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Primary Liver Cancer:
Hepatocellular Carcinoma and
Cholangiocarinoma
Patrick M. Horne, MSN, ARNP, FNP-BC
Assistant Director of Hepatology Clinical Research
Division of Gastroenterology, Hepatology and
Nutrition
University of Florida Health
Disclosures
• Financial relationships to disclose within
the past 12 months:
• Grant support with Bayer/Onyx
Objectives
• Discuss the diagnosis and management of
hepatocellular carcinoma (HCC) and
cholangiocarinoma
• Review current screening and staging of
both HCC and cholangiocarinoma
• Selection of the optimal, evidence-based
surgical and nonsurgical treatment
modalities
• Review current treatment options
Background of HCC
• World wide
– 6th most common cancer – 748,271 new cases per
year
– 3rd leading cause of cancer-related mortality –
695,843 deaths per year
• US incidence has tripled over the last three decades
– Estimated new cases: >20,000 new cases annually
– Fastest Growing Death Rate in the US
– Dismal 5-year survival 10%
• 80%-90% of HCC cases occur in cirrhotic livers
• Leading cause of death in cirrhosis
Globocan 2008. McGlynn KA et al. Int J Cancer. 2001;94:290-296; McGlynn KA et al. Cancer Epidemiol Biomarkers Prev. 2006;15:1198-1203; El-Serag
HB. Gastroenterology. 2004;127:S27-S34; Altekruse SF et al. J Clin Oncol. 2009;27:1485-1491
U.S.-HCC Risk Factors
Patients with HCC
Distribution of Markers
N = 239
HCV
HBV
Alcohol
Cryptogenic
Other
El-Serag HB, Rudolph KL. Gastroetnerology 2007;132:2557-2576. Snowberger N, et al. Alim Pharm Ther 2007;26:1187.
Risk Factors for HCC
Host Factors
• Cirrhosis
• HBV, HCV, NASH, Alcohol
• Hemachromatosis,
• α-1 antitrypsin deficiency
• HBV
• Male gender
• Family history of HCC
• Coinfection with HCV, HBV, or HIV
• Older age
Viral Factors
• HBV DNA levels >2,000 IU/mL
(10,000 copies/mL, REVEAL Study)
• HBV genotype C*
• Basal core promoter mutation
• Presence of HBeAg
• History of reversions from
anti-HBe to HBeAg
Likely Factors
• Diabetes
• Obesity
AASLD practice guidelines. AASLD website. Available at: http://www.aasld.org/practiceguidelines. Accessed 02/10/11; Keeffe. Clin Gastroenterol Hepatol.
2008;6:1315; Mahtab. Hepatobiliary Pancreat
Dis Int. 2008;7:457; Lin. Hepatology. 2007;46:1034.
HCC Pathogenesis
Farazi PA and DePinho RA. Nat Rev cancer 2006.
HCC Incidence has Tripled
Dismal 5 year survival (~10%)
SEER = Surveillance, Epidemiology, and End Results. Altekruse SF et al. J Clin Oncol. 2009;27:1485-1491
Groups for Whom HCC Surveillance is Recommended
AASLD Practice Guidelines
•
•
Cirrhosis
– Viral hepatitis – HCV, HBV
– Non-alcoholic fatty liver/non-alcoholic steatohepatitis
(NAFLD/NASH)
– Alcohol and other
Hepatitis B carriers
– Asian males over 40 yrs
– Asian females over 50 yrs
– All cirrhotic hepatitis B carriers
– Positive family history of HC
– Non-cirrhotic HBV carriers with high HBV DNA levels or
more severe current/past levels of inflammatory activity
AASLD=American Association for the Study of Liver Diseases; HBV=hepatitis B virus.
Practice guidelines page. AASLD website. Available at: http://www.aasld.org/practiceguidelines.
Current Recommendation for Surveillance
• AASLD practice guidelines
– Ultrasound every 6 months
• Goal
– Detect early tumor and improve survival
• AFP
– Normal in 40% of patients with HCC
– Inadequate sensitivity and specificity in the diagnostic
range – normal in small HCC
– Values >200 ng/mL high PPV in cirrhotic patients with a
mass
El Serag. Gastroenterology. 2008;134:1752; Practice guidelines page. AASLD website. Available at:
http://www.aasld.org/practiceguidelines. Accessed 10/12/11; Sheu. Gastroenterology. 1985;89:259.
