1

HCC Surveillance: Evidence and Populations

Jordan J Feld MD MPH

Toronto Western Hospital Liver Centre

Sandra-Rotman Centre for Global Health

University of Toronto

Disclosures – Dr. J. Feld

Research grants: Abbvie, Boehringer Ingelheim, Gilead, Roche, Vertex

Consulting or speaker fees: Abbvie, Achillion, Boehringer Ingelheim, Gilead,

Janssen, Merck, Roche, Vertex

Outline

Evidence supporting the concept of surveillance

in general – is it effective?

Is surveillance cost-effective?

Can surveillance be improved upon by targeting

higher risk populations?

The only true RCT18,816 HBV 35-59 yo randomized AFP/US q 6m vs no screen

Findings:

•No small HCC in controls

•Better outcome in small HCC screened group

•Reduced liver-related mortality with screening – rate ratio 0.63

(0.41-0.98)

Caveats:

- 58% screening compliance

- Not ITT

- Resection was only therapy

- Variable reporting of results

- Did not account for cluster

randomization

Agorham Cochrane Database Syst Rev 2012

Su

rviv

al

Months

Stage 1

Stage 2 screened

Stage 2 control

Stage 3

Zhang J Can Res Clin Onc 2004

Other Evidence for Surveillance

Chen et al J Med Screen 2003

5581 patients randomized to AFP vs nothing no

mortality difference (p=0.86)

Inadequate therapy for those with HCC

RCTs are difficult…slow, expensive and possibly

even unethical (minimal harm to surveillance)

Alternative…cohort, case-control studies

Cohort Studies

Historical control

HCC at first screen

HCC during f/u surveillance

5 yr survival: 42% vs 0%, p=0.0008

Pro

po

rtio

n o

f p

ati

en

ts a

liv

e

Years

1,487 HBsAg +ve had AFP followed by US vs

24 historical control HCCs

• Screening program identified early, treatable/curable HCCs

• Similar study 75% curable w/ screen vs 15% withoutMcMahon Hepatology 2000, Solmi Am J Gastro 1996

2

Risk of bias

Lead-time bias

Diagnose HCC earlier survival after diagnosis

increased but absolute survival unchanged

Length-time bias

Diagnose slow-growing HCCs at an early stage

Apparent prolonged survival

Certainly issues but can be accounted for in analysis

- Very little evidence – poorly done RCT from China on a

different population (HBV rather than cirrhosis)

- Risk of harm – biopsy??

- Question suggestion that compliance better in the West

- Do not accept that it is unethical and argue the opposite,

that screening without evidence is unethical

- Australian study found only 10% of patients would agree

to randomization

- Sherman & Bruix do not accept their position

Not everyone endorses screening

Compliance: A valid concern

SEER-Medicare database

1,873 patients with HCC with prior dx of cirrhosis

17% regular surveillance

38% inconsistent surveillance

45% no surveillance

Of these – AFP + US 52%, AFP alone 46%, US 2%

Factors associated with surveillance:

Patient - age, SES, race

MD – specialty (GI/Hep), academic, region

Davila Hepatology 2010

Even when surveillance is done, not always effective…

more on that from Dr. Singal

• Despite these caveats, most experts accept that if

done properly, surveillance has the potential to

improve HCC outcomes

• Pre-requisite for further discussion

If we accept that surveillance is effective, the next question is cost

Cost-Effective Analysis Many CEAs of HCC screening

Variable results

Differing models

Surveillance strategies (tests & intervals)

Natural history of cirrhosis

Incidence of HCC

Performance characteristics of the tests

Treatment of HCC – (transplant, TACE, sorafenib)

Costs – of surveillance tests AND HCC dx & therapy

All assume that surveillance has some degree of

effectiveness

Utilities adjustment – under and overused

3

Cost-Effectiveness

Most studies found ICERs of 3.2%)

c. More CE the greater the benefit of HCC tx (>20%)

