HCC Presentation
Transcript of HCC Presentation
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