Презентация на тему PopQuiz: Managing Patients With Advanced HCC

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the United States has tripled over the past 20

yrs. Which of the following best explains the expected continued increase in HCC incidence in the US?

HBV infection
HCV infection
Diabetes mellitus and obesity
Alcohol abuse
Aflatoxin ingestion
Hemochromatosis
Cigarette smoking

the United States has tripled over the past 20

yrs. Which of the following best explains the expected continued increase in HCC incidence in the US?

HBV infection
HCV infection
Diabetes mellitus and obesity
Alcohol abuse
Aflatoxin ingestion
Hemochromatosis
Cigarette smoking

higher among Asian population
Mittal S, et al. J Clin

Gastroenterol. 2013;47:S2-S6.

12

10

8

6

4

2

0

Rate per 100,000

White

Black

Asian

Hispanic

1975-1977 1993-1995 2005-2007

1.2

2.0

3.7

2.8

4.0

7.6

6.6

8.4

10.3

4.3

8.2

estimated as:
The #5 cancer killer in men (up from

#7 in 2005)
The #8 cancer killer in women (not among top 10 in 2005)

Siegel R, et al. CA Cancer J Clin. 2016;66:7-30.

Pathogenesis
Glucose Metabolism





Lipid Metabolism





Glycolysis ↓
Glucose uptake ↓
Gluconeogenesis ↑
Cytokine/adipokine production ↑
Lipogenesis

↑
Fatty acid ß-oxidation ↓
Cytokine/adipokine production ↑
Lipoprotein export ↓

HCV

Clinical Outcome

Impaired treatment response
Liver fibrosis and cirrhosis
Cardiovascular outcomes
Type 2 diabetes mellitus
HCC

Hepatic Steatosis

Insulin Resistance

Adapted with permission from Kralj D, et al. Hepatitis C Virus, Insulin Resistance,
and Steatosis. J Clin Transl Hepatol 2016;4(1):66-75. doi: 10.14218/JCTH.2015.00051.

clinic with history of self-administered tattoos
Saw a television ad

about HCV and decided to see his physician; found to be positive for HCV
Screening MRI: splenomegaly, hepatic nodularity consistent with cirrhosis, and 2.6-cm lesion in right lobe of liver that showed rapid arterial enhancement with significant washout on delayed images

done in order to make the diagnosis of HCC?
Biopsy

for histologic examination
AFP first; if normal, proceed to biopsy
CEA or CA19-9 to rule out other histologies
No further testing
CT scan or ultrasound to further examine vascular characteristics

done in order to make the diagnosis of HCC?
Biopsy

for histologic examination
AFP first; if normal, proceed to biopsy
CEA or CA19-9 to rule out other histologies
No further testing
CT scan or ultrasound to further examine vascular characteristics

al. J Med Imaging Radiat Oncol. 2013;57:314-320.
T1 image: isointense

tumor

T2 image: hyperintense tumor

T1 arterial phase: arterial enhancement

T1 portal phase: rapid portal venous phase washout

T1 20-min delayed image: hypointense tumor

recently emigrated from Shanghai infected with HBV since childhood
Upon

evaluation for a new job, she is found to have abnormal liver transaminases
Follow-up imaging shows a 6-cm well-circumscribed lesion within the left lobe of her liver with vascular characteristics consistent with HCC; no stigmata of cirrhosis are noted
Serum bilirubin, albumin, platelets, and INR are normal, and AFP is elevated at 1769 ng/mL
CT of the torso shows no evidence of other lesions

the optimal next step in the management of this

pt?

Biopsy of the lesion
Full evaluation for potential transplantation
Follow the lesion to determine the rate of growth
Immediate resection when feasible
Chemoembolization or radioembolization
Local treatment to the mass to reduce the size followed by resection

the optimal next step in the management of this

pt?

