤3cm

Normal

Single HCC

Portal pressurebilirubin

Yes

Associated diseases

No

Increased

Adapted from Bruix J and Llovet JM, Lancet 2009;373:614–616

A Look To The Future

Molecular Therapies Under Evaluation for HCC in Phase III (2011)

Targeted Population Phase III Comparison

Adjuvant Prevent recurrences 1. Sorafenib vs placebo2. Retinoids vs placebo

Intermediate HCC Improve TACE 1. TACE ± sorafenib2. TACE ± brivanib

Advanced HCC First line:

Second line:

1. Sorafenib ± erlotinib2. Sorafenib vs brivanib3. Sorafenib vs sunitinib4. Sorafenib vs lifitinib5. Sorafenib ± Y906. Sorafenib ± doxorubicin

1. Brivanib vs placebo2. Everolimus vs placebo3. Ramucirumab vs placebo

NEGATIVE:ASCO 2010

HALTED:2010

Conclusion

Burden of HCC is increasingRequirements for diagnosis depends on patient

characteristics and tumor characteristics BCLC staging system recommended by US and

European guidelines BCLC system provides framework for selection

of treatment Many studies ongoing for treatment of HCC