1. Natural History and Staging System for HCC

2. Child–Pugh scoring system
Points 1 2 3
Encephalopathy (grade)
None
1–2
3–4
Ascites
Slight
Moderate
Albumin (g/dL)
>3.5
2.8–3.5
<2.8
Prothrombin time prolonged (sec)
or INR
<4
<1.7
4–6
>6
>2.3
Bilirubin (mg/dL)
<2
2–3
>3
for primary biliary cirrhosis
4–10
>10
Class A: 5–6 points
Class B: 7–9 points
Class C: 10–15 points
Pugh RN, et al. Br J Surg ;60: ; Riley TR et al. Am Fam Physician 2001; 64: 2

3. Natural history and prognostic indicators for survival in Cirrhotic Patients
Markedly longer survival in patients with compensated cirrhosis vs those with decompensated cirrhosis
Median survival
Compensated cirrhosis: > 12 years
Decompensated cirrhosis: ~ 2 years
1 year risk
D’Amico G, et al. J Hepatology. 2006;44: 3 3

4. Probability of survival (%)
Natural history and prognostic indicators for survival in Cirrhotic Patients
100 80 60 40 20
100 75 50 25
Compensated cirrhosis n=806
Survival (%)
1 yr
2 yr
1 yr
2 yr
1 yr
2 yr
Child–Pugh A
Child–Pugh B
Child–Pugh C
Probability of survival (%)
100 80 60 40 20
Survival (%)
Decompensated cirrhosis n=843
1 yr
2 yr
1 yr
2 yr
Months
Compensated
Decompensated
Compensated cirrhosis: absence of jaundice, ascites, portal-systemic encephalopathy or variceal bleeding
D’Amico G, et al. J Hepatology. 2006;44:

5. Liver cirrhosis: Prognosis by stage
Classification system proposed at the Baveno V workshop1
Compensated
Decompensated
8–12%
10–20%
4–6%
5–8%
6–15%
7–10%
Ascites Bleeding
Ascites Bleeding
No varices
No varices
Varices
Varices
Bleeding
Bleeding
Ascites
Ascites
DEATH
DEATH
~30%
26%
10–15%
3–5% 1%
STAGE 1
STAGE 1
STAGE 2
STAGE 2
STAGE 3
STAGE 3
STAGE 4
STAGE 4
STAGE 5
STAGE 5
Sepsis Renal failure
Sepsis Renal failure
STAGE 6 ? N%
= expected 1-year outcome rates
1. de Franchis R [Editor]. Portal Hypertension V: Proceedings of the Fifth Baveno International Consensus Workshop, 5th Ed. 2010 5

6. Survival rates among untreated patients with unresectable HCC
Meta-analysis of patients included in the placebo or no-treatment arms of 30 randomized controlled trials (n=1927)
Survival rates highly heterogeneous
Shorter survival for:
Impaired PS
CP-B or -C
Presence of PVT 6
1. Cabibbo G et al. Hepatology 2010:51: ; 2. Cabibbo G et al. Hep Med Evidence Res2010:2;

7. The TNM staging system Advantage of TMN in HCC
Stage
Tumor
Node
Metastases I T1 N0 M0 II T2
IIIA T3
IIIB T4
IIIC
Any T N1 IV
Any N M1
M = metastases; N = node; T = tumor.
Advantage of TMN in HCC
The TNM system and the simplified TNM system are used in many cancers, and therefore there is familiarity with the system1
Commonly used in the USA in HCC patients1
Widely tested in the surgical HCC population2
1.Bruix J, Sherman M. Hepatology. 2011;53:
2. Pons F, et al. HPB (Oxford). 2005;7: Kee K, et al. Int J Cancer. 2007;120: 7

8. The TNM staging system Disadvantages of the TNM in HCC
There is lack of homogeneity in outcomes for patients within certain current TNM categories1
Poor stratification of survival at intermediate stages2
Requires evidence of microvascular invasion, something that is not available except from surgical specimens3
Use is limited as it is based on pathological findings and does not consider liver function or tumors < 5 cm4
Changes to the TNM system have been proposed by several authors, but it still lacks adequate prognostic accuracy1,2,4
1. Wildi S, et al. Br J Surg. 2004;91: Marrero JA, et al. Hepatology. 2005;41:
3. Bruix J, Sherman M. Hepatology. 2011;53:
4. Pons F, et al. HPB (Oxford). 2005;7:35-41.