Biopsy of the lesion
Full evaluation for potential transplantation
Follow the lesion to determine the rate of growth
Immediate resection when feasible
Chemoembolization or radioembolization
Local treatment to the mass to reduce the size followed by resection

> supply
Survival
1 yr: 91%
2 yrs: 75%
5 yrs:

> 70%
Recurrence
5 yrs: < 15%

Ablation
Effective when ≤ 3 cm
Multiple modalities
Thermal
Chemical
Minimally invasive
Survival
1 yr: 90%
3 yrs: 75%
5 yrs: 60% to 70%
Recurrence
5 yrs: 70%

Resection
Noncirrhotics
Choice of therapy
Cirrhotics
Reserve for CTP A
Avoid R hepatectomy
Best for solitary HCC
Only 5% to 15% eligible
Survival
1 yr: 95%
3 yrs: 85%
5 yrs: 50%
Recurrence
5 yrs: 70%

NCCN Guidelines. Hepatobiliary Cancers. Version 2.2016.

HCC evaluated, only 35 were ideal candidates for resection




Llovet

JM, et al. Hepatology. 1999;30:1434-1440.

Survival (%)

Mos

Log-rank P = .00001

Portal hypertension, normal bilirubin

No portal hypertension, normal bilirubin

Portal hypertension, bilirubin ≥ 1 mg/dL

with a history of alcohol abuse, who quit drinking

11 yrs ago, presents to the ED with hematemesis
On evaluation, he is found to have bleeding esophageal varices, ascites, splenomegaly, and a platelet count of 61,000
MRI shows 2 lesions—2.7 cm and 2.1 cm—within the right lobe. These both show peripheral enhancement on the arterial phase with central washout and peripheral enhancement on delayed images
Splenomegaly, ascites, and small perigastric varices are also seen

stabilized, and discharged, further management of this pt should

include which of the following?

Referral to liver service for possible cadaveric or live donor transplantation
Referral to hepatobiliary surgery for potential right hepatectomy
Immediate chemoembolization
Thermal or cryoablation to the 2 individual lesions
PET scan to look for metastatic lesions
Systemic treatment with sorafenib

stabilized, and discharged, further management of this pt should

include which of the following?

Referral to liver service for possible cadaveric or live donor transplantation
Referral to hepatobiliary surgery for potential right hepatectomy
Immediate chemoembolization
Thermal or cryoablation to the 2 individual lesions
PET scan to look for metastatic lesions
Systemic treatment with sorafenib

70%
TACE
Single
Increased
Associated diseases
Normal
No
Yes
Sorafenib
Portal pressure/bilirubin
3 nodules ≤ 3 cm
Resection
Symptomatic (20%); survival

3 mos

RCTs (50%); 3-yr survival: 10% to 40%

Terminal stage (D)

Okuda 1-2, PS 0-2, Child-Pugh A-B

Intermediate stage (B)
Multinodular, PS 0

Okuda 3, PS > 2, Child-Pugh C

Very early stage (0)
Single < 2 cm
Carcinoma in situ

Early stage (A)
Single or 3 nodules
< 3 cm, PS 0

Advanced stage (C)
Portal invasion, N1, M1, PS 1-2

PS 0, Child-Pugh A

HCC

BCLC Staging and Treatment Strategy

Llovet JM, et al. J National Cancer Inst. 2008;100:698-711.
Subramaniam S, et al. Chin Clin Oncol. 2013;2:33.

71-yr-old asymptomatic man with a history of hemochromatosis goes

to a new gastroenterologist and is found to have a 7-cm mass in the right lobe consistent with HCC
He is not a surgical candidate because of significant cardiovascular disease but has relatively well-preserved hepatic function

options would be most suitable for this pt?
Radiofrequency ablation
Stereotactic

body radiotherapy
Chemoembolization or radioembolization
Referral for potential liver transplantation
Sorafenib

options would be most suitable for this pt?
Radiofrequency ablation
Stereotactic

body radiotherapy
Chemoembolization or radioembolization
Referral for potential liver transplantation
Sorafenib

candidate?
Optimize medical therapy, consider PVE
Intraoperative evaluation
Resect
Unresectable
Consider ablation (RFA, cryo, percutaneous ETOH);

