ArticlePDF AvailableLiterature Review

Hepatocellular Cancer: New Kids on the Block

Authors:
  • KMG Klinik Silbermühle GmbH

Abstract

Background: With over 600,000 newly diagnosed hepatocellular cancer (HCC) patients worldwide every year and ongoing clinical research, it is surprising that many of the new molecular entities have not yet resulted in significant prolongation of progression-free or overall survival. Nevertheless, there are a number of promising agents currently under investigation. Given the unique tumor biology and heterogeneous clinical manifestations of HCC, the application of molecular and cellular markers could also benefit patient selection, disease prognosis and trial design. Summary: This paper provides an overview of the current therapeutic strategies for HCC in the curative and palliative settings. Furthermore, we introduce some of the promising small molecules and antibodies that may find their way into clinical practice, with a focus on substances that are currently in phase III testing. Finally, we summarize the role of promising biomarkers, such as circulating tumor or cancer stem cells. Key message: Despite the rising prevalence of HCC and active clinical research, few therapeutic options besides sorafenib have been established. This review discusses the new therapeutic agents in the pipeline. Practical implications: Although many promising preclinical studies have resulted in phase I-II trials on HCC, so far only the tyrosine and Raf kinase inhibitor sorafenib has made its way into the hands of physicians. This multikinase inhibitor is the only approved option for systemic treatment of advanced HCC. Currently, the development of promising approaches for disease management is guided by biomarkers such as molecular markers or cellular characteristics. The use of biomarkers may facilitate early diagnosis in high-risk groups and therefore enhance outcomes by detecting patients whose disease is still curable.
© 2015 S. Karger AG, Basel
2296–3774/15/0014–0195$39.50/0
Mini-Review
Gastrointest Tumors 2014;1:195–200
Hepatocellular Cancer: New Kids on
the Block
Andreas-Claudius Hoffmann
a Guido G.H. Gerken
b
a Department of Medical Oncology, Molecular Oncology Risk-Profile Evaluation,
West German Cancer Center, and
b Department of Gastroenterology and Hepatology,
University Hospital Essen, Essen , Germany
Key Words
Biomarkers · Circulating tumor cells · Hepatocellular cancer · New molecular substances ·
Systemic and local ablative therapy
Abstract
Background: With over 600,000 newly diagnosed hepatocellular cancer (HCC) patients world-
wide every year and ongoing clinical research, it is surprising that many of the new molecular
entities have not yet resulted in significant prolongation of progression-free or overall sur-
vival. Nevertheless, there are a number of promising agents currently under investigation.
Given the unique tumor biology and heterogeneous clinical manifestations of HCC, the ap-
plication of molecular and cellular markers could also benefit patient selection, disease prog-
nosis and trial design. Summary: This paper provides an overview of the current therapeutic
strategies for HCC in the curative and palliative settings. Furthermore, we introduce some of
the promising small molecules and antibodies that may find their way into clinical practice,
with a focus on substances that are currently in phase III testing. Finally, we summarize the
role of promising biomarkers, such as circulating tumor or cancer stem cells. Key Message:
Despite the rising prevalence of HCC and active clinical research, few therapeutic options be-
sides sorafenib have been established. This review discusses the new therapeutic agents in
the pipeline. Practical Implications: Although many promising preclinical studies have re-
sulted in phase I–II trials on HCC, so far only the tyrosine and Raf kinase inhibitor sorafenib
has made its way into the hands of physicians. This multikinase inhibitor is the only approved
option for systemic treatment of advanced HCC. Currently, the development of promising ap-
proaches for disease management is guided by biomarkers such as molecular markers or cel-
lular characteristics. The use of biomarkers may facilitate early diagnosis in high-risk groups
and therefore enhance outcomes by detecting patients whose disease is still curable.
