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 low-grade 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
immuno-suppressant 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 single-agent
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 Sub-Saharan 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 Sub-Saharan 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
|
Product
Names
|
Description
|
Partners
|
Latest
Stage of Development
|
Indication
Details
|
|
4SC AG
|
4SC-201 (Compound #), BYK408740
(Former compound #),resminostat (Generic)
|
Oral pan-histone deacetylase
(HDAC) inhibitor
|
Yakult Honsha Co. Ltd.
|
Phase II
|
First-line treatment of
advanced hepatocellular carcinoma (HCC); Second-line treatment of
hepatocellular carcinoma (HCC)
|
|
Active Biotech AB
|
ABR-215050 (Compound #),tasquinimod (Generic), TASQ (Informal)
|
Oral quinoline-3-carboxamide
derivative that binds S100 calcium binding protein A9 (S100A9; calgranulin B;
MRP14)
|
Ipsen Group
|
Phase II
|
Treat advanced or metastatic
hepatocellular carcinoma (HCC)
|
|
Astex Pharmaceuticals Inc.
|
SGI-110 (Compound #), S110
(Former compound #)
|
Hypomethylating agent
|
Phase II
|
Treat advanced hepatocellular
carcinoma (HCC)
|
|
|
AstraZeneca plc
|
BAY 86-9766 (Compound #), RDEA119
(Former compound #),Refametinib (Informal)
|
Selective inhibitor of
mitogen-activated ERK kinase (MEK)
|
Bayer AG
|
Phase II
|
Treat hepatocellular carcinoma (HCC)
|
|
Eli Lilly and Co.
|
LY2157299 (Compound #)
|
Transforming growth factor (TGF) beta
receptor 1 (TGFBR1; ALK5) inhibitor
|
Phase II
|
Treat hepatocellular carcinoma (HCC)
|
|
|
GenSpera Inc.
|
G-202 (Compound #)
|
Prodrug of plant-derived cytotoxin
12ADT
|
Phase II
|
Treat advanced, progressive hepatocellular
carcinoma (HCC)
|
|
|
GlaxoSmithKline plc
|
Tykerb (Brand), Tyverb (Brand),
GW572016 (Compound #), lapatinib(Generic),
Tykerb (Other), Tyverb (Other)
|
HER1 and HER2 receptor kinase
inhibitor
|
Eddingpharm Inc.
|
Phase II
|
Treat hepatocellular carcinoma (HCC)
|
|
Green Cross Corp.
|
JX594 (Compound #)
|
Engineered oncolytic virus
|
Phase II
|
Treat hepatocellular carcinoma (HCC)
|
|
|
Incyte Corp.
|
INC280 (Compound #), INCB28060
(Former compound #)
|
Oral c-Met receptor tyrosine kinase
inhibitor
|
Novartis AG
|
Phase II
|
Treat advanced hepatocellular
carcinoma (HCC)
|
|
Jennerex Biotherapeutics Inc.
|
JX-594 (Compound #), TG6006 (Compound
#),pexastimogene devacirepvec (Generic),
Pexa-Vec (Informal), JX-5940TG6006 (Other)
|
Recombinant vaccinia virus (addition
of GM-CSF and deletion of thymidine kinase)
|
Transgene S.A.;Green Cross Corp.;
Lee's Pharmaceutical Holdings Ltd.
|
Phase II
|
Treat advanced hepatocellular cancer
(HCC); Treat hepatocellular carcinoma (HCC); Treat primary liver cancer or
cancer metastatic to the liver; Treat unresectable primary hepatocellular
carcinoma (HCC)
|
|
MolMed S.p.A.
|
NGR-hTNF (Compound #), Arenegyr (Former)
|
Recombinant fusion protein that
selectively binds to alanyl membrane aminopeptidase (ANPEP; APN; CD13)
|
Phase II
|
Treat hepatocellular carcinoma (HCC)
|
|
|
Novartis AG
|
SOM230 (Compound #),pasireotide (Generic), Signifor (Informal)
|
Somatostatin analog
|
Phase II
|
Treat metastatic hepatocellular
carcinoma (HCC)
|
|
|
Pfizer Inc.
|
CP-675 (Compound #), CP-675,206
(Compound #), CP-675206 (Compound #), ticilimumab (Former),tremelimumab (Informal)
|
Human mAB against CTLA-4
|
AstraZeneca plc
|
Phase II
|
Treat hepatocellular carcinoma (HCC)
|
|
Innovus Pharmaceuticals Inc.
|
lansoprazole (Generic), PrevOnco (Informal)
|
Lansoprazole formulated with NexMed's
NexACT delivery technology
|
Apricus Biosciences Inc.
|
Phase II/III
|
Treat hepatocellular carcinoma (HCC)
|
|
AbbVie Inc.
|
ABT-869 (Compound #),linifanib (Generic)
|
Inhibitor of vascular endothelial
growth factor (VEGF) and platelet derived growth factor (PDGF) receptor
|
Phase III
|
Treat advanced or metastatic hepatocellular
carcinoma (HCC); Treat liver cancer
|
|
|
ArQule Inc.
