Hepatocellular Carcinoma Clinical Trials Research Articles

Targeted therapy of hepatocellular carcinoma: Present and future

Following the encouraging results of sorafenib in advanced hepatocellular carcinoma (HCC), targeted therapy has become a new direction of research in the treatment of HCC. Emerging data provide evidence that the pathogenesis and progression of HCC are mediated by a number of molecular defects and dysregulated pathways. Novel targeted therapies are designed to inhibit the aberrant pathways at a molecular level with an aim to improve the clinical outcome. For the past few years, an increasing number of targeted agents have been tested in HCC in the clinical setting. This review aims to summarize the current status of clinical development of targeted therapy in HCC, with focus on novel agents targeting angiogenesis, signal transduction and epigenetic dysregulation of tumors. The review also discusses the lessons learned from outcomes of completed clinical trials and provides perspectives on future clinical trials in HCC.

NSC 74859‐mediated inhibition of STAT3 enhances the anti‐proliferative activity of cetuximab in hepatocellular carcinoma

Cetuximab [an epidermal growth factor receptor (EGFR) inhibitor], which was shown to be effective in rectal and non-small cell lung cancers (NSCLCs), was only modestly effective in clinical trials of hepatocellular carcinoma (HCC). STAT3, which is thought to be a determinant of HCC sensitivity to antitumour drugs, may be involved. To evaluate the efficacy of combination therapy using cetuximab and NSC 74859 (a novel STAT3 inhibitor) in EGFR and STAT3 overexpressing hepatoma cells. Hepatoma cell lines were treated with cetuximab, NSC 74859 or a combination of both drugs. Efficacy of treatment was evaluated by determining cell viability using MTT assays and proliferation by cell counting. Expression and activation of STAT3 were determined using Western blot analysis. We evaluated the role of STAT3 in single and combination therapy using siRNA-mediated knock-down of STAT3 or STAT3 overexpression strategies. HepG2 and Huh-7 cells, which had lower levels of pSTAT3 than SK-HEP1 cells, were more sensitive to cetuximab treatment when compared with SK-HEP1 cells. Although none of these cell lines was sensitive to NSC 74859 alone, NSC 74859 potentiated the antiproliferative effect of cetuximab in all three cell lines. siRNA knock-down of STAT3 increased the sensitivity of these cell lines to cetuximab, whereas STAT3 overexpression antagonized these effects. Enhanced growth inhibition in hepatoma cells treated with both NSC 74859 and cetuximab suggests that cetuximab resistance is probably mediated via STAT3. Combination therapy using both inhibitors of EGFR and STAT3 signalling warrants further investigation under in vivo condition.

Adding to the toolbox: Receptor tyrosine kinases as potential targets in the treatment of hepatitis C

Adding to the toolbox: Receptor tyrosine kinases as potential targets in the treatment of hepatitis C

Association Between Single Nucleotide Polymorphisms in the Cyclooxygenase-2, Tumor Necrosis Factor-α, and Vascular Endothelial Growth Factor-A Genes, and Susceptibility to Hepatocellular Carcinoma

Cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), and tumor necrosis factor-α (TNF-α) are mediators of inflammation and angiogenesis; all of them are produced in liver cirrhosis (LC) and in hepatocellular carcinoma (HCC). It was proposed that there is an association between single nucleotide polymorphisms (SNPs) and HCC. These allelic variants influence the transcriptional activity of these genes, and therefore the proteins levels. The VEGF-A pathway is a potential therapeutic target in HCC, and several antiangiogenic agents have entered clinical trials in HCC. We evaluated the frequency of SNPs of COX-2, TNF-α, and VEGF-A genes in patients with HCC versus LC patients and a control group. The aim of this article was to verify the correlation between the allelic variations and the risk of developing HCC. The study included 96 HCC, 79 LC patients, and 162 healthy subjects. The evaluation of SNPs was performed by the restriction fragment length polymorphism (RFLP-PCR) method. The SNPs analyzed were: -1195 G>A of the COX-2 gene, -308 G>A of the TNF-α gene, and +936 C>T of the VEGF-A gene. Chi-square and Fisher exact tests were used for statistical analysis. Our results confirm that carriers with the C allele in the VEGF-A gene are more frequent in HCC versus LC (p=0.039), suggesting that this SNP may predispose to the development of HCC.

