Hepatocellular CarcinomaMarkus Heim

Basel

Outline

1. Epidemiology

2. Surveillance

3. (Diagnosis)

4. Staging

5. Treatment

Epidemiology of HCC• Worldwide, liver cancer is the sixth most common cancer (749’000 new

cases), the third cause of cancer-related death (692’000), and accounts for 7% of all cancers

• 90% of liver cancers are HCCs

• 80%-90% of HCCs arise in cirrhotic livers, > 95% of HCC develop on the background of chronic liver disease

• Incidence of HCC increases with age, reaching a peak at 70 years 
(in Chinese and black African populations, mean age is younger)

• Male to female ratio = 2.4

Global HCC incidence (per 100’000 per year)

Switzerland

• Total: 5.2

• Men: 8.7

• Women: 2.0

http://gco.iarc.fr/today/home

Global HCC mortality (per 100’000 per year)

Switzerland

• Total: 4.0

• Men: 6.7

• Women: 1.7

Projection of HCC Incidence 2030

Valery et al. Hepatology, 2018;67:600-611

HCC risk factors

EASL clinical practice guidelines HCC, J Hepatol 2018

Others10%

Alcohol32%

HBV13%

HCV44%

Western Europe

Non-alcoholic fatty liver disease (NAFLD) and HCC

• Incidence of NAFLD is increasing

• Incidence of NASH-cirrhosis is increasing

• Incidence of NAFLD associated HCC is increasing

• 2/3 occurs in NASH-cirrhosis

• 1/3 in non-cirrhotic NAFLD

HCC surveillance with 6 monthly US (+AFP)

EASL clinical practice guidelines HCC. J Hepatol, 2018

PAGE-B
(Platelet, Age, Gender, hepatitis-B)

Age Gender Platelet count

years points points 10E9/l points

16 - 29 0 Male 6 ≥ 200 0

30 - 39 2 Female 0 100 - 199 1

40 - 49 4 < 100 2

50 - 59 6

60 - 69 8

≥ 70 10

Low Risk ≤ 9 almost 0 % HCC at 5 y

Intermediate 10 - 17 3 % HCC at 5 y

High Risk ≥ 18 17 % HCC at 5 years

HCC risk in CHB treated with entecavir or tenofovir

Papatheodoridis, Hepatology. 2017;66:1444

European, 10-center, cohort study, 1’951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for 1 year

Overall No cirrhosis Cirrhosis

0.49% 0.47% 3.22%

1.57%

1.22% 0.73%

Surveillance recommendation of AASLD

Diagnosis, Staging and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology, 2018

• all cirrhotics

• HBV infection:

• all blacks

• asian male > 40y

• asian female > 50

• family history of HCC

Natural history of HCC• The natural history of hepatocellular carcinoma is variable.

• In many patients the tumor has a long-lasting subclinical incubation period and often grows as a solitary mass to a size at which it can be detected by ultrasound (1-2 cm diameter).

• In other patients the onset of the tumor is multinodal with great variations in the growth rates.

• The median time of doubling volume for a small HCC may range from 1 to 20 months

• Prognostication of patients with hepatocellular carcinoma takes into account

• the size and number of tumor nodules

• vascular invasion and metastasis

• the degree of liver impairment

Diagnosis

• Diagnosis should be made by an experienced center

• In cirrhotic patients, diagnosis can be made using stringent criteria on multiphase imaging (CT/MRI LI-RADS®).
Diagnosis can also be established by liver biopsy.

• In non-cirrhotic patients, diagnosis requires a biopsy.

Tang et al, Radiology. 2018:2018;286:29

Staging

• Number and size of tumor nodules

• Macro-vascular invasion

• Metastasis

• Liver function (Child-Pugh)

• ECOG Performance Status 
(Eastern Cooperative Oncology Group)

Forner, Reig, Bruix. Lancet 2018

Treatment allocations

Early stage Intermediate stageAdvanced

stageTerminal

stage

curative treatments

treatments with impact on survival

best supportive

care

Resection Liver transplantation Ablation (RF, MW)

TACE
Transarterial Chemoembolisation

TARE Transarterial Radioembolisation (Y90)

Sorafenib Lenvantinib Regorafenib Cabozantinib

TARE

Treatmen of early stage HCC

• Resection is the treatment of choice for localized HCC occurring in the absence of cirrhosis, or resectable HCC occurring in the setting of cirrhosis with intact liver function and absence of clinically significant portal hypertension. (AASLD 2018)

• Thermal ablation with radiofrequency is the standard of care for patients with BCLC 0 and A tumours not suitable for surgery (evidence high; recommendation strong). (EASL 2018)

• In patients with very early stage HCC (BCLC-0) radiofrequency ablation in favourable locations can be adopted as first-line therapy even in surgical patients (evidence moderate; recommendation strong). (EASL 2018)

Early Stage HCC: resection versus ablationRetrospective study including 12’968 patients from a nationwide Japanese survey with ≤ 3 tumors and liver damage A or B treated

with surgical resection (5361), percutaneous ethanol injection (2059) or radiofrequency ablation (5548) between 2000 and 2005

Overall survivalTime to recurrence

Surgical resection RFA PEI

Age (years) 66 69 69

Liver function

Albumin 39 37 37

Bilirubin 13.6 15.3 15.3

Platelet count 126 99 95

Tumor number (%)

single 83.2 73.3 70.4

two 13.2 19.8 21.5

three 3.7 6.9 8.1

Tumor size (median, mm) 23 20 17

Hasegawa et al. J Hepatol 2013;58:724-729

Microwave versus RFA• Randomized controlled, single-blinded phase 2

trial at 4 centers in France and Switzerland

• patients with HCC, ≤ 3 lesions of ≤4 cm, not eligible for surgery

• primary outcome: proportion of lesions with local tumour progression at 2 years follow-up