|
ARQ 197 (Compound #), tivantinib (Generic)
|
Small molecule inhibitor of c-Met
receptor tyrosine kinase
|
Daiichi Sankyo Co. Ltd.; Kyowa Hakko
Kirin Co. Ltd.
|
Phase III
|
Treat hepatocellular carcinoma (HCC);
Treat unresectable hepatocellular carcinoma (HCC) in patients who have failed
one prior systemic therapy
|
|
Astellas Pharma Inc.
|
Tarceva (Brand), R1415 (Compound #),
RG115 (Compound #), CP-358,774 (Former compound #), OSI-774 (Former compound
#),erlotinib (Generic), Tarceva
(Other)
|
Small molecule inhibitor of EGFR
tyrosine kinase activity
|
Chugai Pharmaceutical Co. Ltd;Genentech
Inc.;Roche
|
Phase III
|
Treat hepatocellular carcinoma (HCC)
|
|
Bayer AG
|
Stivarga (Brand), BAY 73-4506
(Compound #),regorafenib (Generic),
DAST Inhibitor (Informal), fluoro-sorafenib (Other)
|
Dual acting signal transduction
(DAST) inhibitor of multiple kinases
|
Phase III
|
Treat advanced hepatocellular
carcinoma (HCC); Treat hepatocellular carcinoma (HCC)
|
|
|
BioAlliance Pharma S.A.
|
BA-003 (Compound #),doxorubicin (Generic), Livatag doxorubicin
Transdrug (Other)
|
Nanoparticle formulation of
doxorubicin
|
Phase III
|
Treat advanced hepatocellular
carcinoma (HCC); Treat hepatocellular carcinoma (HCC)
|
|
|
Bristol-Myers Squibb Co.
|
BMS-582664 (Compound #), Brivanib(Other)
|
Dual inhibitor of VEGFR-2 and
fibroblast growth factor (FGF) receptor 1 (FGFR1; CD331)
|
Phase III
|
First- and second-line treatment of
hepatocellular cancer (HCC); First-line treatment of hepatocellular carcinoma
(HCC); Treat hepatocellular carcinoma (HCC)
|
|
|
Celsion Corp.
|
ThermoDox heat-activated liposome
(Informal)
|
Doxorubicin encapsulated in a
heat-activated liposome
|
Yakult Honsha Co. Ltd.; Zhejiang
Hisun Pharmaceutical Co. Ltd.
|
Phase III
|
Treat colorectal liver metastases;
Treat liver cancer; Treat metastatic liver cancer; Treat non-resectable
hepatocellular carcinoma (HCC)
|
|
Delcath Systems Inc.
|
Chemostat doxorubicin (Informal)
|
Doxorubicin delivered using the
Chemosat percutaneous hepatic perfusion system
|
Phase III
|
Treat hepatocellular carcinoma (HCC)
|
|
|
Eisai Co. Ltd.
|
E7080 (Compound #),Lenvatinib (Other)
|
Inhibitor of multiple VEGF receptor
tyrosine kinases
|
SFJ Pharmaceuticals Inc.
|
Phase III
|
Treat hepatocellular carcinoma (HCC)
|
|
Eli Lilly and Co.
|
IMC-1121B (Compound #), LY3009806
(Compound #),ramucirumab (Generic)
|
Human IgG1 mAb VEGFR-2 antagonist
|
Phase III
|
Treat advanced, inoperable liver
cancer in treatment-naïve patients; Treat hepatocellular carcinoma (HCC)
|
|
|
Kowa Co. Ltd.
|
K-333 (Compound #), NIK-333 (Compound
#),peretinoin (Generic),
Ruchiko (Other)
|
Oral acyclic retinoid with a vitamin
A-like structure
|
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)
|
|
|
Light Sciences Oncology Inc.
|
Litx (Former), Aptocine talaporfin sodium (Informal)
|
Photodynamic therapy (PDT) using
photosensitizing agent talaporfin sodium (LS11)
|
Phase III
|
Treat hepatoma; Treat liver
metastases from colorectal cancer; Treat unresectable hepatocellular
carcinoma (HCC)
|
|
|
Progen Pharmaceuticals Ltd.
|
PI-88 (Compound #),muparfostat (Generic)
|
Sulfated mannopentaose phosphate
anti-angiogenic agent that inhibits VEGF, FGF and heparanase activity
|
Medigen Biotechnology Corp.
|
Phase III
|
Adjuvant treatment of hepatitis
virus-related hepatocellular carcinoma (HCC) after surgical resection; Treat
hepatocellular carcinoma (HCC) following primary tumor resection; Treat
primary liver cancer
|
|
Taiho Pharmaceutical Co. Ltd.
|
Teysuno (Brand), S-1 (Compound #), TS-1
(Compound #), tegafur/gimeracil/oteracil potassium (Generic), Teysuno
(Informal)
|
Oral combination of 5-fluorouracil
(5-FU) plus two enzyme inhibitors
|
Nordic Group
|
Phase III
|
Treat hepatocellular carcinoma (HCC);
Treat liver cancer
|
|
Taiho Pharmaceutical Co. Ltd.
|
TSU-68 (Compound #),orantinib (Generic)
|
Low-molecular-weight
anti-angiogenetic agent that inhibits receptor tyrosine kinase
|
Phase III
|
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.
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