Transcript Staging systems for HCC

Natural History and
Staging System for HCC
Child–Pugh scoring system
Points
1
2
3
Encephalopathy (grade)
None
1–2
3–4
Ascites
None
Slight
Moderate
Albumin (g/dL)
Prothrombin time prolonged (sec)
or INR
>3.5
<4
<1.7
2.8–3.5
4–6
1.7-2.3
<2.8
>6
>2.3
<2
2–3
>3
<4
4–10
>10
Bilirubin (mg/dL)
for primary biliary cirrhosis
Class A:
5–6 points
Class B:
7–9 points
Class C:
10–15 points
Pugh RN, et al. Br J Surg. 1973 ;60: 646-649; Riley TR et al. Am Fam Physician 2001; 64: 1555-60
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;44:217-231
Natural history and prognostic
indicators for survival in Cirrhotic Patients
Compensated cirrhosis
n=806
75
80
60
40
20
0
1 yr
2 yr
1 yr
2 yr
1 yr
2 yr
Child–Pugh A Child–Pugh B Child–Pugh C
50
100
25
Decompensated cirrhosis
n=843
Survival (%)
Probability of survival (%)
100
Survival (%)
100
80
60
40
0
0 12 24 36 48 60 72 84 96 108 120
20
1 yr
Months
2 yr
Compensated
1 yr
2 yr
Decompensated
Compensated cirrhosis: absence of jaundice, ascites, portal-systemic encephalopathy or
variceal bleeding
D’Amico G, et al. J Hepatology. 2006;44:217-231
Liver cirrhosis: Prognosis by stage
Classification system proposed at the Baveno V workshop1
Decompensated
Compensated
8–12%
10–20%
4–6%
No varices
varices
1%
STAGE 1
5–8%
Varices
Varices
6–15%
3–5%
STAGE 2
7–10%
Bleeding
Bleeding
Ascites
Ascites
10–15%
STAGE 3
Ascites
Ascites
Bleeding
Bleeding ~30%
DEATH
26%
STAGE 4
STAGE 5
Sepsis
Sepsis
Renal
Renal failure
failure
N%= expected 1-year outcome rates
STAGE 6 ?
1. de Franchis R [Editor]. Portal Hypertension V: Proceedings of the Fifth Baveno International Consensus Workshop, 5th Ed. 2010
5
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:
–
–
–
1. Cabibbo G et al. Hepatology 2010:51:1274-1283; 2. Cabibbo G et al. Hep Med Evidence Res2010:2;163-73.
Impaired PS
CP-B or -C
Presence of PVT
6
The TNM staging system
Stage
Tumor
Node
Metastases
I
T1
N0
M0
II
T2
N0
M0
IIIA
T3
N0
M0
IIIB
T4
N0
M0
IIIC
Any T
N1
M0
IV
Any T
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;53:1020-2.
2. Pons F, et al. HPB (Oxford). 2005;7:35-41. 3. Kee K, et al. Int J Cancer. 2007;120:2650-2655.
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;91:400-8.
2. Marrero JA, et al. Hepatology. 2005;41:707-16.
3. Bruix J, Sherman M. Hepatology. 2011;53:1020-2.
4. Pons F, et al. HPB (Oxford). 2005;7:35-41.
CLIP staging system for HCC
Variable
0
1
2
Child-Pugh score
A
B
C
Uninodular and
extension ≤ 50%
Multinodular and
extension ≤ 50%
Massive or
extension > 50%
< 400
≥ 400
No
Yes
Tumor morphology
AFP (ng/dL)
Portal vein thrombosis
Median survival
Combined score 0:
Combined score 2:
Combined score 4-6:
35.7 months
8.5 months
3.2 months
Modified from The CLIP investigators. Hepatology 2000; 31: 840-845
Survival according to the CLIP scoring system
CLIP 0 (n = 229)
Survival rate (%)
(n = 722)
CLIP 1 (n = 241)
p < 0.01
CLIP 2 (n = 136)
0
1
p < 0.0001
p < 0.0001
2
CLIP 3 (n = 70)
NS
4
CLIP 4 (n = 31)
3
NS
5
CLIP 5 (n = 8)
6
0
CLIP 6 (n = 7)
2
4
6
8
NS
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;38:207-15.
The Barcelona Clinic Liver Cancer
(BCLC) staging classification for HCC
BCLC stage
Performance
status
Tumor volume,
number and invasiveness
0
Very early
0
Single < 2 cm
Carcinoma in situ
A
A
Early
0
Single or 3 nodules < 3 cm
A–B
B
Intermediate
0
Multinodular
A–B
C
Advanced
1–2
Portal invasion N1M1
A–B
D
Terminal
>2
Any of above
C
Child-Pugh
Llovet JM et al. J Gastroenterol 2005; 40: 225-235
Prognosis of newly diagnosed HCC patients
(1999  2005) by BCLC class
%
S
u
r
v
i
v
a
l
Log-rank P
A vs B P=0.0002
B vs C P<0.0001
C vs D P=0.057
A
B
C
D
Months
Cammà et al. Aliment Pharmacol Ther 2008; 28: 62-75
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
No
Tumor greater or less
than 50% of cross-sectional
area of liver
No
No. of nodules, tumor size,
presence of PVT and
metastasis
Staging System
TNM
No
No
No
CLIP
CTP
< 400 or
≥ 400 ng/mL
No
No. of nodules, tumor
greater or less than 50%
area of liver, PVT
CUPI
Ascites
Bilirubin, AP
< 500 or
≥ 500 ng/mL
Symptoms
TNM
CTP
No
No
TNM
Bilirubin
AP
< 35 or
≥ 35 μg/mL
Yes
PVT
JIS
GRETCH
AFP: alpha fetoprotein; AP: alcaline phosphatase; CTP: Child-Turcotte-Pugh; PS: performance status; PVT: portal vein thrombosis
Marrero JA et al. Hepatology 2005; 41: 707-716
Staging of HCC: Several different systems are
available
Tumour
System
Tumour
features
Histol.
grade
TNM1