TACE, EBRT

Child-Pugh A/B

Child-Pugh C

Consider “bridging” therapy (eg, TACE)

Systemic therapy

RFA, microwave or cryoablation

Numerous lesions

Assess tumor size, location and extrahepatic metastases

Yes

No

Liver only

Extrahepatic mets

< 3 cm

Evaluate for transplant

3-5 cm

Tumor size, number

Unresectable

TACE, SBRT

PV patent

Radioembolization, SBRT

PV occluded

> 5 cm

TACE, radioembolization, SBRT

PMH significant only for diabetes presents with back pain

and is found to have a lytic lesion at T11
CT scan of the torso shows multiple metastases up to 3 cm in size throughout both lungs and an 8-cm lesion within the liver. Several bony metastases are also seen
ECOG PS is 1 and lab tests are relatively well preserved
Liver biopsy demonstrates well-differentiated HCC. The pt strongly desires systemic therapy following the completion of radiation to his back. He refuses to participate in clinical trials

the best choice for this pt?
Sorafenib
Gemcitabine plus cisplatin or

oxaliplatin
Nivolumab
Capecitabine
Best supportive care

the best choice for this pt?
Sorafenib
Gemcitabine plus cisplatin or

oxaliplatin
Nivolumab
Capecitabine
Best supportive care

Res. 2004;64:7099-7109. Wilhelm SM, et al. Mol Cancer Ther.

2008;7:3129-3140.

RAS

Vascular cell

Angiogenesis:

VEGFF

VEGFR-2

PDGFR-β

Paracrine
stimulation

Mitochondria

Apoptosis

Tumor cell

PDGF

VEGF

EGF/HGF

Proliferation

Survival

Mitochondria

HIF-2

Nucleus

Autocrine loop

Apoptosis

ERK

RAS

MEK

RAF

Nucleus

ERK

MEK

RAF

Differentiation
Proliferation
Migration
Tubule formation

PDGF-β

EGF/HGF

Multispecific, blocks tyrosine kinase receptors regulating tumor proliferation and angiogenesis

Advanced HCC
Primary endpoints: OS, time to symptomatic progression
Secondary endpoint:

TTP (independent review), disease control rate, safety

Stratified by macroscopic vascular invasion and/or extrahepatic spread; ECOG PS; geographical region

Pts with advanced HCC, Child-Pugh A, at least 1 untreated lesion, ECOG PS ≤ 2, no previous systemic treatment, life expectancy ≥ 12 wks
(N = 602)

Sorafenib 400 mg PO BID, continuous dosing (n = 299)

Placebo 2 tablets PO BID, continuous dosing (n = 303)

Llovet JM, et al. N Engl J Med. 2008;359:378-390.
Kane RC, et al. Oncologist. 2009;14:95-100.

unresectable HCC
Llovet JM, et al. N Engl J Med.

2008;359:378-390.
Kane RC, et al. Oncologist. 2009;14:95-100.

asymptomatic man without significant past medical history comes in

for a checkup. He is worried because his old college roommate, with whom he briefly shared needles, was recently diagnosed with HCV. He also tests positive for HCV
Screening ultrasound shows two ~ 4-cm lesions within the liver, along with portal vein thrombosis and a small amount of ascites
AFP is elevated at 845 ng/mL, and his serum bilirubin is 2 x ULN
This pt is not interested in clinical trials

the optimal treatment choice for this pt?
Referral for liver

transplantation
Sorafenib
Microwave ablation
Chemoembolization
Radioembolization

the optimal treatment choice for this pt?
Referral for liver

transplantation
Sorafenib
Microwave ablation
Chemoembolization
Radioembolization

Vein Thrombosis
Radioembolization achieved survival benefit independent of PVT
Ozkan ZG,

et al. Cancer Biother Radiopharm. 2015;30:132-138.