Case #1
• 67 year old white male
with HBV cirrhosis on
antiviral therapy with
good viral control.
• Abnormal US on
surveillance.
• AFP = 5.
• Cirrhotic liver, stigmata of
portal hypertension.
Single 2.5 cm arterially
enhancing lesion in the
left lobe of the liver.
Diagnostic Algorithm for HCC in Cirrhosis
New Liver Nodule on US
<1 cm
>1 cm
Repeat US at 3 months
Growing/changing
character
4-phase MDCT / dynamic
contrast enhanced MRI
Arterial hypervascularity AND
venous or delayed phase washout
Stable
Investigate
according to size
Adapted from Bruix J, Sherman M.
Hepatology July, 2010. Available at
http://www.aasld.org/practiceguidelines/Pages
/NewUpdatedGuidelines.aspx.
Accessed 08/03/10.
Yes
Other contrast enhanced
study (CT or MRI)
No
HCC
Arterial hypervascularity AND
venous or delayed phase washout
Biopsy
Yes
No
Radiologic Diagnosis of HCC in Cirrhosis
Arterial phase enhancement
Cabrera R, Nelson DR. Aliment Pharmacol Ther. 2010 15;31(4):461-76.
Venous phase “washout”
Radiologic Diagnosis of HCC
Child-Pugh Scoring for Cirrhosis
Points 
1
2
3
Total bilirubin, mg/dL
<2
2-3
>3
Serum albumin g/L
>35
28-35
<28
Prothrombin time INR
<1.7
1.7-2.2
>2.2
Ascites
None
Mild
Severe
Hepatic encephalopathy
None
Grade 1/2
Grade 3/4
Class
Points
Surgical Risk
1-yr Survival
A
5-6
Good
90%
B
7-9
Moderate
80%
C
10-15
Poor
45%
INR=international normalized ratio.
Child, ed. The Liver and Portal Hypertension. Philadelphia, PA: Saunders;1964:50-64;
Pugh. Br J Surg. 1973;60:646. D’Amico G et al. J Hepatology 2006; 44:217-231.
Model for End-Stage Liver Disease (MELD)
Predicts Severity of Liver Disease
MELD = 9.57 x loge (creatinine) + 3.78 x loge
(total bilirubin) + 11.2 x loge (INR) + 6.43
• Predicts severity of liver disease and cirrhosis-related mortality (3 month
survival)
• Used in allocation of organs for transplant
• Originally designed to predict survival after TIPS procedure
• Mortality by MELD score
• 10-19: 8%
• 20-29: 24%
• 30-39: 60%
•
>40: 81%
Weisner RE et a. Gastro 2003. Kamath P and Kim WR. Hepatology. 2007.
New Classification of Cirrhosis
Stage
Clinical Criteria
1-yr Mortality
1
No Varices
1%
2
Presence of Varices
3%
3
Presence of Ascites
20%
4
GI bleeding
54%
5
Renal failure, Infection
67%
D’Amico G J. Hepatology 2006;44:217-231; Arvaniti V et al Gastroenterology 2010;139:1246-1256.
BCLC Staging System and Treatment Allocation
What is the best treatment option
for this patient?
Surgery:
C Liver Transplantation
U Liver Resection
R
A
T
I
V
E
Ablation:
Percutaneous ethanol injection
(PEI)
Radiofrequency (RFA)
P
a
l
l
i
a
t
i
v
e
Transarterial:
Chemoembolization
90Y microspheres
Systemic Therapies:
Sorafenib
Clinical Trials
Liver Transplantation for HCC:
Milan Criteria
Single tumor, <5 cm
Up to 3 tumors, all <3 cm
Absence of macroscopic vascular invasion and extra-hepatic spread
•
•
5-yr survival with transplantation: ~ 70%
5-yr recurrent rates: < 15%
Mazzaferro V, et al. N Engl J Med. 1996;334:693-699. Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.
Patient Survival of HCV LT recipients
with HCC and without HCC
Cabrera R et al. American Journal of Clinical Oncology. 2012 Aug;35(4):345-50.
Candidates for RFA and PEI
• Includes individuals who are not candidates for surgery –
resection or transplantation
• Radiofrequency ablation generally preferred over
percutaneous ethanol injection
– Necrotic effect more predictable across tumor sizes
– Meta-analyses (4 RCTs) suggest better local control and
survival benefit with RFA vs PEI
Bruix J, et al. AASLD HCC Guidelines. July 2010.