© 2015 S. Karger AG, Basel
Published online: April 1, 2015
Priv.-Doz. Dr. Andreas-Claudius Hoffmann
Depar tment of Medical Oncology, Molecular Oncology Risk-Profile Evaluation
West Ger man Cancer Center, Univer sity Hospit al Essen
Hufelandstrasse 55, DE–45147 Essen (Germany)
E-Mail hof fmann
@ more-oncology.com
www.karger.com/gat
DOI: 10.1159/000380787
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DOI: 10.1159/000380787
Hoffmann and Gerken: Hepatocellular Cancer: New Kids on the Block
www.karger.com/gat
© 2015 S. Karger AG, Basel
Introduction
Hepatocellular cancer (HCC) is diagnosed 600,000 times per year worldwide and is
among the ten most common causes of cancer-related deaths in Germany, with a significant
rise in incidence over the last two decades
[1] . In Germany high BMI, diabetes mellitus and
non-alcoholic fatty liver disease are the mainstay of the recent upsurge, and therefore liver
cancer is related to our changing lifestyle more than many other cancers. The 5-year survival
rates of symptomatic patients are 10–20% and rise significantly with early detection, but
cost-efficient and commonly available screening tools are rare. Several interdisciplinary
choices exist in the curative and palliative setting, but so far there are only few tools to indi-
vidualize treatment decisions. An optimized management of patients at risk of developing
HCC and those with diagnosed liver cancer is therefore urgently needed.
Current Options in Diagnosis and Treatment
Curative therapeutic options in HCC are limited to early stages and include mostly
resection or orthotopic liver transplantation. Liver transplantation and tumor resection
have proven to be the most effective standard therapies and provide 5-year survival rates
of 70% for patients within the Milan criteria, i.e. with a single tumor <5 cm in size or up to
three tumors <3 cm in size. If patients qualify for liver transplantation, the strict Milan
criteria make neoadjuvant, so-called bridging methods, necessary. Otherwise a tumor size
doubling time of approximately 4 months results in high dropout rates
[2] . If 2–3 lesions or
one single lesions >3 cm are present, dropout rates of 90% after 18 months have been
reported
[3] . Choosing the adequate bridging method in this patient cohort is therefore
inevitable, but reliable guidance tools are missing up to now. The 5-year survival rates
reach 50% with radiofrequency ablation and transarterial chemoembolization. Another
capable localized approach to treat HCC is represented by selective intraarterial radio-
nuclide therapy (SIRT). It has been discussed whether some patients may benefit from
concomitant local ablative and systemic therapy, but subgroup identifiers are missing so
far
[4] . However, these therapeutic procedures most often do not provide a complete cure,
as half of the treated patients experience tumor recurrence within 3 years
[5] . These high
recurrence rates after resection and liver transplantation are most likely due to minimal
residual disease and the fact that the majority of patients are diagnosed at an advanced
stage. In 2008, results of a phase III study of sorafenib in patients with advanced HCC, the
so-called SHARP trial, were published in the New England Journal of Medicine
[6] . In this
trial, patients who had not received prior systemic treatment received either sorafenib at a
dose of 400 mg daily or placebo. The resulting benefit in median overall survival was about
3 months, which led to FDA approval of the drug as first-line systemic treatment in advanced
HCC. Nearly 7 years after the first results of the SHARP trial were presented at the annual
meeting of the American Society of Clinical Oncology (ASCO), there still is no other approved
systemic option for advanced HCC. The diagnostic and therapeutic options in HCC rely in
many aspects on radiological imaging methods, which therefore play an important role in
the management of HCC. As of today, the gold standard in the staging and follow-up of HCC
is represented by computed tomography. The sensitivity of detecting and distinguishing
tumorous lesions can be increased when employing magnetic resonance imaging, espe-
cially when applying emerging techniques such as diffusion-weighted imaging
[7] . Adding
hepatocyte-specific contrast agents to this process enhances sensitivity and specificity,
especially when physicians are forced to differentiate between small lesions
[8] . Though
alpha-fetoprotein (AFP) combined with imaging techniques is currently the standard in
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© 2015 S. Karger AG, Basel
monitoring of therapeutic outcome, relapse or lack of response to surgical or intervention-
al therapy is still hard to predict. Serum-based markers like AFP, des-gamma-carboxy
prothrombin or the lectin 3 fraction of AFP (AFP-L3) are incapable of predicting clinical
outcome with high accuracy and reproducibility
[9] .
In patients with cirrhosis regular screening for HCC is suggested, but currently there are
no cost-efficient and commonly available screening tools for other high-risk groups. The
current standard for screening in risk groups is ultrasound combined with AFP measurement
[10] . Ultrasound, though effective and non-invasive, is very much dependent on user and
hardware. In Germany and especially in North Rhine-Westphalia, ultrasound performed
worse than any other imaging tool
[11] . Recent studies indicate that only very few patients
actually underwent screening in the last 3 years before they were diagnosed with HCC
[12] .