• Hypothesis (H1): microwave is superior to RFA

• Microwave ablation 71 patients
RFA 73 patients

• Treatment complications comparable

• Overall survival not different

Violi et al. Lancet Gastroenterol Hepatol 2018 (published online 1.March)

Liver transplantation for HCC

• Transplantation is the treatment of choice for patients with early stage HCC occurring in the setting of clinically significant portal hypertension and/or decompensated cirrhosis, though access is limited by the extreme organ shortage. (AASLD 2018)

• LT is recommended as the first-line option for HCC within Milan criteria but unsuitable for resection (evidence high; recommendation strong). (EASL 2018)

Selective internal radiotherapy (SIRT)

• Biocompatible polymer resin microspheres of a median diameter of 32.5 microns (range between 20 and 60 microns) loaded with yttrium-90

• beta radiation penetrating an average of 2.5 mm in tissue

• Yttrium-90 has a half-life of 64.1 hours 
(94% delivered to tissue over 11 days)

C.A., 75y, male

SIRT

SIRT versus TACE

Salem et al. Gastroenterology, 2016;151:1155-1163

Randomized phase 2 study; Chicago; 2009-2015; BCLC A (80%) and B (20%); 24 patients treated with Y90, 21 with TACE.

• 380 patients included, randomized to SIRT vs sorafenib

• Sample size calculated to detect a 4 month difference (10.7 m in sorafenib vs 15 m in SIRT) in median survival with 80% power, 5% type error.

• BCLC stage: 
A = 4/5%, B = 28/27%, C = 68/67%

• Portal venous invasion 63%/58%

• 63% had 1 SIRT treatment

• 72% had hemi-liver, 18% sector, 10 segmental SIRT

• Median overall survival in the per-protocol population was the same in both groups (9.9 months)

Lancet Oncol. 2017;18:1624-1636

• Serious adverse events occurred in 77% of SIRT and 82% of sorafenib treated patients

• 139 of the 216 patients in the sorafenib group discontinued sorafenib for drug-related toxicity (108 permanently)

Grade 3 events SIRT Sorafenibfatigue 9% 19%

liver dysfunction 11% 13%increased liver values 9% 7%

haematological abnormalities 10% 14%diarrhoea 1% 14

abdominal pain 3% 6%increased creatinine 2% 6%

hadn-foot skin reaction

• 360 patients included, randomized to SIRT vs sorafenib

• 130 treated with SIRT, 162 with sorafenib

• Sample size calculated to detect a 4.5 month difference (9.35 m in sorafenib vs 14 m in SIRT) in median survival with 90% power, 5% type error.

• BCLC stage: 
B = 51/55%, C = 48/45%

• Portal venous invasion 30%/30%

• Median overall survival in the per-protocol population was 8.8 months in SIRT vs 10 months in Sorafenib group (p = 0.38).

• Significantly fewer ≥3 AEs in SIRT (28%) versus sorafenib (51%).

DAA treatment of HCV cirrhosis and HCC

• Current DAA efficacy and safety allows to treat cirrhosis
(large numbers of older patients, advanced disease treated with DAA’s)

• DAAs reduce mortality caused by worsening of liver function

• (Increasing the proportion of HCCs diagnosed?)

• Any increased incidence of HCC would nullify the survival benefit

Note of caution from Barcelona

• Increased incidence of

• De novo (i.e. indident) HCC

• Recurrent HCC

• More aggressive and faster progression of HCC in patients treated with DAA’s

• Scientific hypothesis: DAA cure leads to resolution of inflammation, and the lack of inflammation (T cells) weakens the tumor immuno surveillanceJ Hepatol. 2016 Oct;65(4):719-726

58 patients with prior HCC, treated with DAA, median FU 5.7 m, 28% tumor recurrence

Benefit of SVR: ~75% decrease of de novo HCC-risk

Kanwal et al, Gastroenterology. 2017;153:996

22’500 patients

Li et al, Hepatology. 2017

No increased HCC recurrence risk after DAA treatment

267 patients with CHC and cured HCC, 189 received DAA, 78 no treatment

ANRS, J Hepatol. 2016;65:734 Ikeda et al, Dig Dis Sci. 2017;62:2932

178 patients with CHC and cured HCC, 89 received DAA, 89 matched controls

without DAA treatment

HCC and DAA treatment

• Compelling evidence that DAA treatment reduces risk of decompensation and de novo HCC in patients with CHC and cirrhosis

• Circumstantial evidence (Barcelona) that DAA treatment increases risk of HCC recurrence, but this could not be confirmed in larger cohorts

Patients with CHC and advanced fibrosis/cirrhosis should be treated and cured with DAAs, irrespective of previous history of HCC

Summary

1. Epidemiology HCC incidence will probably increase cave NAFLD!

2. Surveillance US (6monthly) in cirrhotics (and F3). In patients with HBV controversial

3. (Diagnosis) Expert center: imaging and/or biopsy

4. Staging BCLC (Barcelona Clinic Liver Cancer)

5. TreatmentConstantly evolving concepts and treatment modalities Tumor boards in expert centers Treat HCV cirrhotics, but continue screening