Hepatocellular carcinoma
Hepatocellular carcinoma (HCC, also called malignant hepatoma) is the
most common type of liver cancer. Most cases of HCC are secondary to
either a viral hepatitis infection (hepatitis B or C) or cirrhosis (alcoholism
being the most common cause of hepatic cirrhosis).
Compared to other cancers, HCC
is quite a rare tumour in the
United States. In countries where
hepatitis is not endemic, most
malignant cancers in the liver are
not primary HCC but metastasis
(spread) of cancer from
elsewhere in the body, e.g., the
colon. Treatment options of HCC
and prognosis are dependent on
many factors but especially on tumour size and staging. Tumour grade is
also important. High-grade tumours will have a poor prognosis, while lowgrade tumors may go unnoticed for many years, as is the case in many
other organs.
Signs and symptoms
HCC may present with jaundice, bloating from ascites, easy bruising from
blood clotting abnormalities or as loss of appetite, unintentional weight
loss, abdominal pain, especially in the right upper quadrant, nausea,
emesis, or fatigue.
Risk factors
The main risk factors for hepatocellular carcinoma are;
Alcoholism
Hepatitis B
Hepatitis C (25% of causes globally)
Aflatoxin
Cirrhosis of the liver
Hemochromatosis
Wilson's disease (while some theorise the risk increases, case studies are
rare and suggest the opposite where Wilson's disease actually may confer
protection)
Type 2 Diabetes (probably aided by obesity)
The risk factors which are most important varies widely from country to
country. In countries where Hepatitis B is endemic, such as China, Hepatitis
B will be the predominant cause of Hepatocellular Carcinoma. Whereas in
countries, such as the United States, where Hepatitis B is rare because of
high vaccination rates, the major cause of HCC is Cirrhosis (often due to
alcohol abuse).
The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5
to 7.1 times the non diabetic risk) depending on the duration of diabetes
and treatment protocol. A suspected contributor to this increased risk is
circulating insulin concentration such that diabetics with poor insulin
control or on treatments that elevate their insulin output (both states that
contribute to a higher circulating insulin concentration) show far greater
risk of hepatocellular carcinoma than diabetics on treatments that reduce
circulating insulin concentration. On this note, some diabetics who engage
in tight insulin control (by keeping it from being elevated) show risk levels
low enough to be indistinguishable from the general population. This
phenomenon is thus not isolated to diabetes mellitus type 2 since poor
insulin regulation is also found in other conditions such as metabolic
syndrome (specifically, when evidence of non alcoholic fatty liver disease or
NAFLD is present) and again there is evidence of greater risk here too.
While there are claims that anabolic steroid abusers are at greater risk
(theorized to be due to insulin and IGF exacerbation), the only evidence
that has been confirmed is that anabolic steroid users are more likely to
have hepatocellular adenomas (a benign form of HCC) transform into the
more dangerous hepatocellular carcinoma.
When hepatocellular adenomas grow to a size of more than 6–8 cm, they
are considered cancerous and thus become a risk of hepatocellular
carcinoma. Although hepatocellular carcinoma most commonly affects
adults, children who are affected with biliary atresia, infantile cholestasis,
glycogen-storage diseases, and other cirrhotic diseases of the liver are
predisposed to developing hepatocellular carcinoma.
Children and adolescents are unlikely to have chronic liver disease,
however, if they suffer from congenital liver disorders, this fact increases
the chance of developing hepatocellular carcinoma.
Young adults afflicted by the rare fibrolamellar variant of hepatocellular
carcinoma may have none of the typical risk factors, i.e. cirrhosis and
hepatitis.
Pathogenesis
Hepatocellular carcinoma, like any other cancer, develops when there is a
mutation to the cellular machinery that causes the cell to replicate at a
higher rate and/or results in the cell avoiding apoptosis. In particular,
chronic infections of hepatitis B and/or C can aid the development of
hepatocellular carcinoma by repeatedly causing the body's own immune
system to attack the liver cells, some of which are infected by the virus,
others merely bystanders. While this constant cycle of damage followed by
repair can lead to mistakes during repair which in turn lead to
carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C.
Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic
hepatitis B, however, the integration of the viral genome into infected cells
can directly induce a non-cirrhotic liver to develop HCC. Alternatively,
repeated consumption of large amounts of ethanol can have a similar
effect. Besides, cirrhosis is commonly caused by alcoholism, chronic
hepatitis B and chronic hepatitis C. The toxin aflatoxin from certain
Aspergillus species of fungus is a carcinogen and aids carcinogenesis of
hepatocellular cancer by building up in the liver. The combined high
prevalence of rates of aflatoxin and hepatitis B in settings like China and
West Africa has led to relatively high rates of heptatocellular carcinoma in
these regions. Other viral hepatitides such as hepatitis A have no potential
to become a chronic infection and thus are not related to hepatocellular
carcinoma.
Diagnosis
Hepatocellular carcinoma (HCC) most commonly appears in a patient with
chronic viral hepatitis (hepatitis B or hepatitis C, 20%) or/and with cirrhosis
(about 80%). These patients commonly undergo surveillance with
ultrasound due to the cost-effectiveness.
In patients with a higher suspicion of HCC (such as rising alpha-fetoprotein
and des-gamma carboxyprothrombin levels), the best method of diagnosis
involves a CT scan of the abdomen using intravenous contrast agent and
three-phase scanning (before contrast administration, immediately after
contrast administration, and again after a delay) to increase the ability of
the radiologist to detect small or subtle tumors. It is important to optimize
the parameters of the CT examination, because the underlying liver disease
that most HCC patients have can make the findings more difficult to
appreciate.
On CT, HCC can have three distinct patterns of growth:
A single large tumor
Multiple tumors
Poorly defined tumor with an infiltrative growth pattern
A biopsy is not needed to confirm the diagnosis of HCC if certain imaging
criteria are met.
The key characteristics on CT are hypervascularity in the arterial phase
scans, washout or de-enhancement in the portal and delayed phase studies,
a pseudocapsule and a mosaic pattern. Both calcifications and intralesional
fat may be appreciated.
CT scans use contrast agents, which are typically iodine or barium based.
Some patients are allergic to one or both of these contrast agents, most
often iodine. Usually the allergic reaction is manageable and not life
threatening.
An alternative to a CT imaging study would be the MRI. MRI's are more
expensive and not as available because fewer facilities have MRI machines.
More important MRI are just beginning to be used in tumor detection and
fewer radiologists are skilled at finding tumors with MRI studies when it is
used as a screening device.[citation needed] Mostly the radiologists are
using MRIs to do a secondary study to look at an area where a tumor has
already been detected.[citation needed] MRI's also use contrast agents.
One of the best for showing details of liver tumors is very new: iron oxide
nano-particles appears to give better results.[citation needed] The latter
are absorbed by normal liver tissue, but not tumors or scar tissue.[citation
needed]
In a review article of the screening, diagnosis and treatment of
hepatocellular carcinoma, 4 articles were selected for comparing the
accuracy of CT and MRI in diagnosing this malignancy. Radiographic
diagnosis was verified against post-transplantation biopsy as the gold
standard. With the exception of one instance of specificity, it was
discovered that MRI was more sensitive and specific than CT in all four
studies.
Pathology
Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The
nodular type may be solitary (large mass) or multiple (when developed as a
complication of cirrhosis). Tumor nodules are round to oval, grey or green
(if the tumor produces bile), well circumscribed but not encapsulated. The
diffuse type is poorly circumscribed and infiltrates the portal veins, or the
hepatic veins (rarely).
Microscopically, there are four architectural and cytological types (patterns)
of hepatocellular carcinoma: fibrolamellar, pseudoglandular (adenoid),
pleomorphic (giant cell) and clear cell. In well differentiated forms, tumor
cells resemble hepatocytes, form trabeculae, cords and nests, and may
contain bile pigment in cytoplasm. In poorly differentiated forms, malignant
epithelial cells are discohesive, pleomorphic, anaplastic, giant. The tumor
has a scant stroma and central necrosis because of the poor vascularization.
Staging
Important features that guide treatment include: size
spread (stage)
involvement of liver vessels
presence of a tumor capsule
presence of extrahepatic metastases
presence of daughter nodules
vascularity of the tumor
MRI is the best imaging method to detect the presence of a tumor capsule.
Prevention
Since hepatitis B or C is one of the main causes of hepatocellular carcinoma,
prevention of this infection is key to then prevent hepatocellular carcinoma.
Thus, childhood vaccination against hepatitis B may reduce the risk of liver
cancer in the future.
