1. Hepatocellular Carcinoma Detection and Treatment
Scott Cotler, MD
Associate Professor of Medicine Chief, Section of Hepatology
University of Illinois at Chicago

2. Annual Report to the Nation on the Status of Cancer 1975-2002
Annual Percent Change
NCI SEER registries
Based on 10% of US population
Rates calculated based on 2000 census data
Incidence projected to increase another 80% by 2020
Liver Cancer in Men
J Natl Cancer Institute 2005;97:

3. Impact of Surveillance for HCC
On Survival: China
n=86
n=67
P<0.01
Prospective study in an Urban Chinese population
HBV or history of HBV
Age 35-59
Screening—AFP and US on 6 months basis
Screening group completed on 58% of screening offered
Screening led to detection of HCC at an earlier stage
37% reduction in mortality
Therapy consisted of surgery or ablative therapy, but not liver transplantation
Zhang B-H, et al. J Cancer Res Clin Oncol 2004;130:417-22

4. Impact of Surveillance for HCC On Survival: US
Surveillance associated with stage at diagnosis
Stage is key determinant of access to transplantation
Long term survival dependent on receiving a liver transplant
Retrospective analysis of 269 patients
SOC: suriveillance within 1 year of diagnosis
Substandard—no surveillance within 1 year of diagnosis, but recognized cirrhosis
Absence of surveillance—not know to be cirrhotic
A: proportion diagnosed within the Milan criteria
B: LRT is locoregional therapy—TACE or RFA
Of 60 patients who had OLT for HCC, only 8% recurrence rate at median f/u of 39 mos
Stravitz RT, et al. Am J Med 2008;121:

5. Surveillance Recommendations
Hepatitis B carriers
Asian males > 40
Asian females > 50
Africans > 20
All cirrhotics with hepatitis B
Family history of HCC
Non-hepatitis B cirrhosis
AASLD Practice Guideline
Groups in which risk of HCC exceeds 0.2%/year
Want to screen at risk patients who have potential treatment options
Bruix J & Sherman M. Hepatology 2005;42:

6. Surveillance Recommendations
Ultrasonography
6-12 month interval
Nodule >1 cm warrants further evaluation
AFP was deemed an inadequate screening test
Sensitivity of US is 65-80%
Advanced cirrhosis with small lesion 20-30%
4-12 mos for tumor to go from undetectable to 2 cm. If want to detect small tumors, screen q6 mos.
CT if AFP > 20
Bruix J & Sherman M. Hepatology 2005;42:

7. Biomarkers for HCC AFP: sensitivity 60-80%, specificity 70-90%
AFP-L3 isoform
AFP-L3 >10% total AFP associated with an increased risk of HCC development
Golgi protein 73 (GP73)
More sensitive than AFP in detecting HCC in preliminary studies
Des-gamma-carboxy-prothrombin (DCP)
Limited sensitivity in some studies for HCC < 3 cm
HCC-specific autoantibodies
AFP should not be used alone for screening
DCP: data are mixed
Golgi protein 73 (GP73)
Preliminary studies used Western blotting
Need a quantitative ELISA
Combinations of tumor associated antibodies appear promising
Wright LM, et al. Cancer Detect Prevent 2007;31:35-44

8. Further Evaluation of Liver Nodules
<1 cm
Low likelihood of HCC
US every 3-6 months, revert to routine surveillance if no growth over 2 years
>1 cm and < 2 cm
Treat as HCC if characteristic features on 2 dynamic studies (CT & MRI)
Biopsy if radiologic features are atypical
Difficult to identify lesions < 2 cm by US
False negative rate >10%
Small risk of bleeding (<5%), rare tumor seeding
Typical—hypervascular with washout in portal-venous phase
US, CT, and MRI miss 30-40% of lesions < 1 cm
US minimum lesion size detected under ideal situation is 0.5 cm
US sensitivity for 2-3 cm lesions is 82-93%
Middle category: more likely to be HCC
Limitations
30-40% false negative rate for FNA
Risk of tumor seeding
Further strategies need to be developed for this group
Recent data suggesting MR angiography may have increased sensitivity for this group (84%)
Contrast-enhanced sonography increases sensitivity and specificity
Bruix J & Sherman M. Hepatology 2005;42:

