1. A New Model to Estimate Survival for Hepatocellular Carcinoma Patients
Po-Hong Liu, Chia-Yang Hsu, Cheng-Yuan Hsia, Yun-Hsuan Lee
Yi-Hsiang Huang, Chien-Wei Su, Fa-Yauh Lee, Han-Chieh Lin, Teh-Ia Huo
Taipei Veterans General Hospital
National Yang-Ming University
TAIWAN

2. The Authors Have Nothing to Disclose
Disclosure
The Authors Have Nothing to Disclose

3. Staging System for HCC Staging: critical step in cancer management
Prognosis of HCC is complex
Tumor extent
Liver dysfunction
General medical condition
HCC: hepatocellular carcinoma
J Hepatol 2016;64:

4. Current Scoring Systems
Model
Tumor
Status
Liver Function
Performance Status
Serum AFP
Serum ALK-P
TIS
Yes
CTP No
CLIP
Tokyo
JIS
MESIAH
MELD
NIACE
French
Bilirubin
Karnofsky
CUPI
Symptoms
AFP: alpha-fetoprotein; ALK-P: alkaline phosphatase; CLIP: Cancer of the Liver Italian Program; CUPI: Chinese University Prognostic Index; JIS: Japan Integrated Scoring; MESIAH: Model to Estimate Survival In Ambulatory HCC; TIS: Taipei Integrated Scoring
J Hepatol 2016;64:

5. Do We Need Another Score ?
Model
Tumor
Status
Liver Function
Performance Status
Serum AFP
Serum ALK-P
TIS
Yes
CTP No
CLIP
Tokyo
JIS
MESIAH
MELD
NIACE
French
Bilirubin
Karnofsky
CUPI
Symptoms
New Score ?
AFP: alpha-fetoprotein; ALK-P: alkaline phosphatase; CLIP: Cancer of the Liver Italian Program; CUPI: Chinese University Prognostic Index; JIS: Japan Integrated Scoring; MESIAH: Model to Estimate Survival In Ambulatory HCC; TIS: Taipei Integrated Scoring
J Hepatol 2016;64:

6. Aim of the Study
To establish a new prognostic Model to Estimate Survival for HCC (MESH Score) Patients
Our approach
Assess pre-treatment status
Use common variables
Simplistic approach & user-friendly
Statistically robust

7. Methods & Study Flowchart
All Patients
Derivation Cohort (n = 1,591)
Selecting Predictors
Forward Cox Regression
MESH Score
Validation Cohort (n = 1,591)
Kaplan-Meier Curve
Discriminatory Ability
Homogeneity
Subgroup Analysis
1:1 Randomization
Single-center
3,182 Patients ( )

8. Choosing Survival Predictors
All candidate baseline survival predictors were included in initial analysis
All predictors are dichotomized
Clinical knowledge (Age, Milan, Single/Multiple)
Conventional definitions (ALT, ALK-P, AFP)
Youden index in ROC curve (CTP scores, AFP, PS)
AFP, alpha-fetoprotein; ALK-P: alkaline phosphatase; ALT: alanine transaminase; CTP: Child-Turcotte-Pugh; ROC: Receiver-Operating-Characteristics, PS: performance status

9. Predictors of Survival
Univariate analysis
Multivariate analysis HR
p value β CI
Age (<65/≥65 years)
1.133
0.133
Sex (male/female)
0.926
0.127
HBsAg (negative/positive)
0.883
0.136
Anti-HCV (negative/positive)
0.774
0.005
Non-significant
Alcoholism (no/yes)
1.330
0.007
ALT (<40/≥40 IU/L)
1.120
0.186
Platelet (≥150K/<150K/μL)
1.349
<0.001
ALK-P (<200/≥200 IU/L)
4.150
1.953
0.669
CTP score (5/6-15)
3.083
2.055
0.720
Performance status (0-1/2-4)
4.563
2.415
0.882
Serum AFP (<20/≥20 ng/mL)
2.035
1.540
0.432
Single/Multiple tumor
1.486
Early/Non-early tumor (Milan)
2.919
1.823
0.601
Vascular invasion + Metastasis
5.530
2.752
1.012

