Reviews in Basic and Clinical Gastroenterology and HepatologyTargeted Therapies for Hepatocellular Carcinoma
Section snippets
Therapeutic Strategies for HCC
According to the Barcelona Clinic Liver Cancer (BCLC) algorithm,13, 14 HCC can be classified into 5 stages based on tumor burden, liver function, and health status. Besides its use in prognosis, this staging system assigns a specific therapeutic strategy to each stage. Recent studies found that the BCLC algorithm provided the best prognostic stratification, compared with other staging proposals.15 It has been endorsed by the American Association for the Study of Liver Diseases and the European
Pathogenesis and Targeted Therapies
High-throughput genomic technologies such as array-based gene expression profiling or parallel sequencing have increased our capacity to analyze human oncogenome.25 Large numbers of samples can be analyzed and compared simultaneously, and integrative analytic tools have allowed us to associate certain oncogenes with specific tumor types (eg, MITF with melanoma,26 CDK8 with colorectal cancer27); genomes of lung tumor,28 glioma,29 sarcoma,30 and prostate tumors have been analyzed.31
It is
Signal Transduction
HCCs have been categorized into 3 subgroups, based on gene expression patterns.39, 40, 41 One subgroup is characterized by altered expression of genes that regulate proliferation of the cell cycle, involving pathways such as mammalian target of rapamycin (mTOR),42 insulin-like growth factor,43 and RAS;44 and also includes gene signatures previously associated with aggressive clinical behavior (eg, proliferation,45 G3,46 cluster A47). A second subgroup is characterized by activation of the WNT
Oncogene Addiction
Proliferation and survival of some cancer cells require activation of specific oncogenes and inactivation of specific tumor suppressors, called oncogene addiction.66 It originally was described when researchers found that malignant phenotypes of some tumors required activation of certain oncogenes67; not all genetic variants associated with cancer cells are required for their proliferation and survival. Osteosarcomas require MYC, and thus tumor growth slows when MYC is inactivated.68
TKIs and HCC
The mainstreams of molecular therapy are currently mAbs and TKI. What are the differences between inhibiting a kinase with a small-molecule TKI vs a mAb? mAbs are larger molecules that cannot cross the blood-brain barrier and require intravenous administration. Their half-life is longer than that of TKI, which allows for weekly dosing. Pharmacokinetic studies have shown that plasma levels of TKI can vary among patients, probably because they are administered orally.75 mAbs are unable to pass
Sorafenib for HCC
Sorafenib was approved for HCC in 2007,78 and it is the standard of care for patients with advanced-stage HCC (BCLC-C). In the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study,12 a double-blind RCT with a primary end point of overall survival,79 sorafenib significantly increased survival times of patients with HCC, from 7.9 to 10.7 months, with a manageable profile of side effects. Consequently, sorafenib therapy should be given to the control group in trials of
Reagents in Development
There are 16 reported phase 2 and 3 trials analyzing TKI in patients with HCC (Table 412, 82, 83, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96). Unfortunately, the patient populations included in most of the phase 2 trials are heterogeneous in terms of underlying liver disease and staging systems; the studies also vary in primary end points (response rate, progression-free survival, overall survival) and measures of tumor response (RECIST or World Health Organization criteria). Overall survival
Clinical Benefits and Cost Effectiveness
The magnitude of effects of oncologic drugs is estimated based on the clinical end points used to measure efficacy and absolute (eg, increased time of survival) and relative (eg, the hazard ratio) differences measured, compared with controls. Regulatory agencies use different end points in deciding whether to approve reagents for treatment of cancer patients, including overall survival, progression-free survival, and time to progression (Table 2). The hazard ratio for FDA approval of sunitinib
Improving Efficacy of Treatment
Imatinib was developed using rational drug design110: the development of therapeutic reagents based on specific biologic targets. Screens of chemical libraries for inhibitors of BCR–ABL activity identified a precursor of imatinib. Since its approval for treatment of chronic myeloid leukemia in 2001, several other TKIs have been approved for treatment of patients with solid tumors, including non–small-cell lung cancer, pancreatic cancer, breast cancer, CRC, and HCC (Table 2). Most of these were
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Conflicts of Interest The authors disclose the following: Josep M. Llovet has research support from Bayer Pharmaceutical and Bristol Myers Squibb. He also has consultancy agreements with Bayer Pharmaceutical, Bristol Myers Squibb, Imclone, and Biocompatibles. Augusto Villanueva discloses no conflicts.
Funding Josep M. Llovet is supported by grants from the National Institutes of Health–National Institute for Diabetes and Digestive and Kidney Diseases (1R01DK076986-01), European Commission-FP7 Framework Programme (HEPTROMIC, proposal 259744, 2010), National Institute of Health (Spain) grant I+D Program (SAF-2007-61898, SAF-2010-16055), and the Samuel Waxman Cancer Research Foundation.