Clinical Management of Hepatocellular Carcinoma

DANISH NAGDA, MS III PERELMAN SCHOOL OF MEDICINE SURGERY 200 PRESENTATION

HCC: Common and Increasing

y 694,000 deaths from liver cancer yearly worldwide[1] y Age-adjusted US incidence has increased 2-fold from 1985-

1998[2]


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

y 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 wash-in followed by wash-out two concordant contrast imaging techniques one contrast imaging technique only

Pathognomonic features < 2 cm node > 2 cm node

Prospective validation*

89 patients with a 7-20 mm nodule

CE-US+MRI

Sensitivity Specificity

33.3% 100%

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

Abdominal tri-phasic spiral CT tri-

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

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

Ultrasound alone

Ultrasound + AFP

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

2010 AASLD Algorithm for Investigation of Small Nodules Found On Screening in Patients with Cirrhosis
Liver nodule
< 1 cm > 1 cm

Reapeat US at 3 months

4 phase MDCT/dynamic Contrast enhanced MRI

Arterial hypervascularity AND venous or delayed phase washout Growing/changing character Stable Yes Other contrast enhanced Study (CT or MRI) No

Investigate according to size

HCC

Arterial hypervascularity AND venous or delayed phase washout

Biopsy

Yes

No

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

Staging Systems and Treatment Strategies in Hepatocellular Carcinoma

Variables Used in HCC Staging Systems

System Europe-US GETCH/ French CLIP PVT; AFP < 35 or > 35 ug/L Number of nodules, tumor > or < 50% area of liver, and PVT; AFP< 400 or 400 ng/mL Tumor size, number of nodules, and PVT Number of nodules, tumor size, presence of PVT, and presence of metastasis Bilirubin, alkaline phosphatase CTP AHPBA Tumor Staging Liver Function Endorsement

BCLC TNM Asia JIS Okuda/ Tokyo CUPI

CTP No

AASLD, EASL AJCC

TNM Tumor > or < 50% of cross-sectional area of liver TNM; AFP< 500 or 500 ng/mL

CTP Ascites, albumin, and bilirubin Bilirubin, ascites, alkaline phosphatase

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

Comparison of HCC Staging Systems

y BCLC system uses key independent predictors of survival:  Performance score, portal vein thrombosis, tumor diameter y 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 y BCLC is the only staging system that stratifies patients

into treatment groups

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

The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma Is Endorsed by EASL/AASLD
Performance status Tumor volume,number and invasiveness Child-Pugh Expected survival

BCLC stage

Very Early/Early

Single < 5 cm or 3 nodes < 3 cm each Large/multinodular

A&B

50-75% at 5 yr

B Intermediate

A&B

16 months

C Advanced

1-2

Vascular invasion and/or extrahepatic spread Any of the above

A&B

6 months

D End-stage

3-4

< 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) y Systemic therapy: - Targeted molecular therapy - Symptomatic treatment

Treatment of Very Early / Early Stage HCC

The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma Is Endorsed by EASL/AASLD
Performance status Tumor volume,number and invasiveness Child-Pugh Expected survival

BCLC stage

Very Early/Early

Single < 5 cm or 3 nodes < 3 cm each

A&B

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 cm Child-Pugh A: Low portal hypertension Normal bilirubin
74% 50% 25% Log Rank 0.00001

100 80

Survival (%)

60 40 20 0 0 12 24 36 48

60

72

84

96

months

< 10 mmHg HVPG (n= 35) 10 mmHg HVPG and normal bilirubin (n=15) 10 mmHg HVPG and Bilirubin >1 mg/dL (n=27)
Llovet JM et al, Hepatology 1999;30:1434-40

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

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

+
Absence of macroscopic vascular invasion, absence of extrahepatic spread
Strategy to expand criteria include use of locoregional therapy to downstage patients to Milan criteria
Ref: Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.

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

HCC
Single 5 cm 3 nodes 3 cm Single 5 cm 3 nodes 3 cm Single 5 cm 3 nodes 3 cm
*

Cases
48

5-yr survival
75%*

Recurrence
8%

Reference
Mazzaferro et al 1996

Barcelona Paris Berlin

79 45 120

75% 74% 71%

4% 11% 16%

Llovet et al 1998 Bismuth et al 1999 Jonas et al 2001

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 Criteria Liver Resection or Transplantation
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.

Per-Protocol Analysis
100

ITT Analysis
100

Transplantation (n=43)
Cumulative survival (%)

Cumulative survival (%)

80

80

Resection (n=228)

60

Resection (n=204)

60

Transplantation (n=85)

40

40

20 0 0 12 36 24 Months after surgery 48

p=0.017

20 0 60 0 12 24 Months 36 48

p=0.088

60

Survival predictors:

HCV neg, 3 cm tumor, single tumor, no venous invasion.

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

Treatment of Early HCC: the Initial Tumor Volume Predicts Survival After Percutaneous Ablation
A retrospective study of 282 consecutive patients with a HCC within Milan criteria treated at BCLC, Barcelona during a 15-yr period.