Moreover, only some of the patients were actually referred to a specified physician. Though
increasing education and demands for quality control may lead to better results, the clinical
reality shows that many patients with risk factors will not be referred to those physicians
with high experience in gastroenterology or hepatology in time and therefore most likely be
diagnosed at advanced stages. Minimally invasive, yet highly specific serum markers are
therefore urgently needed.
New Therapeutic Approaches and Biomarkers
Though the multikinase inhibitor sorafenib is currently the only approved systemic
treatment in HCC and has been in use for more than 7 years, there still is no reliable
biomarker to define patients who would benefit most while others may only suffer from an
increased toxicity in comparison to localized approaches. A recent report by Peng et al.
[13]
supported the usability of vascular endothelial growth factor receptors (VEGFRs), tyrosine
kinase receptors that are a target for the small molecule, as potential pre-therapeutic
markers. They used immunohistochemistry to stain for active, phosphorylated VEGFR1
(pVEGFR1) and phosphorylated VEGFR2 (pVEGFR2). They also showed that autocrine
VEGF promoted phosphorylation of VEGFR1 and VEGFR2 and internalization of pVEGFR2
in HCC cells, which was both pro-proliferative through a protein lipase C-extracellular
kinase pathway and self-sustaining through increasing VEGF, VEGFR1 and VEGFR2 mRNA
expressions. In high VEGFR1/2-expressing HepG2 cells, sorafenib treatment inhibited cell
proliferation, reduced VEGFR2 mRNA expression in vitro and delayed xenograft tumor
growth in vivo. The authors were also able to show that in an advanced HCC population
on sorafenib treatment for postoperative recurrence, the absence of VEGFR1 or VEGFR2
expression in resected tumor tissues before sorafenib treatment was associated with
poorer overall survival. Therefore, VEGFRs could be a biomarker for defining subgroups of
patients who would benefit most from sorafenib. Screening of serum biomarkers for
sorafenib sensitivity by the SHARP investigators yielded no conclusive results, with VEGF
and angiopoietin-2 being prognostic but not predictive
[14] . Since HCC seems to be a tumor
that is vascularized more than other malignancies, it may be especially detainable by anti-
angiogenic treatment
[15] . While the small-molecule inhibitors sunitinib, brivanib, erlo-
tinib and linifanib were not successful
[16] , two of the more promising substances also
targeting VEGFRs are currently in phase III trial testing, the recombinant monoclonal anti-
VEGFR2 antibody ramucirumab and the small molecule lenvatinib (E7080), like sorafenib
a multikinase inhibitor. The latter is currently being tested in a multicenter, randomized,
open-label, phase III trial comparing the efficacy and safety versus sorafenib in first-line
treatment in unresectable HCC. Another approach is the combination of cytotoxic agents
like doxorubicin with anti-angiogenesis. The CALGB 80802 phase III trial with sorafenib
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DOI: 10.1159/000380787
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© 2015 S. Karger AG, Basel
with or without doxorubicin hydrochloride in patients with locally advanced or metastatic
liver cancer is still active and results are awaited. The results of the prodromal phase II trial
were encouraging with a median overall survival of 13.7 months in the combination arm
[17] . Sorafenib in an adjuvant setting after resection or radiofrequency ablation did not
deliver beneficial results as presented at the ASCO annual meeting 2014 and cannot be
advised currently. Other studies examined the use of radioembolization with yttrium-90
microspheres on overall survival in advanced HCC with or without portal venous obstruction
and no extrahepatic extension versus sorafenib, while the combination of both yielded
higher peri-transplant biliary complications and potentially tended towards more acute
rejections
[18] .
The inhibition of the mammalian target of rapamycin delivered promising preclinical and
phase I data. Zhu et al.
[19] recently reported negative outcomes on this pathway in HCC. They
reported on the results of the EVOLVE-1 trial, a randomized, double-blind, phase III study
conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C HCC and Child-
Pugh A liver function whose disease progressed during or after sorafenib or who were intol-
erant of sorafenib. No significant difference in overall survival was seen between treatment
groups, with a median overall survival of 7.6 months with everolimus and 7.3 months with
placebo. Also the median time to progression did not differ significantly between everolimus
and placebo (3.0 vs. 2.6 months). The disease control rate was 56.1 vs. 45.1% and also not
significant. Nonetheless there are still promising substances being tested right now like the
dual orally available inhibitor of TORC1/TORC2 called CC-223 or the disubstituted amino-
thiazole HBF 079.