9. Noninvasive Criteria for Diagnosis of HCC in Cirrhosis
Focal lesion >2 cm with arterial hypervascularity and venous washout on 1 dynamic imaging technique (CT or MRI)
Focal lesion >2 cm with arterial hypervascularity + AFP >200
Biopsy if atypical vascular pattern or non-cirrhotic liver
Advantages of noninvasive criteria for lesions >2 cm
Avoidance of 10-20% false negative rate with biopsy
Avoid small risk of tumor seeding
Limitations: misclassification of vascular dysplastic nodules and primary hepatic lymphomas
Bruix J & Sherman M. Hepatology 2005;42:

10. CT: Arterial Phase CT arteriography Capsule, mosaic pattern
Necrosis and fibrous elements
Majority of blood flow to liver is from portal venous supply, so liver does not enhance substantially during the arterial phase
In a patient with cirrhosis, arterial enhancement followed by portal venous washout has a sensitivity of 80% and specificity of 95% for HCC

11. CT: Portal Venous Phase
CT arterial portography
Portal perfusion defect
Tumor washout with enhancement of liver parenchyma during portal venous phase

12. Metastatic Workup Physical examination CT chest, abdomen, pelvis
Bone scan
Head CT (selected cases)
Brain mets rare

13. Additional Imaging Techniques
Contrast-enhanced ultrasonography (CEUS)
Uses microbubbles to detect hypervascularity and characteristic washout of malignant lesions
Increases sensitivity and specificity of conventional ultrasound
FDG-PET
Relatively low sensitivity for diagnosis of HCC, particularly with well-differentiated tumors
May be useful for identifying extrahepatic metastases including involvement of the lung, bone, and lymph nodes
18 flourodeoxyglucose
In one study, sensitivity of PET was 55%
False positives did occur with PET assessment for extrahepatic disease
Could consider in patients with lesion > 5 cm, who have greater risk for mets
PET might be particularly good at identifying involved lymph nodes
Rahbin N, et al. Acta Radiologica 2008;49: ; Yoon KT, et al. Oncology 2007;72:

14. Therapy: Surgical Resection
Solitary HCC
Normal bilirubin
Absence of significant portal hypertension
HVPG <10
(esophageal varices, ascites, or splenomegaly with plt <100,000)
Perioperative mortality 1-3%
5 year survival: up to 70%
Recurrence: 50% at 3 years, 70% at 5 years
Tumor size is not a clear cut limiting factor
Location is more important
No benefit from chemoembolization prior to resection
Recurrence includes dissemination and de novo tumors
Most powerful predictors are microvascular invasion and satellite lesions
Bruix J, Hepatology 2002;35:519-24

15. Ablative Therapy Radiofrequency ablation (RFA)
90% CR for lesions <3 cm
Not optimal for larger lesions or tumors near the hilum or large vessels
AE: hemorrhage, infection/abscess, gallbladder injury, liver failure
Transarterial chemoembolization (TACE)
Direct drug delivery + ischemic necrosis
Improves 2-year survival for unresectable HCC
AE: abdominal pain, nausea, fever, infection/abscess, gallbladder injury, liver failure
RFA
Use energy to achieve coagulative necrosis of tumor tissue
CR=complete ablation
RFA is a thermoablative therapy
Effective up to 3 cm, want to achieve a 1 cm rim
Larger probes available but efficacy questionable
TACE
Tumor is dependent on arterial blood flow
Drug eluting beads available, don’t use lipiodol with beads
Often used as a bridge to transplant
Post-emboliztion syndrome—occurs to some extent in nearly all patients
For both RFA and TACE, liver failure is rare
Most frequently use adriamycin and cisplatin

16. Therapy: Chemoembolization
Chemoembo being delivered through a 3-Fr coaxial micro catheter positioned as close as possible to the feeding arterial branches. The ethiodal is very radiodense allowing the operator to identify any nontarget embolization and access how well the tumor is taking up the chemotherapeutic agents.
Mix chemo agent with ethiodol, serves as a delivery vehicle and is radioopaque