In the case of patients with cirrhosis, alcohol consumption is to be avoided.
Also, screening for hemochromatosis may be beneficial for some patients.
Management
Liver transplantation to replace the diseased liver with a cadaveric liver or a
living donor graft has historically low survival rates (20%-36%). During
1996–2001 the rate had improved to 61.1%, likely related to adoption of
the Milan criteria at US transplantation centers. Expanded Shanghai criteria
in China resulted in overall survival and disease-free survival rates similar to
the Milan criteria. Studies from the late 2000 obtained higher survival rates
ranging from 67% to 91%. If the liver tumor has metastasized, the immunosuppressant post-transplant drugs decrease the chance of survival.
Considering this objective risk in conjunction with the potentially high rate
of survival, some recent studies conclude that: "LTx can be a curative
approach for patients with advanced HCC without extrahepatic metastasis".
For those reasons, and others, it is considered nowadays that patient
selection is a major key for success.
A receptor tyrosine kinase inhibitor, Sorafenib, approved by the US FDA in
December 2005 and in Europe in July 2006, may be used in patients with
advanced hepatocellular carcinoma. Sorafenib is a small molecule that
inhibits tumor-cell proliferation and tumor angionesis. It has been shown in
a Spanish phase III clinical trial to add two months to the lifespan of late
stage HCC patients with well preserved liver function. It also increases the
rate of apoptosis in other tumor models. The results indicated that singleagent sorafenib might have a beneficial therapeutic effect. In this study, for
instance, the median overall survival was of 9.2 months and the median
time to progression was of 5.5 months. Also, the survival benefit
represented a 31% relative reduction in the risk of death.
Surgical resection to remove a tumor together with surrounding liver tissue
while preserving enough liver remnant for normal body function. This
treatment offers the best prognosis for long-term survival, but only 10-15%
of patients are suitable for surgical resection. This is often because of
extensive disease or poor liver function. Resection in cirrhotic patients
carries high morbidity and mortality. The expected liver remnant should be
more than 25% of the total size for a non-cirrhotic liver, while that should
be more than 40% of the total size for a cirrhotic liver. The overall
recurrence rate after resection is 50-60%.
Percutaneous ethanol injection (PEI) well tolerated, high RR in small (<3 cm)
solitary tumors; as of 2005, no randomized trial comparing resection to
percutaneous treatments; recurrence rates similar to those for
postresection. However a comparative study found that local therapy can
achieve a 5-year survival rate of around 60% for patients with small HCC.
Transcatheter arterial chemoembolization (TACE) is usually performed for
unresectable tumors or as a temporary treatment while waiting for liver
transplant. TACE is done by injecting an antineoplastic drug (e.g. cisplatin)
mixed with a radioopaque contrast (e.g. Lipiodol) and an embolic agent
(e.g. Gelfoam) into the right or left hepatic artery via the groin artery. As of
2005, multiple trials show objective tumor responses and slowed tumor
progression but questionable survival benefit compared to supportive care;
greatest benefit seen in patients with preserved liver function, absence of
vascular invasion, and smallest tumors. TACE is not suitable for big tumors
(>8 cm), presence of portal vein thrombus, tumors with portal-systemic
shunt and patients with poor liver function.
Radiofrequency ablation (RFA) uses high frequency radio-waves to destroy
tumor by local heating. The electrodes are inserted into the liver tumor
under ultrasound image guidance using percutaneous, laparoscopic or open
surgical approach. It is suitable for small tumors (<5 cm). A large
randomised trial comparing surgical resection and RFA for small HCC
showed similar 4 years-survival and less morbidities for patients treated
with RFA.
Focused External Beam Radiation Stereotactic Radiotherapy (SRT) is a
technique of using highly focussed radiation to small target volume. SRT has
been tried successfully in the liver for treatment of metastases, and
currently clinical studies are underway to evaluate its efficacy in treating
Hepatocellular Carcinoma. The early results are promising. With the advent
of modern computer technology, it is now possible to direct treatment to
involved areas of the liver, while sparing normal healthy liver tissue.