Abstract 2917: Novel function of androgen receptor: Cancer suppressor in hepatocellular carcinoma

Abstract Purpose: Hepatocellular Carcinoma (HCC) is one of the most malignant cancers worldwide. Due to the male prevalence of HCC, androgen signals have been suspected to be involved in the disease process. Although it has been known for the past five decades that androgens promote HCC progression, failure of antiandrogens in HCC clinical trials puzzled the field. Increasing evidences implied that androgen/AR signals might function differently during cancer progression. Therefore, it is necessary to examine the roles of AR in late stage HCC progression. Methods: Immunohistological staining on patient HCC tissues were performed. Using conditional knockout of AR specifically in the hepatocyte (h-ARKO), we characterized the pathophysiological function of AR in HCC. Cancer survival, pathological malignancy, and cancer metastasis was measured in the late stage of cancer development (40∼60-wks). Results: To our surprise, the h-ARKO mice exhibited poorer survival, malignant histological tumor patterns, and higher lung metastasis rates. Moreover, we found less collagen deposition, and higher cellular proteolysis activity in the h-ARKO mice tumors compared to wild type mice implicating invasive characteristic in the h-ARKO tumors. We further validated the mechanism that AR could suppress cancer progression through multiple pathways. We found AR functions as p38 phosphorylation suppressor while p38 phosphorylation increasing by cancer malignancy so that to obtain cell anoikis resistance. Therefore, androgen/AR signals enhance cell anoikis. We also found AR suppressed cancer cells invasion via suppression of MMP9 transcription. We further demonstrated that MMP9 suppression was through NFκB deactivation in the HCC cells. This is the first report that AR functions as cancer suppressor in late stage of cancer development. Furthermore, we demonstrated a potential application of this finding for HCC therapy. We introduced the combination therapy concept that using low doses of Sorafenib (multiple kinase inhibitor that pass clinical trials) and expression of AR in the HCC cells or metastasis mice model. It's exciting that AR could synergistically facilitate Sorafenib effects to increase cell anoikis and suppress cell invasion. Combination therapy in the mice metastasis model pertain more metastasis-free and better cancer survival in the mice. Conclusion: This study revealed the biphasic, yet, opposite functions of AR in HCC progression. It not only explained the failure of antiandrogen in HCC therapy, but also implicated a critical timing of using anti-Androgen/AR signals. Last, our hypothetical preclinical trial shed a light on future medicine for late stage HCC therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2917.

Modified RECIST (mRECIST) Assessment for Hepatocellular Carcinoma

The endpoint in cancer research is overall survival. Nonetheless, other potential surrogate endpoints, such as response rate and time to progression, are currently used. Measurement of response rate in hepatocellular carcinoma (HCC) has become a controversial issue. The World Health Organization (WHO) criteria underestimate the actual response rate; thus, they were amended in 2000 by a panel of experts convened by the European Association for the Study of the Liver (EASL) to take into account treatment-induced tumor necrosis. Applying these guidelines, there was an association between response rate and outcome prediction. More recently, the Response Evaluation Criteria in Solid Tumors (RECIST) guideline was proposed as a method for measuring treatment response based on tumor shrinkage, which is a valuable measure of antitumor activity of cytotoxic drugs. This method was initially adopted by regulatory agencies, such as the U.S. Food and Drug Administration (FDA), for drug approval. However, anatomic tumor response metrics can be misleading when applied to molecular-targeted therapies or locoregional therapies in HCC. In 2008, a group of experts convened by the American Association for the Study of Liver Diseases (AASLD) developed a set of guidelines aimed at providing a common framework for the design of clinical trials in HCC and adapted the concept of viable tumor-tumoral tissue showing uptake in arterial phase of contrast-enhanced radiologic imaging techniques-to formally amend RECIST. These amendments conformed the AASLD-JNCI (Journal of the National Cancer Institute) guidelines and are summarized and clarified in the current article. They are referred to herein as the modified RECIST assessment (mRECIST). Further studies are needed to confirm the accuracy of this measurement compared with conventional gold standards such as pathologic studies of explanted livers.