9. CLIP staging system for HCC
Variable 1 2
Child-Pugh score A B C
Tumor morphology
Uninodular and extension ≤ 50%
Multinodular and extension ≤ 50%
Massive or extension > 50%
AFP (ng/dL)
< 400
≥ 400
Portal vein thrombosis No
Yes
Median survival
Combined score 0: months
Combined score 2: months
Combined score 4-6: months
Modified from The CLIP investigators. Hepatology 2000; 31:

10. Survival according to the CLIP scoring system6 5 4 3 2 1
CLIP 0 (n = 229)
CLIP 1 (n = 241)
CLIP 2 (n = 136)
CLIP 3 (n = 70)
CLIP 4 (n = 31)
CLIP 5 (n = 8)
CLIP 6 (n = 7)
p <
p < 0.01 NS
(n = 722)
Survival rate (%) 2 4 6 8 10
Survival period (year)
Survival at 3, 5, and 10 years, respectively, for each CLIP group was
86%, 72%, and 23% for CLIP 0
70%, 47%, and 19% for CLIP 1
53%, 37%, and 8% for CLIP 2
20%, 7%, and 0% for CLIP 3
15%, 15%, and 15% for CLIP 4
0%, 0%, and 0% for CLIP 5/6
Kudo M, et al. J Gastroenterol. 2003;38:

11. Tumor volume, number and invasiveness Single or 3 nodules < 3 cm
The Barcelona Clinic Liver Cancer (BCLC) staging classification for HCC
BCLC stage
Performance status
Tumor volume, number and invasiveness
Child-Pugh
Very early
Single < 2 cm
Carcinoma in situ A
Early
Single or 3 nodules < 3 cm
A – B B
Intermediate
Multinodular C
Advanced
1 – 2
Portal invasion N1M1 D
Terminal
> 2
Any of above
Llovet JM et al. J Gastroenterol 2005; 40:

12. Prognosis of newly diagnosed HCC patients
(1999  2005) by BCLC class
Log-rank P
A vs B P=0.0002
B vs C P<0.0001
C vs D P=0.057 A % S u r v i a l B C D
Months
Cammà et al. Aliment Pharmacol Ther 2008; 28: 62-75 12

13. Staging systems for HCC
Hepatic function
AFP PS
Tumor staging
BCLC
CTP No
Yes
Tumor size, No. of nodules and PVT
Okuda
Ascites
Albumin
Bilirubin
Tumor greater or less than 50% of cross-sectional area of liver
TNM
No. of nodules, tumor size, presence of PVT and metastasis
CLIP
< 400 or
≥ 400 ng/mL
No. of nodules, tumor greater or less than 50% area of liver, PVT
CUPI
Bilirubin, AP
< 500 or
≥ 500 ng/mL
Symptoms
JIS
GRETCH
Bilirubin AP
< 35 or
≥ 35 μg/mL
PVT
AFP: alpha fetoprotein; AP: alcaline phosphatase; CTP: Child-Turcotte-Pugh; PS: performance status; PVT: portal vein thrombosis
Marrero JA et al. Hepatology 2005; 41:

14. Staging of HCC: Several different systems are available
Tumour
Spread
Liver
Symptoms
Tumour features
Histol. grade
AFP
Vascular invasion
Metastases
Child-Pugh
Bilirubin AP
Ascites
Cancer symptoms
TNM1 
Okuda2
JIS3
CLIP4
GRETCH5
BCLC6
CUPI7
AFP, alpha-fetoprotein; AP, alkaline phosphatase; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Lliver Italian Program; CUPI, Chinese University Prognostic Index; GRETCH, Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC, hepatocellular carcinoma; Histol., histological; JIS, Japan Integrated Stage; TNM, tumor nodes metastases.
1. American Cancer Society. Available at: 2. Schafer DF, et al. Lancet 1999;353:1253-7; 3. Makuuchi M, et al. World J Gastroenterol 2006;12:828-9; 4. CLIP. Hepatology 1998;28:751-5; 5. Chevret S, et al. J Hepatol 1999;31:133-41; 6. Llovet JM, et al. Semin Liver Dis 1999;19:329-38; 7. Leung T, et al. Cancer 2002;94: 14

15. HCC staging is complex and multifaceted
Staging is used for prognosis and to guide treatment1
Staging HCC1
Most patients have underlying liver disease
Key prognostic indicators are not clearly defined
Prognostic indicators vary during the course of disease
Factors affecting staging2,3
Tumour stage
Liver function
Health status
Impact of treatment
Patient
ECOG PS
BCLC4
CUPI5
Child- Pugh
GRETCH6
TNM
Okuda7
CLIP8
JIS9
Liver
Tumour
BCLC, Barcelona Clinic Liver Cancer; CLIP, cancer of the liver Italian program; CUPI, Chinese University Prognostic Index; ECOG PS, Eastern Cooperative Oncology Group performance status; GRETCH, Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC, hepatocellular carcinoma; JIS, Japan Integrated Stage; TNM, tumor nodes metastases.
1. Llovet JM, et al. Lancet 2003;362:1907–17; 2. Marrero JA, et al. Clin Liver Dis 2006;10:339–51; 3. Marrero JA, et al. Hepatology 2005;41:707–16; 4. Llovet JM, et al. Semin Liver Dis 1999;19:329–38; 5. Leung T, et al. Cancer 2002;94:1760–1769; 6. Chevret S, et al. J Hepatol 1999;31:133–41; 7. Schafer DF, et al. Lancet 1999;353:1253–7; 8. CLIP. Hepatology 1998;28:751–5; 9. Makuuchi M, et al. World J Gastroenterol 2006;12:828–9. 15