Selective internal radiation therapy can be used to destroy the tumor from
within (thus minimizing exposure to healthy tissue). There are currently two
products available, SIR-Spheres and TheraSphere The latter is an FDA
approved treatment for primary liver cancer (HCC) which has been shown in
clinical trials to increase survival rate of low-risk patients. SIR-Spheres are
FDA approved for the treatment of metastatic colorectal cancer but outside
the US SIR-Spheres are approved for the treatment of any non-resectable
liver cancer including primary liver cancer. This method uses a catheter
(inserted by a radiologist) to deposit radioactive particles to the area of
interest.
Intra-arterial iodine-131–lipiodol administration Efficacy demonstrated in
unresectable patients, those with portal vein thrombus. This treatment is
also used as adjuvant therapy in resected patients (Lau at et, 1999). It is
believed to raise the 3-year survival rate from 46 to 86%. This adjuvant
therapy is in phase III clinical trials in Singapore and is available as a
standard medical treatment to qualified patients in Hong Kong.
Combined PEI and TACE can be used for tumors larger than 4 cm in
diameter, although some Italian groups have had success with larger
tumours using TACE alone.
High intensity focused ultrasound (HIFU) (not to be confused with normal
diagnostic ultrasound) is a new technique which uses much more powerful
ultrasound to treat the tumour. Still at a very experimental stage. Most of
the work has been done in China. Some early work is being done in Oxford
and London in the UK.
Hormonal therapy Antiestrogen therapy with tamoxifen studied in several
trials, mixed results across studies, but generally considered ineffective
Octreotide (somatostatin analogue) showed 13-month MS v 4-month MS in
untreated patients in a small randomized study; results not reproduced.
Adjuvant chemotherapy: No randomized trials showing benefit of
neoadjuvant or adjuvant systemic therapy in HCC; single trial showed
decrease in new tumors in patients receiving oral synthetic retinoid for 12
months after resection/ablation; results not reproduced. Clinical trials have
varying results.
Palliative: Regimens that included doxorubicin, cisplatin, fluorouracil,
interferon, epirubicin, or taxol, as single agents or in combination, have not
shown any survival benefit (RR, 0%-25%); a few isolated major responses
allowed patients to undergo partial hepatectomy; no published results from
any randomized trial of systemic chemotherapy.
Cryosurgery: Cryosurgery is a new technique that can destroy tumors in a
variety of sites (brain, breast, kidney, prostate, liver). Cryosurgery is the
destruction of abnormal tissue using sub-zero temperatures. The tumor is
not removed and the destroyed cancer is left to be reabsorbed by the body.
Initial results in properly selected patients with unresectable liver tumors
are equivalent to those of resection. Cryosurgery involves the placement of
a stainless steel probe into the center of the tumor. Liquid nitrogen is
circulated through the end of this device. The tumor and a half inch margin
of normal liver are frozen to -190°C for 15 minutes, which is lethal to all
tissues. The area is thawed for 10 minutes and then re-frozen to -190°C for
another 15 minutes. After the tumor has thawed, the probe is removed,
bleeding is controlled, and the procedure is complete. The patient will
spend the first post-operative night in the intensive care unit and typically is
discharged in 3 – 5 days. Proper selection of patients and attention to detail
in performing the cryosurgical procedure are mandatory in order to achieve
good results and outcomes. Frequently, cryosurgery is used in conjunction
with liver resection as some of the tumors are removed while others are
treated with cryosurgery. Patients may also have insertion of a hepatic
intra-arterial catheter for post-operative chemotherapy. As with liver
resection, the surgeon should have experience with cryosurgical techniques
in order to provide the best treatment possible.
Interventional radiology
Agaricus blazei mushrooms inhibited abnormal collagen fiber formation in
human hepatocarcinoma cells in an in vitro experiment.
A systematic review assessed 12 articles involving a total of 318 patients
with hepatocellular carcinoma treated with Yttrium-90 radioembolization.
Excluding a study of only one patient, post-treatment CT evaluation of the
tumor showed a response ranging from 29 to 100% of patients evaluated,
with all but two studies showing a response of 71% or greater.
Gallium maltolate demonstrated in vitro efficacy against several HCC cell
lines[36] and produced very encouraging results in a clinical case of
advanced HCC that had not responded to therapy with sorafenib. Gallium is
known, from gallium scanning results, to be taken up preferentially by many
hepatocellular carcinoma tumors. Therapeutic doses of gallium follow the
same uptake pathway, causing inhibition of tumor growth and eventual
apoptosis of tumor cells, while sparing healthy tissue.