10. Predictors of Survival
Univariate analysis
Multivariate analysis HR
p value β CI
Age (<65/≥65 years)
1.133
0.133
Sex (male/female)
0.926
0.127
HBsAg (negative/positive)
0.883
0.136
Anti-HCV (negative/positive)
0.774
0.005
Non-significant
Alcoholism (no/yes)
1.330
0.007
ALT (<40/≥40 IU/L)
1.120
0.186
Platelet (≥150K/<150K/μL)
1.349
<0.001
ALK-P (<200/≥200 IU/L)
4.150
1.953
0.669
CTP score (5/6-15)
3.083
2.055
0.720
Performance status (0-1/2-4)
4.563
2.415
0.882
Serum AFP (<20/≥20 ng/mL)
2.035
1.540
0.432
Single/Multiple tumor
1.486
Early/Non-early tumor (Milan)
2.919
1.823
0.601
Vascular invasion + Metastasis
5.530
2.752
1.012

11. Predictors of Survival
Univariate analysis
Multivariate analysis HR
p value β CI
Age (<65/≥65 years)
1.133
0.133
Sex (male/female)
0.926
0.127
HBsAg (negative/positive)
0.883
0.136
Anti-HCV (negative/positive)
0.774
0.005
Non-significant
Alcoholism (no/yes)
1.330
0.007
ALT (<40/≥40 IU/L)
1.120
0.186
Platelet (≥150K/<150K/μL)
1.349
<0.001
ALK-P (<200/≥200 IU/L)
4.150
1.953
0.669
CTP score (5/6-15)
3.083
2.055
0.720
Performance status (0-1/2-4)
4.563
2.415
0.882
Serum AFP (<20/≥20 ng/mL)
2.035
1.540
0.432
Single/Multiple tumor
1.486
Early/Non-early tumor (Milan)
2.919
1.823
0.601
Vascular invasion + Metastasis
5.530
2.752
1.012

12. The MESH Score Score range from 0 to 6 Prognostic Factors 11
Tumor Burden (Milan)
Small
Large
Vascular invasion or metastasis
Absent
Present
Child-Turcotte-Pugh score 5
≥ 6
Performance status
0-1
≥ 2
Serum AFP level
< 20 ng/mL
≥ 20 ng/mL
Serum ALK-P level
< 200 IU/L
≥ 200 IU/L
Score range from 0 to 6

13. Validation of MESH Score

14. Kaplan-Meier Curve in Validation Cohort
Significant Survival Differences across all MESH Scores

15. Comparing Prognostic Performances
Model
Homogeneity (Wald χ2)
Corrected Akaike Information Criteria
BCLC
HKLC
TIS
CLIP
MESIAH
MESH
Homogeneity: small difference in survival for patients among the same classification within each system Akaike information criterion: amount of information loss during model creation
BCLC: Barcelona Clinic Liver Cancer; HKLC: Hong Kong Liver Cancer

16. Discriminatory Ability
Model
Death at 1-year
Death at 3-year
Death at 5-year
BCLC
0.794
0.741
0.713
HKLC
0.821
0.766
0.735
TIS
0.832
0.768
0.724
CLIP
0.838
0.772
0.732
MESIAH
0.867
0.806
0.773
MESH
0.860
0.805
0.769 * * * * * *
MESH Score: High Prognostic Accuracy in Validation Cohort
Discriminatory ability: The ability to identify survivor and non-survivor
* p<0.05

17. MESH Score in Different Clinical Settings
HBV- & HCV-related HCC
Curative & Non-curative Treatment
BCLC & HKLC

18. MESH Score for Different Etiologies
Model
Homogeneity (Wald χ2)
Corrected Akaike Information Criteria
HBV-related HCC (41%)
CLIP
MESIAH
MESH
HCV-related HCC (23%)
92.821
HBV: hepatitis B virus; HCV: hepatitis C virus

19. MESH Score for Different Treatments
Model
Homogeneity (Wald χ2)
Corrected Akaike Information Criteria
Curative treatment (SR, RFA, transplantation, 44%)
CLIP
42.873
MESIAH
63.767
MESH
60.457
Non-curative treatment (All other treatment, 56%)
RFA: radiofrequency ablation, SR, surgical resection