16. Prospective validation of the BCLC staging system
Assessment of BCLC discrimination in the 195 HCC patients
Univariate model (All patients n = 195)
Linear trend 2 test
LHR 2 test (p value)
AIC
Okuda
3.98
8.87 (0.0118)
933.06
CLIP
4.17
7.83 (0.0979)
938.10
UNOS-TNM
20.03
28.31 (0.0000)
915.62
JIS
12.45
15.77 (0.0013)
928.16
BCLC
43.01
(0.0000)
885.98
Multivariate model All patients (n = 195)
Log-likelihood
Full model
434.80 –
899.60
Removing Okuda
436.29
2.97 (0.2258)
898.58
Removing CLIP
436.36
3.11 (0.5385)
894.72
Removing UNOS-TNM
437.47
5.32 (0.1494)
898.94
Removing JIS
435.43
1.26 (0.7386)
896.86
Removing BCLC
449.92
48.90 (0.0000)
923.84
The BCLC staging system gives a more precise prognostic stratification in a study group treated mainly with radical therapies
Cillo U, et al. J Hepatol. 2006;44: 16

17. AASLD PRACTICE GUIDELINES 2011: Staging and treatment of HCC
Stage 0 PST 0, Child–Pugh A
Stage A–C PST 0–2, Child–Pugh A–B
Stage D PST >2, Child–Pugh C
Very early stage (0)
single <2cm Carcinoma in situ
Early stage (A)
1 HCC or 3 nodules <3cm, PST 0
Intermediate stage (B)
Multinodular, PST 0
Advanced stage (C) Portal invasion, N1, M1, PST 1–2
End stage (D)
1 HCC
3 nodules ≤3cm
Portal pressure/ bilirubin
Increased
Associated diseases
Normal No
Yes
Resection
Liver transplantation
RFA
TACE
Sorafenib
Symptomatic treatment
Curative treatments
Palliative treatments
Llovet JM, et al. J Natl Cancer Inst. 2008; 100: 698–711 17 17

18. HCC presentation and survival by BCLC stage in untreated patients from randomized trials
Stage 0 PS 0, Child-Pugh A
Stage A–C Okuda 1–2, PS 0–2, Child-Pugh A–B
Stage D PS >2, Child-Pugh C
Very early stage (0) Single <2 cm carcinoma in situ
Early stage (A) 1–3 nodules <3 cm, PS 0
Intermediate stage (B) Multinodular, PS 0
Advanced stage (C) Portal invasion, N1, M1, PS 1–2
End stage (D)
30% of pts at presentation3
50% of pts at presentation3
20% of pts3
BCLC stage 0-A
BCLC stage B
BCLC stage C
BCLC stage D
Asymptomatic HCC: 96% 1-year survival4
50% 1-year survival5
25% 1-year survival5
11% 1-year survival5
1. Lencioni R et al. Radiol 2005; 234:961–967; 2. Llovet JM, et al. J Natl Cancer Inst 2008;100:698–7; 3. Bruix B, Llovet J. Hepatology 2002;35:51924; 4. Cottone M et al. Gastroenterology 1989; 96: ; 5. Cabibbo G et al. Hepatology 2010:51: 18

19. Tumour doubling in untreated nodules
59 small HCCs in 39 patients:
No correlation to initial tumour size
No significant relation to cirrhosis severity (trend to faster DT if more severe)
Serial tumour volume measurements over time identified different growth patterns
Almost constant growth rate (n=8)
Declining growth rate over time (n=9)
Months
Change in tumour volume
No or very slow initial growth (DT > 200 days); subsequent increasing growth rate (n=10)
Barbare L et al. Hepatology 1992;16:132-7.

20. Clinical Importance of Early Detection & Precise staging of HCC
T1: Resection
Ablation
T2: Transplant
5-yr survival rates – 70%
This diagram illustrating the T stages of HCC shows the critical importance of early detection and precise staging of HCC, in terms of treatment. According to many previous studies, HCCs detected in their T1 and T2 stages have been shown to provide much better survival rates after, resection, ablation, or transplantation, than that in T3 and T4 lesions. The 5 yr survival rates of those with early detected HCCs is in the range of 50-70%. So, clearly, we need more sensitive imaging modalities to detect HCCs in its early stages.
HCCs detected in T1 & T2 stages show much better survival
Sensitive imaging modalities to detect HCCs in its early stages
El-Serag HB, et al. Gastroenterology 2008; 134: 20

21. The natural history of HCC – a summary
Common worldwide, although disease aetiology varies
Often occurs in conjunction with liver cirrhosis
Liver function of prognostic importance in cirrhotic patients
CP-A survival > CP-B survival > CP-C survival
Multitude of staging systems exist
Tumour characteristics alone are unlikely to adequately predict prognosis
Integrated staging systems are mandatory
BCLC staging system links integrated staging and treatment strategy
The natural history of intermediate/advanced stage HCC is dismal and prognosis for patients still remains very poor
In fact, surgical or locoregional treatments of large tumour burden may further worsen liver function, which might be compromised already
There is a pressing need for improved management strategies to improve survival
HCC, hepatocellular carcinoma; CP, Child-Pugh. 21