Prognosis
The usual outcome is poor, because only 10–20% of hepatocellular
carcinomas can be removed completely using surgery. If the cancer cannot
be completely removed, the disease is usually deadly within 3 to 6 months.
This is partially due to late presentation with large tumours, but also the
lack of medical expertise and facilities. However, survival can vary, and
occasionally people will survive much longer than 6 months. The prognosis
for metastatic or unresectable hepatocellular carcinoma has recently
improved due to the approval of sorafenib (Nexavar®) for advanced
hepatocellular carcinoma.
Epidemiology
HCC is one of the most common tumors worldwide. The epidemiology of
HCC exhibits two main patterns, one in North America and Western Europe
and another in non-Western countries, such as those in sub-Saharan Africa,
central and Southeast Asia, and the Amazon basin. Males are affected more
than females usually and it is most common between the age of 30 to 50,
Hepatocellular carcinoma causes 662,000 deaths worldwide per year about
half of them in China.
Africa and Asia
In some parts of the world, such as sub-Saharan Africa and Southeast Asia,
HCC is the most common cancer, generally affecting men more than
women, and with an age of onset between late teens and 30s. This
variability is in part due to the different patterns of hepatitis B and hepatitis
C transmission in different populations - infection at or around birth
predispose to earlier cancers than if people are infected later. The time
between hepatitis B infection and development into HCC can be years, even
decades, but from diagnosis of HCC to death the average survival period is
only 5.9 months according to one Chinese study during the 1970-80s, or 3
months (median survival time) in Sub-Saharan Africa according to Manson's
textbook of tropical diseases. HCC is one of the deadliest cancers in China
where chronic hepatitis B is found in 90% of cases. In Japan, chronic
hepatitis C is associated with 90% of HCC cases. Food infected with
Aspergillus flavus (especially peanuts and corns stored during prolonged
wet seasons) which produces aflatoxin poses another risk factor for HCC.
North America and Western Europe
Most malignant tumors of the liver discovered in Western patients are
metastases (spread) from tumors elsewhere. In the West, HCC is generally
seen as a rare cancer, normally of those with pre-existing liver disease. It is
often detected by ultrasound screening, and so can be discovered by
health-care facilities much earlier than in developing regions such as SubSaharan Africa.
Acute and chronic hepatic porphyrias (acute intermittent porphyria,
porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria)
and tyrosinemia type I are risk factors for hepatocellular carcinoma. The
diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should be sought in
patients with hepatocellular carcinoma without typical risk factors of
hepatitis B or C, alcoholic liver cirrhosis or hemochromatosis. Both active
and latent genetic carriers of acute hepatic porphyrias are at risk for this
cancer, although latent genetic carriers have developed the cancer at a
later age than those with classic symptoms. Patients with acute hepatic
porphyrias should be monitored for hepatocellular carcinoma.
HCC is one of the most common tumors worldwide. The epidemiology of
HCC exhibits two main patterns, one in North America and Western Europe
and another in non-Western countries, such as those in sub-Saharan Africa,
central and Southeast Asia, and the Amazon basin. Males are affected more
than females usually and it is most common between the age of 30 to 50,
Hepatocellular carcinoma causes 662,000 deaths worldwide per year about
half of them in China.
Africa and Asia
In some parts of the world, such as sub-Saharan Africa and Southeast Asia,
HCC is the most common cancer, generally affecting men more than
women, and with an age of onset between late teens and 30s. This
variability is in part due to the different patterns of hepatitis B and hepatitis
C transmission in different populations - infection at or around birth
predispose to earlier cancers than if people are infected later. The time
between hepatitis B infection and development into HCC can be years, even
decades, but from diagnosis of HCC to death the average survival period is
only 5.9 months according to one Chinese study during the 1970-80s, or 3
months (median survival time) in Sub-Saharan Africa according to Manson's
textbook of tropical diseases. HCC is one of the deadliest cancers in China
where chronic hepatitis B is found in 90% of cases. In Japan, chronic
hepatitis C is associated with 90% of HCC cases. Food infected with
Aspergillus flavus (especially peanuts and corns stored during prolonged
wet seasons) which produces aflatoxin poses another risk factor for HCC.