17. TACE + RFA for Large HCC RCT of 291 patients with HCC >3 cm
Rationale: reducing tissue perfusion by TACE → ↓ heat loss, ↑efficacy of TACE
Survival benefit for TACE+RFA
Overall, single, multiple lesions
Childs A, B
< 3 lesions, < 7.5 cm
RFA within 2 weeks of TACE
Rx 0, 2, 4 mos, mean 3-4 rx
5 cm probe
Cheng B-Q et al. JAMA 2008;299:

18. Radiation Therapy Yttrium (90Y) radioembolization
Microscopic embolization with glass beads
T1/ hours, path length 5.3 mm
Delivered selectively, segmentally, or diffusely
Safe with branch/lobar portal vein thrombosis
AE: radiation pneumonitis, GI bleeding, liver failure
Focused high dose RT
Made possible by advances in RT planning, image guided therapy, respiratory tracking
Radiation sensitizing agents
Particle therapy (protons or carbon ions)
Yttrium—treatment of advanced HCC
Radiation therapy
Whole liver has low tolerance for RT, particularly in cirrhotics
RILD--VOD like pathology
Image guided therapy—localize tumor at time of treatment

19. Liver Transplantation
Milan: single tumor <5 cm or up to 3 tumors (none >3 cm), without vascular invasion or extrahepatic spread
5-yr post-transplant survival >70%
USCF: Single tumor < 6.5 cm or < 3 tumors, largest < 4.5 cm with total diameter < 8 cm
2-yr survival 86% (95% CI 54-96%)
Sirolimus might impact on recurrence
Milan
Median f/u 26 mos (9-54)
Including CT every 6 mos, AFP
Most tumors recur within 2 years
45 (94%) patients with HCV or HBV
Correct Pre-op staging (n=35) significantly better than incorrect staging (n=13) for patient and recurrence free survival
Milan Criteria Adopted by UNOS
Understaging in about 10% to 15% in general
Rate of exclusion on waiting list is as high as 25%
HCC—24 points, increase by 10% every three months on waiting list
Decision analysis suggest that LDLT is cost-effect if waiting time exceeds 7 months
A number of studies show that 5 year survival >70%
UCSF: Retrospective study of 70 patients
—Included 14 who met the UCSF criteria
but exceeded the Milan criteria (overall, only 10% exceed Milan but meet UCSF)
2 year survival
Evidence not entirely conclusive due to the wide confidence interval
Based on this study would make OLT available to 10% of patients who would have been excluded by Milan criteria
In other studies, size correlates with microvascular invasion and histologic grade
Study from Colorado showed improved tumor free survival. Other studies inconsistent
Mazzafero V, N Engl J Med 1996;334:693-99, Yao FY, Liver Transpl 2002;8:765-74

20. Systemic Chemotherapy: Sorafenib
RCT of 602 patients
>95% Child-Pugh A cirrhosis
>80% with advanced HCC (BCLC stage C, including portal vein thrombosis or extrahepatic spread)
Median survival
Sorafenib-10.7 mos
Placebo-7.9 mos
Adverse effects
Fatigue, diarrhea, hand-foot skin reaction
? Role as an adjuvant agent
Oral multikinase inhibitor also used to treat renal cell carcinoma
Blocks tumor cell proliferation
Targets RAF kinase
Antiangiogenic
Hand-foot: rash/desquamation
First systemic chemotherapeutic agent to show a survival benefit in patients with advanced HCC.
Benefit is modest
Llovet J, et al. J Clin Oncol 2007;25:LBA1

21. Summary The incidence of HCC is increasing in the US
Diagnosis and management require a multidisciplinary approach
Surveillance consists of ultrasound every months in at risk patients
Diagnosis often made by noninvasive criteria
Ablative therapy improves survival and can serve as a bridge to transplant
Transplantation can be curative in selected cases
Median survival: 7-8 mos
US data,
<1% had surgical resection of OLT
<8% local therapy