Screening for HCC

1
Liver Cancer Has the Fastest Growing Death Rate
in the US
Trends in US Cancer Mortality Rates
All Other Cancers (Average)
Corpus Uterus, NOS
Testis
Lung Bronchus (Female)
Esophagus
Thyroid
Liver
Annual Percent Change (1994-2003)
Represents the annual percent change over the
time interval National Cancer Institute Website.
Available at http//seer.cancer.gov/csr/1975_200
3/sections.html. Accessed September 21, 2006.
2
Surveillance for HCC Reduces Mortality in HBV
CarriersA Randomized Controlled Trial

Screened group
Control group Person-years in study 38,444 41,07
7 Deaths from HCC Deaths 32 54 Total mortality
(per 100,000) 83.2 131.5 Rate ratio (95
CI) 0.63 (0.41, 0.98)
Zhang BH, et al. J Cancer Res Clin Oncol 2004
3
Surveillance for HCC Reduces Mortality in HBV
Carriers Randomized Controlled Trial
Survival Probability ()
Zhang BH, et al. J Cancer Res Clin Oncol 2004
4
Comparison of HCC Surveillance Guidelines for
High-Risk Patients
Gebo et al. Management of Chronic Hepatitis C.
Evidence Report/Technology Assessment No. 60.
AHRQ Publication No. 02-E030. Agency for
Healthcare Research Quality 2002 Bruix
Sherman, AASLD Practice Guidelines Management of
Hepatocellular Carcinoma. Hepatology. 2005
42(5) 1208 Wilson et al. Ann Int Med. 2005 142
(12) 1029.
5
Probability of Local Recurrence-free Survival

• In Patients With HCC Treated with PEI (n50) or
  RF Thermal Ablation (RFTA, n52)

The difference between the groups was
statistically significant (P.002). The number of
patients followed up at 6, 12, 18, 24, and 30
months was 46, 37, 24, 16, and five,
respectively, for the PEI group and 49, 46, 33,
24, and 10, respectively, for the RF
group. Lencioni et al. Radiology. 2003.
6
Probability of Event-free Survival

• In Patients with HCC Treated with PEI (n50) or
  RF thermal Ablation (RFTA, n52).

The difference between the groups was
statistically significant (P.012). The number of
patients followed up at 6, 12, 18, 24, and 30
months was 45, 34, 21, 12, and two, respectively,
for the PEI group and 49, 42, 30, 20, and eight,
respectively, for the RF group. Lencioni et al.
Radiology. 2003.
7
Overall and Disease-free Survivals
For Patients Randomized to Percutaneous Local
Ablative Therapy (PLAT)
n90, including 19 patients who withdrew their
consent after randomization and received surgical
resection (SR) Chen et al. Ann Surg. 2006.
8
Milan Criteria Liver Transplantation

• 1 nodule 2.0 to 5.0 cm
• 2 to 3 nodules all 3.0 cm
• No gross intrahepatic portal or hepatic vein
  involvement on imaging
• No lymph node or distant metastasis or
  extrahepatic portal or hepatic vein involvement

Mazzaferro V, et al. N Engl J Med. 1996.
9
Early versus Late Recurrence after Liver
Resection for HCC

• Following surgery for HCC, 213 patients were
  evaluated for risk factors related to the risk of
  recurrence
• Intrahepatic recurrence was observed in 143
  patients
• 109 early (lt2 years) and 34 late recurrences (gt2
  years)
• Independently prognostic factors for risk of
  recurrence were
• Cirrhosis
• Chronic active hepatitis (CAH)
• HCV positivity
• Cumulative effect for multiple risk factors
  (92.5 of recurrences in patients with all 3
  factors)
• For early recurrences, neoplastic vascular
  infiltration plus cirrhosis, HCV positivity, CAH,
  and transaminases were significant
• Only cirrhosis was related to late recurrence
• Survival rate was significantly better in late
  than in early recurrence
• After radical treatment, survival was comparable
  with the group of patients without recurrence

Authors Conclusions Early and late recurrences
are linked to different predictive factors. The
modality of presentation of the recurrence
together with the feasibility of a radical
treatment are the best determinants for the
prognosis.
Portolani N, et al. Ann Surg. 2006.
10
Survival Curves of the Chemoembolisation and
Control Groups
100
Chemoembolisation (N40)
80
60
40
Log Rank Plt.009
20
Control (N35)
0
0
12
24
36
48
60
Time Since Randomization (months)
Patients at Risk
Chemoembolisation
40
29
14
4
2
Control
35
19
7
3
0
Llovet J. et al, Lancet. 2003.
11
Signaling Pathways for Cell Proliferation and
Survival
Wnt receptor
Ligand
Ras
PI3K
DSH
PLC?
Raf
PTEN
GBP
MAPK
Akt
PKC
mTOR
GSK3?
MEK1/2
BAD
ERK1/2
NF-?B
?-Catenin
BcL-XL
C-MYC
C-JUN
NF-?B
?-Catenin
p53
Transcription
Cell survival
Proliferation
Adhesion
Angiogenesis
Differentiation
Feitelson MA, et al. Surg Clin N Am.
200484339-354 Thorgeirsson S and Grisham JW.
Nat Genet. 200231339-346. Wiesenauer CA, et al.
J Am Coll Surg. 2004198410-421. Hwang YH, et
al. Hepatol Res. 200429113-21. El-Serag H and
Rudolph KL. Gastroentrology. 20071322557-2576.
12
Agents Targeting the VEGF Pathway
VEGF
Endothelial cell
VEGFR-1
VEGFR-2
Small-moleculeTK inhibitors
Podar et al. Blood. 2005..