North America and Western Europe
Most malignant tumors of the liver discovered in Western patients are
metastases (spread) from tumors elsewhere. In the West, HCC is generally
seen as a rare cancer, normally of those with pre-existing liver disease. It is
often detected by ultrasound screening, and so can be discovered by
health-care facilities much earlier than in developing regions such as SubSaharan Africa.
Acute and chronic hepatic porphyrias (acute intermittent porphyria,
porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria)
and tyrosinemia type I are risk factors for hepatocellular carcinoma. The
diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should be sought in
patients with hepatocellular carcinoma without typical risk factors of
hepatitis B or C, alcoholic liver cirrhosis or hemochromatosis. Both active
and latent genetic carriers of acute hepatic porphyrias are at risk for this
cancer, although latent genetic carriers have developed the cancer at a
later age than those with classic symptoms. Patients with acute hepatic
porphyrias should be monitored for hepatocellular carcinoma.
Pre-clinical
Current research includes the search for the genes that are disregulated in
HCC, protein markers, non-coding RNAs (such as TUC338) and other
predictive biomarkers. As similar research is yielding results in various other
malignant diseases, it is hoped that identifying the aberrant genes and the
resultant proteins could lead to the identification of pharmacological
interventions for HCC.
Clinical
JX-594, an oncolytic virus, has orphan drug designation for this condition
and is undergoing clinical trials.
HCC treatments in Phase II & Phase III Development at June 2013
Company
Name
4SC AG
Product
Names
4SC-201
(Compound
#),
BYK408740
Descr
iption
Partners
Latest
Stage
of
Develo
pment
Oral pan- Yakult
histone
Honsha Co. Phase II
deacetylas Ltd.
e (HDAC)
Indication Details
First-line treatment of
advanced
hepatocellular
carcinoma (HCC);
Company
Name
Product
Names
Descr
iption
Partners
Latest
Stage
of
Develo
pment
(Former
inhibitor
compound
#),resminostat
(Generic)
Active
Biotech AB
Second-line treatment
of hepatocellular
carcinoma (HCC)
Oral
quinoline-3carboxamid
ABR-215050 e derivative
(Compound
that binds
#),tasquinimo S100
Ipsen Group Phase II
d (Generic), calcium
TASQ
binding
protein A9
(Informal)
(S100A9;
calgranulin
B; MRP14)
SGI-110
Astex
(Compound
Hypomethy
Pharmaceutic #), S110
lating agent
(Former
als Inc.
compound #)
AstraZeneca
plc
BAY 86-9766
(Compound #),
RDEA119
(Former
compound
#),Refametinib
(Informal)
Eli Lilly and Co.
LY2157299
Transformin
(Compound #) g growth
Selective
inhibitor of
mitogenactivated
ERK kinase
(MEK)
Indication Details
Bayer AG
Treat advanced or
metastatic
hepatocellular
carcinoma (HCC)
Phase II
Treat advanced
hepatocellular
carcinoma (HCC)
Phase II
Treat hepatocellular
carcinoma (HCC)
Phase II
Treat hepatocellular
carcinoma (HCC)
Company
Name
Product
Names
Descr
iption
Partners
Latest
Stage
of
Develo
pment
Indication Details
factor (TGF)
beta
receptor 1
(TGFBR1;
ALK5)
inhibitor
GenSpera Inc.
Prodrug of
plantG-202
derived
(Compound #)
cytotoxin
12ADT
Tykerb (Brand),
Tyverb (Brand),
GW572016
GlaxoSmithKlin (Compound
#), lapatinib(Ge
e plc
neric), Tykerb
(Other), Tyverb
(Other)
HER1 and
HER2
receptor
kinase
inhibitor
Phase II
Treat advanced,
progressive hepatocellular
carcinoma (HCC)
Eddingpharm
Phase II
Inc.
Treat hepatocellular
carcinoma (HCC)
Phase II
Treat hepatocellular
carcinoma (HCC)
Novartis AG
Phase II
Treat advanced
hepatocellular carcinoma
(HCC)
JX-594
Recombinan Transgene
Jennerex
(Compound #), t vaccinia
S.A.;Green
Biotherapeutic
TG6006
virus
Cross Corp.;
Phase II
Treat advanced
hepatocellular cancer
(HCC); Treat
Green Cross
Corp.
Engineered
JX594
oncolytic
(Compound #)
virus
Incyte Corp.