Targeting the hepatocyte growth factor (HGF)/c-Met pathway may yield alternatives for
sorafenib treatment and substances are currently tested in the first- and second-line setting.
HGF stimulation of the MET receptor leads to cell survival, cell proliferation and cytoskeletal
changes with enhanced cell mobility. Therefore MET is essential to a process with high plas-
ticity and increasing attention by scientists, the so-called epithelial-mesenchymal transition
(EMT), being the switch from an epithelial to a mesenchymal phenotype. Recently Yu et al.
[20] showed that in breast cancer these switches are highly associated with response respec-
tively resistance to therapy. The substances that are currently in phase III trial testing are
tivantinib (ARQ197) and cabozantinib (XL184). Cabozantinib blocked the HGF-stimulated
MET pathway and inhibited the migration and invasion of HCC cells in a study published by
Xiang et al.
[21] . The small-molecule inhibitor of the tyrosine kinases c-Met and VEGFR2
reduced the number of metastatic lesions in the lung and liver in an experimental metastatic
mouse model. Tivantinib, an orally administered, selective inhibitor of MET with a still unclear
mode of action, showed promising phase II results versus placebo for second-line treatment
of advanced HCC
[22] . Patients with advanced HCC and Child-Pugh A cirrhosis who had
progressed on or were unable to tolerate first-line systemic therapy were enrolled, and after
randomization a tivantinib dose of 240 mg twice daily was administered. For patients with
MET-high tumors, median time to progression was longer with tivantinib than for those on
placebo.
Other promising phase III trials employ new technologies to deliver drugs for local
ablative treatment, like injectable doxorubicin (Livatag
® ) or a delivery system for high-dose
cytotoxic substances (e.g. melphalan, Delcath Hepatic Chemostat
® Delivery System). Fur-
thermore immune-based approaches like the PD-1 inhibitor nivolumab or the CTLA-4
inhibitor tremilimumab in HCV-related HCC may result in changed treatment, but these
substances are not yet in phase III testing in HCC. Cancer stem cells (CSCs) in HCC may be
another promising target.
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© 2015 S. Karger AG, Basel
Circulating Tumor or Cancer Stem Cells
Tissue-derived molecular markers lack the possibility of monitoring the patient during
or after treatment, since this would require repeated biopsies and hence increased risks for
the patient. Therefore, the development of minimally invasive diagnostic methods is necessary.
Especially in the setting of liver transplantation it is of great importance to identify those
patients who will benefit most. Currently, there is a compelling lack of risk prediction strat-
egies that would enable the physician to provide a tailored treatment in terms of primary
intervention as well as adjuvant/neoadjuvant therapy. In addition, it is apparent that one of
the limitations in risk prediction we face today is the limitation to obtain HCC tissue prior
neoadjuvant therapy. Frequently, histological diagnosis (i.e. liver biopsy) is not required, and
patients will receive bridging therapies such as SIRT. Furthermore, there is compelling
evidence that a fraction of tumor cells might harbor the genetic setup that will allow for
implantation and tumor cell dissemination. These cells present with an EMT phenotype and
obtain stem-like cell properties that foster migration and metastatic ability of epithelial HCC
cells. For these reasons, it is important to expand prognostic profiling from tumor tissue-
derived biomarkers to circulating biomarkers. Circulating tumor cells (CTCs) detected in the
peripheral blood of HCC patients may represent a possible solution for this diagnostic dilemma
[23] . The main obstacle to the broad clinical application of available automated CTC detection
methods is the high plasticity and variability of these cells, particularly due to the EMT, a
process closely related to the MET pathway as described earlier. EMT inevitably leads to
decreased detection of CTCs with techniques based mostly on assumed epithelial character-
istics of these cells. Remarkably, changes from epithelial to mesenchymal cell characteristics
are significantly correlated to treatment response
[20] . Furthermore the intratumoral hetero-
geneity of HCC is believed to be caused by subpopulations of cells that are genetically identical
but display distinct phenotypic states, such as CSCs and non-CSCs. The ability of self-renewal
and tumor initiation define CSCs and are relevant to metastasis. CSCs are described as non-
equivalent to CTCs. Only CTCs that have the ability to form ectopic metastasis have CSC char-
acteristics and are known as circulating CSCs. An innovative methodology in CSC-targeted
therapy is the siRNA-mediated downregulation of signaling pathways involved in carcino-
genesis. Though CSC and CTC analysis may not be usable for treatment decisions at the
moment, identifying and characterizing the individual tumor cell composition and the consti-
tution of circulating non-hematopoietic cells in the blood of patients before therapy may add
important information to the process of personalizing therapy
[24] .