Cucchetti J Hep 2012

To improve the efficiency of HCC screening…

need to select the population

4

Risk Stratification

HCC incidence is a driver of effectiveness and

cost-effectiveness of HCC surveillance

1. Patients with HBV

2. Patients with cirrhosis

Identify higher

risk populations

Multiple HBV scoring systems to predict HCC risk

Yang et al JCO 2010, Yang Lancet Oncology 2011

Ris

k o

f H

CC

(%

)

Risk Score

10 year risk

5 year risk

Risk Score

0 5 10 15

20

0.01

100

10

1

0.1

Ris

k o

f H

CC

(%

)

• Other similar systems, include various parameters: cirrhosis, HBV

genotype, PC/BCP mutations, liver function (bili/albumin)

• All perform reasonably well – predict 5 & 10 yr risk, stratify to

low/medium/high risk

• Emerging but limited validation in diverse populations

Factor Points

Sex (M/F) 0 – 2

Age

(30,35,40,45,50,55,60)

0-5

(Family Hx (Y/N) 0 – 2)

(ETOH (Y/N) 0 – 2)

ALT (44) 0 – 2

HBeAg (+/-) 0 – 6

HBV DNA (0 to 6 logs) 0 - 5

Another scoring system

Time (years)

Surv

ival P

rob

ab

ility

Low risk

(20)

Factor Points

Age (50) 0 or 3

Albumin (35) 0 or 20

Bilirubin (18) 0 or 1.5

HBV DNA

(6 logs)

0, 1, 4

Cirrhosis 0 or 15

Wong JCO 2010

• HCC surveillance very unlikely to be cost-effective in low risk population

What about patients with cirrhosis?

EASL 2012 guidelines for screening

J Hepatology 2012.

• Not all cirrhotics are created equal

• Can this be refined?

Study Aim

Develop a scoring system to accurately predict HCC risk in patients with cirrhosis across different etiologies

5

2,416 pts (79.5%)“definite cirrhosis”

12,199 pts seen in clinic FIB-4 > 3.25 AND APRI >1.0

3,064 pts“probable cirrhosis”

• F3/F4 (n=1178) or• Documented varices or• Ascites (n=1567) or•Coarse/nodular/redistributed liver on US (n=2121)

418 HCCs overall

192 HCCs with

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Summary

Etiology of cirrhosis strongly influences risk of HCC in a large cohort of ambulatory patients

Viral > steatohepatitis >> autoimmune

HCC incidence in AILD and possibly NAFLD likely below cost-effective thresholds for US surveillance

The HCC risk index predicts 10-year HCC risk in patients with cirrhosis

Uses available clinical and laboratory parameters

Takes into account changing risk with time

Conclusions Limited high quality evidence supporting HCC

surveillance

Supporting evidence from cohort & case/control

studies

Likely difficult if not impossible to do true RCT

Cost-effectiveness very dependent on HCC

incidence

Not helpful if no treatment options (eg. CP-C

with no option for transplant)

Risk scores for HBV and cirrhotic populations

may be useful to target surveillance more

effectively

Proposed consensus statement

1. Surveillance for HCC is cost-effective in high risk groups

[Level 2C]; however surveillance should only be offered

to patients who are candidates for therapy [Level 5].

2. The risk for HCC is highest in cirrhotic patients with viral

hepatitis (HBV or HCV) followed by those with

steatohepatitis (alcohol or non-alcoholic) [Level 2B].

3. Surveillance should be offered to all patients with other

causes of cirrhosis and certain chronic carriers of HBV

without established cirrhosis [Level 2B].

4. Risk scores may help better identify high risk group, but

their routine use requires further validation [Level 2B].

Not the only concern…

HALT-C

692 of 1005 patients consistent surveillance

US + AFP q 12 months

Study site main predictor of consistent surveillance

Of 83 HCCs, 28% beyond Milan

13% no surveillance

17% no follow-up of suspicious finding

70% missed despite surveillance!!

Similar stats for HCC>2cm

Likely worse in non-academic centres…

Singal Am J Gastro 2012