INC280
(Compound #),
INCB28060
(Former
compound #)
Oral c-Met
receptor
tyrosine
kinase
inhibitor
Company
Name
s Inc.
Product
Names
(Compound
#),pexastimoge
ne
devacirepvec (
Generic), PexaVec (Informal),
JX-5940TG6006
(Other)
Descr
iption
(addition of
GM-CSF and
deletion of
thymidine
kinase)
Recombinan
t fusion
protein that
NGR-hTNF
selectively
(Compound
binds to
MolMed S.p.A.
#), Arenegyr (F alanyl
membrane
ormer)
aminopeptid
ase (ANPEP;
APN; CD13)
Partners
Latest
Stage
of
Develo
pment
Lee's
Pharmaceutic
al Holdings
Ltd.
Indication Details
hepatocellular carcinoma
(HCC); Treat primary liver
cancer or cancer
metastatic to the liver;
Treat unresectable
primary hepatocellular
carcinoma (HCC)
Phase II
Treat hepatocellular
carcinoma (HCC)
Phase II
Treat metastatic
hepatocellular carcinoma
(HCC)
Novartis AG
SOM230
(Compound
#),pasireotide ( Somatostati
Generic),
n analog
Signifor
(Informal)
Pfizer Inc.
CP-675
(Compound #),
Human mAB
CP-675,206
AstraZeneca
Phase II
(Compound #), against
plc
CTLA-4
CP-675206
(Compound #),
ticilimumab
Treat hepatocellular
carcinoma (HCC)
Company
Name
Product
Names
Descr
iption
Partners
Latest
Stage
of
Develo
pment
Indication Details
(Former),treme
limumab (Infor
mal)
Lansoprazol
e
lansoprazole (G formulated
Innovus
Apricus
eneric),
with
Pharmaceutical
Biosciences
PrevOnco
NexMed's
s Inc.
Inc.
NexACT
(Informal)
delivery
technology
AbbVie Inc.
Inhibitor of
vascular
endothelial
growth
ABT-869
factor
(Compound
(VEGF) and
#),linifanib (Ge platelet
derived
neric)
growth
factor
(PDGF)
receptor
ArQule Inc.
Small
molecule
ARQ 197
inhibitor of
(Compound
c-Met
#), tivantinib (G
receptor
eneric)
tyrosine
kinase
Daiichi
Sankyo Co.
Ltd.; Kyowa
Hakko Kirin
Co. Ltd.
Phase II/III
Treat hepatocellular
carcinoma (HCC)
Phase III
Treat advanced or
metastatic hepatocellular
carcinoma (HCC); Treat
liver cancer
Phase III
Treat hepatocellular
carcinoma (HCC); Treat
unresectable
hepatocellular carcinoma
(HCC) in patients who
have failed one prior
systemic therapy
Company
Name
Product
Names
Descr
iption
Astellas
Pharma Inc.
Tarceva
(Brand), R1415
(Compound #),
RG115
(Compound #),
CP-358,774
(Former
compound #),
OSI-774
(Former
compound
#),erlotinib (Ge
neric), Tarceva
(Other)
Small
molecule
inhibitor of
EGFR
tyrosine
kinase
activity
Bayer AG
Stivarga
(Brand), BAY
73-4506
(Compound
#),regorafenib (
Generic), DAST
Inhibitor
(Informal),
fluorosorafenib
(Other)
Dual acting
signal
transduction
(DAST)
inhibitor of
multiple
kinases
BioAlliance
Pharma S.A.
BA-003
(Compound
#),doxorubicin
(Generic),
Livatag
doxorubicin
Transdrug
Nanoparticle
formulation
of
doxorubicin
Partners
Latest
Stage
of
Develo
pment
Chugai
Pharmaceutic
al Co.
Phase III
Ltd;Genentec
h Inc.;Roche
Indication Details
Treat hepatocellular
carcinoma (HCC)
Phase III
Treat advanced
hepatocellular carcinoma
(HCC); Treat
hepatocellular carcinoma
(HCC)
Phase III
Treat advanced
hepatocellular carcinoma
(HCC); Treat
hepatocellular carcinoma
(HCC)
Company
Name
Product
Names
Descr
iption
Partners
Latest
Stage
of
Develo
pment
Indication Details
(Other)
Bristol-Myers
Squibb Co.