New Trends in Local Ablation
• Microwave ablation
• Irreversible electroporation
• Intravenous heat-sensitive liposomal
doxorubicin in combination with RFA
• Combination chemoembolization and RFA
Case #2
• 70 year old white male with HCV
cirrhosis noted with abnormal
ultrasound.
• AFP =11.
• Cirrhotic liver multiple arterially
enhancing lesions in the right and
left hepatic lobes. 2 large
enhancing lesion in the superior
right hepatic lobe which measure
5.6 x 4.9 cm and 5.7 x 5.6 cm.
Randomized Study of
Conventional TACE vs DEB TACE
Patients, %
Child-Pugh B
ECOG 1
Bilobar
Recurrent Disease
DEB
TACE
cTACE
DEB
TACE
cTACE
DEB
TACE
cTACE
DEB
TACE
cTACE
Disease
control
63
32
0
32
59
49
73
54
Objective
response
44
21
63
29
49
40
55
31
Complete
response
25
16
37
14
17
13
27
15
Lammer J, et al. Cardiovasc Intervent Radiol. 2010;33:41-52.
Contraindications to TACE
• Extrahepatic tumor spread
• Lack of portal blood flow
– Portal vein thrombosis, portosystemic anastomoses
or hepatofugal flow
• Advanced liver disease (Child-Pugh Class B or C)
• Clinical symptoms of end-stage cancer
Radioembolization Using Yttrium-90
Single institution cohort study
•
•
•
•
– Endpoints: Response rate,* TTP,* survival, toxicity
273/291 (94%) of patients had follow-up imaging
58% Downstaged, 32 transplanted
Response rate 42% (WHO) and 57% (EASL)
No GI ulcers
Stage
B
Stage
C
TTP
Overall Survival
13.3
months
17.2 months
Child A = 17.3 months
Child B = 13.5 months
6 months
7.3 months
Child A = 13.8 months
Child B = 6.4 months
Salem R et al. Gastroenterology. 2010;138(1):52-64.
New Trends in Loco-Regional
Therapy
•
•
•
•
Doxorubicin-eluting beads
Quadraspheres
Combination TACE or Y90 with sorafenib
SBRT and Proton beam therapy
Case #3
•47 year old white male with
HCV cirrhosis undergoes a
screening abdominal
ultrasound.
•Ultrasound reveals multiple
liver masses.
•Innumerable bilobar arterial
enhancing lesions and vascular
invasion. AFP >50,000.
consistent with diffuse HCC
UF Experience with Sorafenib in HCC (n=31)
1.0
Overall Survival Curve - Median Survival of 36 wks (9 months)
Cum Survival
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
28
32
36
40
44
48
Survival time in weeks
Cabrera R, et al. 2008 Gastrointestinal Cancers Symposium. Abstract 147.
UF Experience: Sorafenib in HCC
Sorafenib 400 mg PO BID
N = 31
Child-Pugh Class A = 64%, B = 36%
BCLC Stage B 23%, Stage C 77%
Median follow-up 22 weeks
Range (1 – 47)
Grade 3 / 4 toxicity
Fatigue
22%
Diarrhea
23%
Hand-foot skin
14%
Dose reduction
65%
Discontinuation
42%
Cabrera R, et al. 2008 Gastrointestinal Cancers Symposium. Abstract 147.
GIDEON Observational HCC Study
• Differences in usage and reported toxicities
• Patients with Child-Pugh B experienced more liverassociated AEs
• Median TTP
• Child-Pugh A, 4.2 months
• Child-Pugh B, 3.6 months
• Median OS:
• Child-Pugh A, 10.3 months
• Child-Pugh B, 4.9 months
OS= overall survival; TTP=time to progression.
Lencioni Int J Clin Pract 2012; Venook. ASCO GI. 2011 (abstr 157); Marrero ASCO. 2011 (abstr 4001).
TACE in Combination With Sorafenib
Sorafenib 400 mg PO BID
TACE
N = 48
Child-Pugh Class A = 72%; Child-Pugh Class B = 28%
BCLC Stage B 81%; Stage C 19%.
Overall AEs
89%
Fatigue
51%
Diarrhea
43%
Hand-foot syndrome
51%
Dose reduction
31/48 (66%)
Discontinuation
18/48 (38%)
Overall Median Survival 18.5 months
(Child B 17.6 months; Stage C 17.0 months)
Cabrera R et al. Aliment Pharmacol Ther. 2011;34(2):205-13.