20. BCLC 0/A and HKLC I/II HCC
MESH Score Discriminate Survival for Earlier HCC

21. BCLC B/C/D and HKLC III/IV/V HCC
MESH Score Discriminate Survival for Later HCC

22. Limitations Choice of predictors and their cut-points
Developed from “treated cohort”
Lack of external validation

23. MESH Score - Summary Simple, common, and accurate
Can be used in different clinical settings
Supplementary to current staging systems

24. Thank You for Your Attention
MESH Score 1
Tumor Burden (Milan)
Small
Large
Vascular invasion or metastasis
Absent
Present
Child-Turcotte-Pugh score 5
≥ 6
Performance status
0-1
≥ 2
Serum AFP level
< 20 ng/mL
≥ 20 ng/mL
Serum ALK-P level
< 200 IU/L
≥ 200 IU/L

25. Supplementary Materials
Cohort characteristics
Detailed MESH score
Choosing cut-off values
Can scores guide treatment decisions ?

26. Benchmark - Detailed MESH Score
Prognostic Factors
Absent
Original MESH
Beta Coefficient
Detailed MESH
Tumor Burden (Milan Criteria) 1
0.601
1.5
Vascular invasion or metastasis
1.012
2.5
CTP score
0.720
Performance status
0.882 2
Serum AFP level
0.432
Serum ALK-P level
0.669
Based on relative ratios of β-coefficients
Detailed MESH score range from 0 to 10

27. Performance of Detail MESH Score
Model
Homogeneity (Wald χ2)
Corrected Akaike information criteria
BCLC
HKLC
TIS
CLIP
MESIAH
MESH
Detailed MESH

28. Choosing Survival Predictors
All candidate baseline survival predictors were included in initial analysis
All predictors are dichotomized
Clinical knowledge (Age, Milan, Single/Multiple)
Conventional definitions (ALT, ALK-P, AFP)
Youden index in ROC curve (CTP scores, AFP, PS)
ALT: alanine transaminase; CTP: Child-Turcotte-Pugh; PS: performance status

29. Alkaline Phosphatase Alk-P may be related to HCC growth
Had been included in CUPI and French score
Cut-points
CUPI score: Alk-P ≥ 200 IU/L
French score: Alk-P ≥ 2x upper limit
Youden Index: 127 IU/L

30. Child-Turcotte-Pugh Score
Child-Pugh class A: 73% patients
Further sub-division
Youden index for CTP score
Cut-point: 5 vs 6-15
New marker for liver dysfunction ?
Albumin-bilirubin (ALBI) grade (1 vs 2-3)
Platelet-albumin-bilirubin (PALBI) grade (1 vs 2-3)

31. Performance Status ECOG PS 1  BCLC stage C
PS is highly associated with survival
PS 1 HCC benefits from aggressive therapy
Youden index for performance status
Cut-point: 0-1 vs 2-4
Hepatology 2013;57:
ECOG: Eastern Oncology Cooperative Group

32. Can Score Guide Treatment Decisions ?
Prognostic scores can stratify BCLC stages
MESIAH score  BCLC 0/A, B, C, D
NIACE score  BCLC A, B, C
MESH score  BCLC 0, A, B, C (Data not shown)
Can prognostic scores guide treatment algorithm ?  A proof-of-concept study
Eur J Gastroenterol Hepatol 2016;28(4):433-40
Hepatology 2012;56(2)614-21

33. Nomogram for Recurrence after RFA (BCLC 0/A)
Point
Number of Tumor
Largest Tumor
Serum Albumin
MELD Score
Risk of recurrence after RFA (BCLC 0/A)
Low risk: nomogram score < 9.8
High risk: nomogram score ≥ 9.8
Platelet Count
Sum up
Total Points
Recurrence-free survival
Medicine 94(43):e1808

34. Scores in Treatment Algorithm
Very Early & Early HCC
Nomogram
Low-Risk
RFA
High-Risk SR

35. Cohort Characteristics
Prospective cohort of 3,182 HCC in Taiwan
Timespan:
HBV-related HCC: 41%
HCV-related HCC: 23%
Curative treatment: 44%

36. Percentages of Patients
Score (%) 1 2 3 4 5 6
MESH
13.2
24.7
21.6
15.4
11.6
9.4
4.2
CLIP
30.5
27.4
15.1
11.4
9.5
5.0
1.0
BCLC
8.3
23.1
15.8
40.3
12.4
HKLC
31.5
27.1
10.1
9.3
22.1