Dual
inhibitor of
VEGFR-2
BMS-582664
and
(Compound
fibroblast
#), Brivanib(Ot growth
factor (FGF)
her)
receptor 1
(FGFR1;
CD331)
Phase III
Celsion Corp.
Doxorubicin
ThermoDox
encapsulate
heat-activated
d in a heatliposome
activated
(Informal)
liposome
Yakult
Honsha Co.
Ltd.; Zhejiang
Phase III
Hisun
Pharmaceutic
al Co. Ltd.
Phase III
Treat hepatocellular
carcinoma (HCC)
SFJ
Pharmaceutic Phase III
als Inc.
Treat hepatocellular
carcinoma (HCC)
Delcath
Systems Inc.
Chemostat
doxorubicin
(Informal)
Doxorubicin
delivered
using the
Chemosat
percutaneou
s hepatic
perfusion
system
Eisai Co. Ltd.
E7080
(Compound
#),Lenvatinib (
Other)
Inhibitor of
multiple
VEGF
receptor
tyrosine
First- and second-line
treatment of
hepatocellular cancer
(HCC); First-line treatment
of hepatocellular
carcinoma (HCC); Treat
hepatocellular carcinoma
(HCC)
Treat colorectal liver
metastases; Treat liver
cancer; Treat metastatic
liver cancer; Treat nonresectable hepatocellular
carcinoma (HCC)
Company
Name
Product
Names
Descr
iption
Partners
Latest
Stage
of
Develo
pment
Indication Details
kinases
IMC-1121B
(Compound #),
Human IgG1
LY3009806
mAb VEGFREli Lilly and Co.
(Compound
2 antagonist
#),ramuciruma
b (Generic)
Phase III
Treat advanced,
inoperable liver cancer in
treatment-naïve patients;
Treat hepatocellular
carcinoma (HCC)
Phase III
Prevent recurrence after
curative treatment of
HCV-related
hepatocellular carcinoma
(HCC); Prevent recurrence
of hepatocellular
carcinoma (HCC) in
patients with HCV; Treat
hepatocellular cancer
(HCC)
Phase III
Treat hepatoma; Treat
liver metastases from
colorectal cancer; Treat
unresectable
hepatocellular carcinoma
(HCC)
Sulfated
mannopenta Medigen
Biotechnolog Phase III
ose
phosphate y Corp.
anti-
Adjuvant treatment of
hepatitis virus-related
hepatocellular carcinoma
(HCC) after surgical
resection; Treat
Kowa Co. Ltd.
K-333
(Compound #),
NIK-333
(Compound
#),peretinoin (
Generic),
Ruchiko
(Other)
Light Sciences
Oncology Inc.
Photodynam
ic therapy
Litx
(PDT) using
(Former), Apto
photosensiti
cine
zing agent
talaporfin sodi
talaporfin
um (Informal)
sodium
(LS11)
PI-88
Progen
(Compound
Pharmaceutical
#),muparfostat
s Ltd.
(Generic)
Oral acyclic
retinoid with
a vitamin Alike
structure
Company
Name
Product
Names
Descr
iption
Partners
Latest
Stage
of
Develo
pment
angiogenic
agent that
inhibits
VEGF, FGF
and
heparanase
activity
Teysuno (Brand
), S-1
(Compound #),
TS-1
Taiho
(Compound #),
Pharmaceutical tegafur/gimera
cil/oteracil
Co. Ltd.
potassium
(Generic),
Teysuno
(Informal)
hepatocellular carcinoma
(HCC) following primary
tumor resection; Treat
primary liver cancer
Oral
combination
of 5fluorouracil Nordic Group Phase III
(5-FU) plus
two enzyme
inhibitors
Lowmolecularweight antiTSU-68
Taiho
angiogenetic
(Compound
Pharmaceutical
agent that
#),orantinib (G
inhibits
Co. Ltd.
eneric)
receptor
tyrosine
kinase
Indication Details
Phase III
Treat hepatocellular
carcinoma (HCC); Treat
liver cancer
Treat hepatocellular
carcinoma (HCC)
Abbreviations
HCC, hepatocellular carcinoma; TACE, transarterial embolization/chemoembolization;
PFS, progression-free survival; PS, performance status; HBV, hepatitis B virus; PEI,
percutaneous ethanol injection; RFA, radiofrequency ablation; RR, response rate; MS,
median survival.