Elzouki An

7/28/2019 Elzouki An

1/39

Clinical Management of Hepatocellular

Carcinoma: Current Options

Abdel-Naser Elzouki, MBChB, DTM&H, MSc, MD, PhD, FRCP (UK)

Professor & Sr. Consultant, Department of Medicine,

Hamad Medical corporation, Doha, Qatar

Email: [email protected]
mailto:[email protected]:[email protected]


2/39

Hepatocellular Carcinoma (HCC): Content

Burden of HCC Diagnosis of HCC

Staging of HCC

Treatment of HCC:

- Very early / early HCC

- Intermediate HCC

- Advanced HCC

A Look to the future


3/39

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[

- 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.


4/39

Evolving Guidelines for Clinical Management

of Hepatocellular Carcinoma

www.aasld.org


5/39

Radiological Diagnosis of Hepatocellular Carcinoma in Patien

With Cirrhosis: EASL/AASLD Guidelines

Imaging techniques contrast-enhanced US, contrast-enhanced spiral CTand 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%


6/39

Abdominal tri-phasic spiral CT

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


7/39

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


8/39

Liver nodule

< 1 cm > 1 cm

Reapeat US at 3 months

Growing/changing

characterStable

Investigateaccording to size

4 phase MDCT/dynamic

Contrast enhanced MRI

Arterial hypervascularity ANDvenous or delayed phase washout

Other contrast enhanced

Study (CT or MRI)

Arterial hypervascularity AND

venous or delayed phase washout

Yes No

Yes No

HCC Biopsy

2010 AASLD Algorithm for Investigation of Small Nodule

Found On Screening in Patients with Cirrhosis

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


9/39

Staging Systems and Treatment Strategies

in Hepatocellular Carcinoma


10/39

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

-


11/39

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 onsurvival

BCLC is the only staging system that stratifies patients into

treatment groups

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


12/39

The Barcelona Clinic Liver Cancer (BCLC) Staging Classificat

for Hepatocellular Carcinoma Is Endorsed by EASL/AASLD

A Very Early/Early

B Intermediate

CAdvanced

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,number

and invasiveness

A & B

A & B

A & B

C

Child-Pugh

Expected

survival

50-75% at 5 yr

16 months

6 months

< 3 months


13/39

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


14/39

Treatment ofVery Early / Early Stage HCC


15/39



A Very Early/Early

BCLC stage

0

Performance

status


< 3 cm each

Tumor volume,number

and invasiveness

A & B

Child-Pugh

Expected

survival

50-75% at 5 yr


16/39

Early Stage Hepatocellular Carcinoma: Survival after Resecti

Is Influenced by Portal Hypertension and Bilirubin

Best candidates for resection : Solitary HCC 5 cm

Child-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

Survival(%

)

months

74%

50%

25%

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

f CC


17/39

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: Mazzaferr o V, et al. N Eng l J Med. 1996;334:693-699.

Strategy to expand criteria include use of locoregional therapy to downstagepatients to Milan criteria

T t t f E l St HCC Li T l t ti i


18/39

Treatment of Early Stage HCC: Liver Transplantation in

Cirrhotic Patients Selected by Milan Criteria

Milan

Barcelona

Paris

Berlin

Center

Single 5 cm

3 nodes 3cm

Single 5 cm

3 nodes 3 cm

Single 5 cm

3 nodes 3 cm

HCC

48

79

45

120

Cases

Mazzaferro et al 199

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

P ti t ith Ci h i d HCC ithi Mil C it i


19/39

Patients with Cirrhosis and a HCC within Milan Criteria

Liver 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

Cumulativesurvival

(%)

0 12 24 36 48 60

0

20

40

60

80

100

Per-Protocol Analysis

Cumulativesurvival(%)

Resection (n=228)

Transplantation(n=85)

p=0.088

Months

0 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.