Conclusions
There are several phase III trials currently recruiting that may change the treatment
landscape in HCC. Still the heterogeneous and unique tumor biology of HCC often results in
negative studies. Therefore individualized approaches already in the phase I setting are
urgently needed, employing panels including molecular and cellular tissue-based as well as
circulating markers.
Disclosure Statement
None of the authors has any conflict of interest relevant to this paper.
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© 2015 S. Karger AG, Basel
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Chapter
Various hepatic pathologies, including primary hepatocellular carcinoma, metastases, and symptomatic simple cysts, may be treated with liver ablation therapy. There are a variety of ablation devices and techniques such as radiofrequency ablation, microwave ablation, cryoablation, and alcohol ablation. In this chapter, we will discuss the current clinical indications, outcomes, and potential complications of interventional treatment for these hepatic pathologies, with particular emphasis on hepatocellular carcinoma. Alternative therapies, including recent molecular-based therapies, will also be discussed. Finally, a brief guide will be provided for a typical interventional thermal ablation procedure.
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No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P
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Importance: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. Objective: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. Design, setting, and participants: EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). Interventions: Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. Main outcomes and measures: The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). Results: No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. Conclusions and relevance: Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. Trial registration: clinicaltrials.gov Identifier: NCT01035229.
Article
MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with pro-metastasis during anti-angiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in HCC patients. Anti-tumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models. Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined. High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G1 phase arrest. Cabozantinib inhibited tumor growth in p-MET-positive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked HGF-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lungs and liver in the experimental metastatic mouse model. HCC patients with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant anti-tumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker.
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To investigate the safety and adverse event profile of sorafenib plus radioembolization (Y90) compared to Y90 alone in patients awaiting liver transplantation. 20 patients with HCC were randomized to Y90 alone (Group A) or Y90 + sorafenib (Group B). Adverse events, dose reductions, and peri-transplant complications were assessed. All patients in the sorafenib group necessitated dose reductions. Seventeen of 20 patients underwent liver transplantation; median time-to-transplant was 7.8 months (range: 4.2-20.3) and similar between groups (p=0.35). In the sorafenib group, there were 4/8 peri-transplant (<30 days) biliary complications (p=0.029) and 3/8 acute rejections (p=0.082); there were none in the Y90-only group. Survival rates were 70% (Group A) and 72% (Group B) at 3 years (p=0.57). The addition of sorafenib to Y90 necessitated dose reductions in all patients awaiting transplantation. Preliminary data suggest that the combination was associated with more peri-transplant biliary complications and potentially trended towards more acute rejections. Caution should be exercised when considering sorafenib in the transplant setting. Further investigation is warranted.
Article
Hepatocellular carcinoma (HCC) is a major health problem. Most HCC patients recur after resection/ablation or are diagnosed at advanced stages. Sorafenib remains the only approved systemic drug for these patients. Molecular therapies targeting signaling cascades involved in hepatocarcinogenesis have been explored in phase III clinical trials. However, none of the drugs tested have shown positive results in first (brivanib, sunitinib, erlotinib and linifanib) or second line (brivanib, everolimus) after sorafenib progression. Reasons for failure are heterogeneous and include lack of understanding of critical drivers of tumor progression/dissemination, liver toxicity, flaws in trial design or marginal antitumoral potency. These trials are also challenging time to progression as a surrogate end-point of survival. Trials ongoing testing drugs head-to-head vs. sorafenib in "all comers" might have difficulties in achieving superior results in first line. Novel trials are currently designed testing drugs in biomarker-based subpopulations of HCC patients. Two types of studies are emerging. 1) Phase II pivotal proof-of-concept studies testing drugs blocking potential oncogenic addiction loops, and 2) Phase II-III studies using biomarker-based trial enrichment for defining activation of signalling pathways in HCC subgroups. These strategies have deemed successful in breast, melanoma and lung cancer, and are expected to change the landscape of trial design and management of HCC patients.