Investigational Treatment Strategies
Adjuvant
Prevent
recurrences
1. Sorafenib vs placebo
Intermediate HCC
Improve TACE
1. TACE ± sorafenib (?)
2. TACE vs Y90
Advanced HCC
First line:
1.
2.
3.
4.
5.
6.
Sorafenib ± erlotinib (failed)
Sorafenib vs brivanib (failed)
Sorafenib vs sunitinib (halted)
Sorafenib vs linfinib (halted)
Sorafenib ± Y90
Sorafenib ± doxorubicin
Second line:
1.
2.
3.
4.
5.
Brivanib vs placebo (failed)
Tivantinib vs placebo (cMET+)
Regorafenib vs placebo
Everolimus vs placebo
Ramucirumab vs placebo
Cabrera R. Clinical Liver Disease. Dec 2012.
Cholangiocarcinoma (CCA)
• Background:
– Arises from the epithelial cells of the bile ducts.
– Rare in the United States.
Worldwide prevalence
Bridgewater J J. of Hepatology 2014
Cholangiocarcinoma
Risk Factors for Cholangiocarcinoma
• Primary sclerosing cholangitis (PSC)
– Almost 30% of cholangiocarcinoma case are in the
setting of PSC.
– Annual incidence is between 0.6-1.5%.
– Lifetime risk is 10-15%.
• Fibropolycystic liver disease
• Parasitic infection
• Viral hepatitis
– Though much lower than risk for HCC
Burka K. Am J Gastroenoterology 2004
Cumulative incidence of
Incidence of Cholangiocarcinoma
Years since PSC diagnosis
Courtesy of Dr. Keith Linder, MD., ASU
AASLD guidelines
• Risk factors for developing CCA
– Elevated serum bilirubin
– Variceal bleeding
– Proctocolectomy
– Chronic UC with colorectal cancer or dysplasia.
Practice guidelines page. AASLD website. Available at: http://www.aasld.org/practiceguidelines.
Biliary strictures
• Signs and symptoms:
– Jaundice, pruritis, abdominal pain, fever, weight
loss
– Cholangitis is unusual.
– Tumor markers?
• CEA
• CA 19-9
Biliary Strictures
Imaging diagnosis of CCA
• Challenging to say the least
– Ultrasound
– CT scan
– MRI with MRCP
– ERCP with brushing
– No clear guidelines as to best modality to use or
frequency
Practice guidelines page. AASLD website. Available at:
http://www.aasld.org/practiceguidelines.
Case 1
• 50 year old male with known history of PSC
undergoes routine ultrasound screening.
Follow up MRCP
Treatment options
• Criteria for surgical resection:
– Absence of retropancreatic and paraceliac nodal
metatases or distant liver metastases
– Absence of invasion of portal vein or main hepatic
artery
– Absence of extrahepatic adjacent organ invasion
– Absence of disseminated disease
• Ultimately, candidacy for resection is
determined at surgery!
Tsao JI et al Ann Surg. 2000
Su CH et al Ann. Surg. 1996
Distal Extrahepatic cholangiocarcinoma
• Considered having the highest rate of
resection.
• Role of adjunct therapy post resection,
commonly recommended but lack of data
determining if true benefit.
Case 2
• 60 year old female presents to the local
Emergency Department with sudden onset
painless jaundice
Bridgewater J J. of Hepatology 2004
Role of Radiotherapy with or without
chemoradiotherapy
• Approaches include external beam
irradiation (ERBT) alone or…
• In combination with chemoradiotherapy
– Most commonly used:
•
•
•
•
5-FU
Gemcitabine
Cisplatin
oxaliplatin
Transplantation with Neoadjuvant
Chemoradiation…
...is more effective than resection for
Hilar Cholangiocarcinoma
All patients
Rea DJ, Heimbach JK, Rosen CB, et al. Liver Transplantation with Neoadjuvant Chemoradiation is More Effective than Resection for
Hilar Cholangiocarcinoma. Ann Surg 2005;242(3):451-61
Resected
Summary
• HCC has good treatment options, including
liver transplantation with diagnosed early.
• Clear screening guidelines
– US every 6 months
– Debate ongoing about role of AFP
• Cholangiocarcinoma more difficult and
outcomes typically poor
• Location of cancer best determination of
therapy options and prognosis.
Thank you