100 90 80 70 Survival (%) 60 50 40 30 20 10 0 0 Patients at risk Single 2 cm Single 2.1-5 cm

97% 96% Log-rank=.0075 72% 63% 56% Single 2 cm

32%

Single 2.1-5 cm

12

24

36

48

60

72

months

34 87

32 78

26 52

17 31

13 19

9 10

7 5

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

Ablation of HCC
y Percutaneous ethanol injection (PEI) y Cryotherapy y Radiofrequency ablation (RFA)

Superiority of Resection vs Alcohol Injection in the Treatment of 2-5 cm HCC: A Nationwide Survey in Japan
The Liver Cancer Study Group: 1988-1996 Clinical stage 1: solitary node 2-5 cm size

100

800 hospitals, patients with < 5 cm tumors

survival rate (%)

90 80

8,010 treated by hepatic resection 4,037 treated by PEIT 841 treated by chemoembolization Clinical stage 1: Ascites Bilirubin Albumin ICGR 15 Protime none < 2.0 mg/dl > 3.5 g/dl < 15% > 80%

70 60 50 40 30 20 10 0 0 12 24 36 48 months

58%
Resection n=2722

39%

PEIT n=587

60

72

84

96

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

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

Mortality rates

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

Treatment of Intermediate Stage HCC

The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma Is Endorsed by EASL/AASLD
Performance status Tumor volume,number and invasiveness Child-Pugh Expected survival

BCLC stage

Very Early/Early

Single < 5 cm or 3 nodes < 3 cm each Large/multinodular

A&B

50-75% at 5 yr

B Intermediate

A&B

16 months

Treatment of HCC: Chemoembolization

y Normal liver gets 75% of blood supply

from portal vein and 25% of blood supply from hepatic artery y Tumor receives most of its blood supply from the hepatic artery y Injection into the hepatic artery spares most of the normal liver y Embolization of the hepatic artery induces ischemic necrosis of tumor

Tumor

Catheter placement for chemoembolization

Hepatic artery Liver Portal vein

Selective arterial radiotherapy with Y90 microspheres

Intermediate HCC: The Outcome of Chemoembolization A Meta-analysis

Random effects model (DerSimonian & Laird). Author,Journal year Lin , Gastroenterology 1988 GRETCH, NEJM 1995 Bruix , Hepatology 1998 Pelletier, J Hepatol 1998 Lo, Hepatology 2002 Llovet, Lancet 2002 Overall Heterogeneity: Q:7.73 P=0.14 Favors treatment Improved survival: from 16 to 20 months Bruix J et al, Gastroenterology 2004;127:S179-88 Favors control Patients 63 96 80 70 79 112
p=0.017

OR (95% IC)
0.01 0.1 0.5 1 2 10 100

503

Treatment of Advanced Stage HCC

The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma Is Endorsed by EASL/AASLD
Performance status Tumor volume,number and invasiveness Child-Pugh Expected survival

BCLC stage

Very Early/Early

Single < 5 cm or 3 nodes < 3 cm each Large/multinodular

A&B

50-75% at 5 yr

B Intermediate

A&B

16 months

C Advanced

1-2

Vascular invasion and/or extrahepatic spread

A&B

6 months

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

Systemic treatment

Benefit

Evidence

Sorafenib Tamoxifen Systemic chemotherapy Interferon

Increased survival No benefit No benefit No benefit

1iA 1iA 1iiA 1iiA

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 BCLC-B stage Previous treatments HBV etiology of cirrhosis TTP (control) Median survival (control) Grade 3/4 toxicity

65 yrs 18% 67% 19% 5.5 mo. (2.8 mo.) 10.7 mo. (7.9 mo.) 30%

51 yrs 4% na 71% 2.8 mo. (1.4 mo.) 6.5 mo. (4.2 mo.) 24%

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 Classification for Hepatocellular Carcinoma Is Endorsed by EASL/AASLD
Performance status Tumor volume,number and invasiveness Child-Pugh Expected survival

BCLC stage

Very Early/Early

Single < 5 cm or 3 nodes < 3 cm each Large/multinodular

A&B

50-75% at 5 yr

B Intermediate

A&B

16 months

C Advanced

1-2

Vascular invasion and/or extrahepatic spread Any of the above

A&B

6 months

D End-stage

3-4

< 3 months

Tailoring Treatment According to the Clinical Stage of HCC

HCC

Very early stage (0)

Early stage (A)

Intermediate stage (B)

Advanced stage (C)

Terminal stage (D)

Single HCC Portal pressure bilirubin Increased Normal 3 nodules 3cm Associated diseases No Yes

Resection

Liver transplantation Curative treatments (30%) 5-year survival: 5070%

PEI/RF

Chemoembolization

Sorafenib Symptomatic treatment (10%) Survival <3 months

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

Adapted from Bruix J and Llovet JM, Lancet 2009;373:614616

A Look To The Future

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

Targeted Population Adjuvant Intermediate HCC Advanced HCC Prevent recurrences Improve TACE First line: Phase III Comparison 1. Sorafenib vs placebo 2. Retinoids vs placebo 1. TACE sorafenib 2. TACE brivanib 1. 2. 3. 4. 5. 6. Sorafenib erlotinib Sorafenib vs brivanib Sorafenib vs sunitinib Sorafenib vs lifitinib Sorafenib Y90 Sorafenib doxorubicin
NEGATIVE: ASCO 2010

HALTED: 2010

Second line:

1. Brivanib vs placebo 2. Everolimus vs placebo 3. Ramucirumab vs placebo

Conclusion
y Burden of HCC is increasing y Requirements for diagnosis depends on patient

characteristics and tumor characteristics y BCLC staging system recommended by US and European guidelines y BCLC system provides framework for selection of treatment y Many studies ongoing for treatment of HCC