A meta‐analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma†

Knowing the spontaneous outcome of hepatocellular carcinoma (HCC) is important for designing randomized controlled trials (RCTs) of new therapeutic approaches; however, survival of patients in the absence of treatment is highly variable, and prognostic factors influencing outcomes are incompletely defined. The aims of this meta-analysis were to estimate the 1-year and 2-year survival rates of untreated HCC patients enrolled in RCTs of palliative treatments, and to identify prognostic factors. RCTs evaluating therapies for HCC with placebo or no-treatment arms were identified on MEDLINE through April 2009. Data were combined in a random effect model. Primary outcomes were 1-year and 2-year survival. Thirty studies met the inclusion criteria. The pooled estimates of the survival rates were 17.5% at 1 year (95% confidence interval [95%CI], 11%-27%; range, 0%-75%) and 7.3% at 2 years (95%CI, 3.9%-13%; range, 0%-50%). Heterogeneity among studies was highly significant (P < 0.0001) both for 1-year and 2-year survival, and persisted when RCTs were stratified according to all patient and study features. Through meta-regression, impaired performance status, Child-Pugh B-C class, and presence of portal vein thrombosis were all independently associated with shorter survival. Ascites was strongly linked to a worse outcome in intermediate/advanced Barcelona Clinic Liver Cancer stages. This meta-analysis confirms the heterogeneity of behavior of untreated HCC and provides a sound basis for stratifying patients with HCC according to expected survival in future trials of new anti-cancer agents.

Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

The insulin-like growth factor (IGF) signaling axis is frequently dysregulated in hepatocellular carcinoma (HCC). Therefore, we investigated whether the specific targeting of the IGF type 1 receptor (IGF-1R) might represent a new therapeutic approach for this tumor. Total and phosphorylated levels of IGF-1R were measured in 21 paired samples of human HCCs and adjacent nontumoral livers using ELISA. The antineoplastic potency of a novel anti-IGF-1R antibody, AVE1642, was examined in five human hepatoma cell lines. Overexpression of IGF-1R was detected in 33% of HCCs and increased activation of IGF-1R was observed in 52% of tumors. AVE1642 alone had moderate inhibitory effects on cell viability. However, its combination with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, induced supra-additive effects in all cell lines that were associated with cell cycle blockage and inhibition of AKT phosphorylation. The combination of AVE1642 with rapamycin also induced a synergistic reduction of viability and of AKT phosphorylation. Of marked interest, AVE1642 alone up-regulated the phosphorylated and total levels of HER3, the main partner of EGFR, and AVE1642-induced phosphorylation of HER3 was prevented by gefitinib. Moreover, the down-regulation of HER3 expression with siRNA reduced AKT phosphorylation and increased cell sensitivity to AVE1642. These findings indicate that hepatoma cells overcome IGF-1R inhibition through HER3 activation in an EGFR-dependent mechanism, and that HER3 represents a critical mediator in acquired resistance to anti-IGF-1R therapy. These results provide a strong rational for targeting simultaneously EGFR and IGF-1R in clinical trials for HCC].