Survival Functions

PVT Not present Present Not present-censored
Present-censored

Cumulative Survival

Follow-up (Mos)

1.0

0.8

0.4

0.2

0

0

0.6

10

20

30

40

50

therapy for HCC been shown to be effective?
Sorafenib following

surgical resection
Sorafenib following chemoembolization
Doxorubicin following liver transplantation
Sorafenib following radiofrequency ablation
Lipiodol I-131 given intra-arterially following resection
None of the above

therapy for HCC been shown to be effective?
Sorafenib following

surgical resection
Sorafenib following chemoembolization
Doxorubicin following liver transplantation
Sorafenib following radiofrequency ablation
Lipiodol I-131 given intra-arterially following resection
None of the above

Asian Pts With HCC
TACE + sorafenib effective and well

tolerated in Asian pts with HCC

Chao Y, et al. Int J Cancer. 2015;136:1458-1467.

1.0

0.8

0.6

0.4

0.2

0

Pts at risk, n

0 192

100 171

300 142

400 126

500 115

600 103

700 98

800 94

900 93

200 155

1000 93

Days From Cycle 1

Probability of PFS

Lower 95% CI Survival Upper 95% CI Censored

demonstrated superior OS in phase III trials when compared

with sorafenib in the first-line setting for metastatic HCC?

Sunitinib
Brivanib
Linifanib
Erlotinib plus sorafenib
Doxorubicin plus sorafenib
None of the above

demonstrated superior OS in phase III trials when compared

with sorafenib in the first-line setting for metastatic HCC?

Sunitinib
Brivanib
Linifanib
Erlotinib plus sorafenib
Doxorubicin plus sorafenib
None of the above

References listed in slide notes.

above (a 68-yr-old diabetic man with HCC metastatic to

the lungs and bone) was treated with sorafenib
After slowly advancing the initial dose, he was able to tolerate a dose of 400 mg twice daily for the first 3 wks; because of fatigue, the dose was reduced to a total of 600 mg/day
After a total of 8 wks, he was re-evaluated because of worsening fatigue, decreased appetite, and an AFP that had risen from 1589 to 4623 ng/mL while on therapy
CT scan showed that his lung metastases had increased in both size and number, with the largest now being 4.5 cm. The solitary liver lesion increased from 8 to 9 cm in longest diameter, and the bone lesions appeared stable. He had no pain or shortness of breath and felt that most of his complaints stemmed from the sorafenib; ECOG PS remained at 1

was shown in a phase III trial to improve

OS in pts who have disease progression following treatment with sorafenib?

Nivolumab
Everolimus
Brivanib
Regorafenib
Ramucirumab
None of the above

was shown in a phase III trial to improve

OS in pts who have disease progression following treatment with sorafenib?

Nivolumab
Everolimus
Brivanib
Regorafenib
Ramucirumab
None of the above

References listed in slide notes.

on Sorafenib
Randomized, double-blind phase III trial





Primary endpoint: OS

(ITT)
Secondary endpoints: PFS, TTP, RR, DCR

Bruix J, et al. ESMO GI 2016. Abstract LBA-03.

Pts with BCLC stage B or C HCC; documented PD on sorafenib ≥ 20 days at ≥ 400 mg/day; Child-Pugh A liver function;
ECOG PS 0-1
(N = 573)

Regorafenib + BSC
160 mg PO daily Wks 1-3
(n = 379)

Placebo + BSC
PO daily Wks 1-3
(n = 194)

Randomized 2:1

All pts treated until PD, death, or unacceptable toxicity

4-wk cycles

risk of death (HR: 0.62; 95% CI: 0.50-0.78; P

< .001)
54% reduction in risk of progression or death (HR: 0.46; 95% CI: 0.37-0.56; P < .001)
DCR (CR + PR + SD): 65.2% vs 36.1% (P < .001)

*HR 0.44; 95% CI: 0.36-0.55; P < .001; †P = .005

Bruix J, et al. ESMO GI 2016. Abstract LBA-03

Abstract LBA-03