T t t f E l HCC th I iti l T V l


20/39

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 7

87 78 52 31 19 10 5

0

10

20

30

40

5060

70

80

90

10097%

63%

32%

96%

56%

72%

Log-rank=.0075

Single 2 cm

Single 2.1-5 cm

Single 2 cm

Single 2.1-5 cm

months

Survival(

%)

Patients at risk

A retrospective study of 282 consecutive patients with a HCC within Milan criteria treated

at BCLC, Barcelona during a 15-yr period.


21/39

Ablation of HCC

Percutaneous ethanol injection (PEI)

Cryotherapy

Radiofrequency ablation (RFA)

S i it f R ti Al h l I j ti i th T t


22/39

Superiority of Resection vs Alcohol Injection in the Treatmen

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

months

survivalrate(%)

800 hospitals, patients with < 5 cm tumors

8,010 treated by hepatic resection4,037 treated by PEIT841 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


23/39

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

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

Mortality rates


24/39


25/39

Treatment ofIntermediate Stage HCC



26/39



A Very Early/Early

B Intermediate

BCLC stage

0

0

Performance

status


< 3 cm each

Large/multinodular

Tumor volume,number

and invasiveness

A & B

A & B

Child-Pugh

Expected

survival

50-75% at 5 yr

16 months

T t t f HCC Ch b li ti


27/39

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 Chemoembolization


28/39

Intermediate HCC: The Outcome of Chemoembolization

A 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


29/39

Treatment ofAdvanced Stage HCC



30/39



A Very Early/Early

B Intermediate

CAdvanced

BCLC stage

0

0

1-2

Performance

status


< 3 cm each

Large/multinodular


extrahepatic spread

Tumor volume,number

and invasiveness

A & B

A & B

A & B

Child-Pugh

Expected

survival

50-75% at 5 yr

16 months

6 months

Levels of Evidence in the Assessment of Benefits in


31/39

Systemic treatment Benefit Evidence

Sorafenib Increased survival 1iA

Tamoxifen No benefit 1iA

Systemic chemotherapy No benefit 1iiA

Interferon No benefit 1iiA

the Treatment of Advanced HCC

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

Randomized Controlled Trials of Sorafenib in


32/39

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; 2Cheng A et al Lancet Oncol 2009;10:25-34


33/39

Treatment ofTerminal Stage HCC



34/39

( ) g g


A Very Early/Early

B Intermediate

CAdvanced

D End-stage

BCLC stage

0

0

1-2

3-4

Performance

status


< 3 cm each

Large/multinodular


extrahepatic spread

Any of the above

Tumor volume,number

and invasiveness

A & B

A & B

A & B

C

Child-Pugh

Expected

survival

50-75% at 5 yr

16 months

6 months

< 3 months

Tailoring Treatment According to the Clinical Stage of HC


35/39

Tailoring Treatment According to the Clinical Stage of HC

Very earlystage (0)

Earlystage (A)

Intermediatestage (B)

Advancedstage (C)

Terminalstage (D)

HCC

PEI/RFLiver transplantationResection Chemoembolization Sorafenib

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

Symptomatictreatment (10%)

Survival


36/39

A Look To The Future

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


37/39

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

Targeted Population Phase III Comparison

Adjuvant Prevent recurrences 1. Sorafenib vs placebo

2. Retinoids vs placebo

Intermediate HCC Improve TACE 1. TACE sorafenib

2. TACE brivanib

Advanced HCC First line:

Second line:

1. Sorafenib erlotinib

2. Sorafenib vs brivanib3. Sorafenib vs sunitinib

4. Sorafenib vs lifitinib

5. Sorafenib Y90

6. Sorafenib doxorubicin

1. Brivanib vs placebo

2. Everolimus vs placebo

3. Ramucirumab vs placebo

NEGATIVE:ASCO 2010

HALTED:2010

Conclusion


38/39

Conclusion

Burden of HCC is increasing

Requirements 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


39/39

Elzouki An

Documents

Transcript of Elzouki An