Spontaneous regression of hepatocellular carcinoma: a systematic review

To estimate the actual frequency of spontaneous regression of hepatocellular carcinoma. A systematic review of the literature published during 1978-2007 has been carried out to identify randomized clinical trials of hepatocellular carcinoma that included a control arm receiving either placebo or best supportive care, and in which patients were followed prospectively for tumor response using predefined criteria. Data extraction was conducted independently by two investigators. A meta-analysis to provide a global estimation of regressions in the control arms was performed using an empiric Bayesian random-effects model. We identified 16 cases of regression (including minor and partial responses) in 10 phase III clinical trials. The rate of spontaneous objective partial regression among patients with hepatocellular carcinoma was 0.406% [95% confidence interval: 0.067-1.043%]. Although very infrequent, spontaneous regression is not an extraordinary event among patients with hepatocellular carcinoma. Therefore, individual responses to any given therapy should be assessed with caution and this fact may be considered at the time of calculating sample size of pilot clinical trials of new agents.

Re: Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma

Re: Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma

Re: Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma

Re: Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma

Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma

The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway. The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model. Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade. MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.

Choosing the best endpoint

Design and endpoints of clinical trials in hepatocellular carcinoma. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; for the Panel of Experts in HCC-Design Clinical Trials.The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC.[Abstract reproduced by permission of J Natl Cancer Inst 2008;100:698–711.]Link to free abstract at: http://jnci.oxfordjournals.org/cgi/content/abstract/100/10/698

Molecular targeted therapies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of this complex disease and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived growth factor receptor, and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time-to-progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug responsiveness will lead to a more personalized medicine.

New Proposed Guidelines for Clinical Trials in Liver Cancer

An expert panel convened by the American Association for the Study of Liver Diseases has developed a set of guidelines for clinical trials that test new therapies in patients with hepatocellular carcinoma (HCC), the most common liver tumor and the third leading cause of cancer-related death globally. Well-designed clinical trials are important for the assessment of any new therapy. That need is particularly acute in liver cancer, because the underlying liver disease that affects most of these patients can complicate interpretation of trial results. Additionally, heterogeneity of inclusion criteria and the development of new targeted agents pose challenges in this disease. A common agreement on trial design, endpoints, and classification of the disease is proposed.The new guidelines reported May 13 in the Journal of the National Cancer Institute specify that researchers should use time-to-event primary endpoints in phase II trials, but they should rely on overall survival as the main endpoint in phase III trials. Clinical endpoints that are most likely to be influenced by the underlying liver problems, such as progression- and disease-free survival, should be avoided. The panel also specifies what treatments should be used in the control arms for various stages of disease. Additionally, patient selection for the trials should be based on the Barcelona-Clinic Liver Cancer staging system, and new drugs should be tested initially on only patients who have good liver function.“These recommendations are intended to provide a framework as of 2008 that will evolve as new evidence becomes available, including more precise information on the natural history of HCC, novel therapies, and predictive biomarkers,” the authors write. “First, it should be established whether outcomes for a given tumor stage are equal in different geographic populations. Second, molecular classification might become clinically practical in the near future, and this might complicate trial design. The small number of centers and investigators currently involved in advanced clinical HCC research in comparison with other prevalent cancers is yet another challenge.” Because of the complexity of the disease, the panel recommends that the design and conduct of phase III trials “should be coordinated by centers with appropriate expertise in this specific cancer.”For more details, see “Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma,” J Natl Cancer Inst; advance access published online on May 13, 2008. An expert panel convened by the American Association for the Study of Liver Diseases has developed a set of guidelines for clinical trials that test new therapies in patients with hepatocellular carcinoma (HCC), the most common liver tumor and the third leading cause of cancer-related death globally. Well-designed clinical trials are important for the assessment of any new therapy. That need is particularly acute in liver cancer, because the underlying liver disease that affects most of these patients can complicate interpretation of trial results. Additionally, heterogeneity of inclusion criteria and the development of new targeted agents pose challenges in this disease. A common agreement on trial design, endpoints, and classification of the disease is proposed. The new guidelines reported May 13 in the Journal of the National Cancer Institute specify that researchers should use time-to-event primary endpoints in phase II trials, but they should rely on overall survival as the main endpoint in phase III trials. Clinical endpoints that are most likely to be influenced by the underlying liver problems, such as progression- and disease-free survival, should be avoided. The panel also specifies what treatments should be used in the control arms for various stages of disease. Additionally, patient selection for the trials should be based on the Barcelona-Clinic Liver Cancer staging system, and new drugs should be tested initially on only patients who have good liver function. “These recommendations are intended to provide a framework as of 2008 that will evolve as new evidence becomes available, including more precise information on the natural history of HCC, novel therapies, and predictive biomarkers,” the authors write. “First, it should be established whether outcomes for a given tumor stage are equal in different geographic populations. Second, molecular classification might become clinically practical in the near future, and this might complicate trial design. The small number of centers and investigators currently involved in advanced clinical HCC research in comparison with other prevalent cancers is yet another challenge.” Because of the complexity of the disease, the panel recommends that the design and conduct of phase III trials “should be coordinated by centers with appropriate expertise in this specific cancer.” For more details, see “Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma,” J Natl Cancer Inst; advance access published online on May 13, 2008.

Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma

The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC.

Assessment of health‐related quality of life and patient benefit as outcome measures for clinical trials in hepatocellular carcinoma

AbstractAim: The purpose of the study was to determine the feasibility and validity of using health‐related quality of life (HRQL) and patient benefit as outcome measures in a phase II trial of octreotide long acting release (LAR) for hepatocellular carcinoma (HCC); and, to determine aspects of HRQL that were most impaired and aspects that changed.Methods: Sixty‐three patients with advanced HCC were treated with octreotide LAR. HRQL was assessed monthly with the Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire (FACT‐Hep) and the Patient Disease and Treatment Assessment Form (Patient DATA Form). Benefit was assessed directly by asking subjects at 1 month about change from baseline using the Patient Benefit Form. Convergent, discriminative and predictive validity were assessed by testing a priori hypotheses.Results: Seventy‐three percent completed a baseline assessment of HRQL. Compliance decreased over time. Fatigue, energy, anxiety, pain, insomnia, and emotional well‐being were the most impaired aspects of HRQL on the Patient DATA Form. Convergent validity was supported by 52 of 57 hypothesized correlations. Predictive validity was supported by associations between survival and four aspects of HRQL. Patients' direct assessments of benefit for common symptoms were moderately associated with changes in their scores on the Patient DATA Form.Conclusion: Use of the FACT Hep and Patient DATA Form is feasible in trials of advanced HCC. The validity of the direct measure of patient benefit was questionable, despite its intuitive attraction. Fatigue, anxiety, insomnia, and impaired emotional well‐being were prominent, are probably under‐recognized in practice, and are worthy of future research.

Reversing Hepatocellular Carcinoma Progression by Using Networked Biological Therapies

The liver is distinguished from other tissues by (a) its detoxifying function, (b) its resistance to apoptosis, and (c) its regenerative response to damage. Hepatocellular carcinoma arises when chronic insults, such as hepatitis or iron overload, constitutively activate this regenerative program. Here, we propose that the proliferative response of the liver to damage underlies the resistance of hepatocellular carcinoma to cytotoxic therapy, and that hepatocellular carcinoma growth should therefore be more readily controlled by using a networked combination of noncytotoxic interventions to interrupt the damage-inducible regenerative pathway. To this end, hepatocellular carcinoma boasts a wealth of potential drug targets, including viral replication, the antiapoptotic immunosuppressant alpha-fetoprotein, hepatic iron overload, inflammatory signaling, extracellular proteases, and growth factors. By blocking these positive feedback loops in parallel, and so returning the host environment to a more normal state, epigenetic repression of tumor-suppressor gene function may be reversed and tumor dormancy restored. Noncytotoxic maneuvers that short circuit damage resistance loops may thus represent an indirect form of gene therapy meriting incorporation into hepatocellular carcinoma clinical trials.

Endpoints in Clinical Trials for Hepatocellular Carcinoma

Endpoints in Clinical Trials for Hepatocellular Carcinoma

Endpoints in Clinical Trials for Hepatocellular Carcinoma

Endpoints in Clinical Trials for Hepatocellular Carcinoma