Okuda2

JIS3

CLIP4

GRETCH5

BCLC6

CUPI7

Spread
AFP
Liver
Vascular
invasion
Metastases


ChildPugh
Bilirubin
Symptoms
AP

Ascites
Cancer
symptoms


















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: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_liver_cancer_staged_25.asp; 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;94:1760-9.
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
ChildPugh
Liver
GRETCH6
Okuda7
CLIP8
JIS9
TNM
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.
Prospective validation of the BCLC
staging system
Assessment of BCLC discrimination in the 195 HCC patients
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
57.94 (0.0000)
885.98
Log-likelihood
LHR 2 test
(p value)
AIC
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
Univariate model
(All patients n = 195)
Multivariate model
All patients (n = 195)
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;44:723-31.
AASLD PRACTICE GUIDELINES 2011:
Staging and treatment of HCC
HCC
Stage 0
Stage A–C
Stage D
PST 0, Child–Pugh A
PST 0–2, Child–Pugh A–B
PST >2, Child–Pugh C
Very early stage (0)
Early stage (A)
single <2cm
Carcinoma in situ
1 HCC or 3 nodules
<3cm, PST 0
Portal pressure/
bilirubin
Increased
Resection
Multinodular,
PST 0
Portal invasion,
N1, M1, PST 1–2
3 nodules ≤3cm
1 HCC
Normal
Intermediate stage (B) Advanced stage (C) End stage (D)
Associated diseases
No
Liver transplantation
Curative treatments
Yes
RFA
TACE
Sorafenib
Palliative treatments
Symptomatic
treatment
Llovet JM, et al. J Natl Cancer Inst. 2008; 100: 698–711
HCC presentation and survival by BCLC stage in
untreated patients from randomized trials
HCC
Stage 0
PS 0, Child-Pugh A
Very early stage (0)
Single <2 cm
carcinoma in situ
Stage A–C
Okuda 1–2, PS 0–2, Child-Pugh A–B
Early stage (A)
1–3 nodules <3 cm,
PS 0
30% of pts at presentation3
Intermediate stage (B)
Multinodular,
PS 0
Stage D
PS >2,
Child-Pugh C
Advanced stage (C)
Portal invasion,
N1, M1, PS 1–2
50% of pts at presentation3
End stage (D)
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; 96:1566-71; 5. Cabibbo G et al. Hepatology 2010:51:1274-1283.
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
Change in tumour volume

Months
No or very slow initial growth
(DT > 200 days); subsequent
increasing growth rate (n=10)
Declining growth rate
over time (n=9)
Almost constant
growth rate (n=8)
Barbare L et al. Hepatology 1992;16:132-7.
Clinical Importance of Early Detection
& Precise staging of HCC
•T1: Resection
Ablation
•T2: Transplant
• 5-yr survival rates
50 – 70%
• 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; 134:1752-1763.
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.