Is the efficacy of sorafenib treatment in patients with hepatocellular carcinoma affected by age?

Cancer is a prevalent disease in the elderly population and hepatocellular carcinoma (HCC) is a major health problem among all tumors. Curative treatments for early-stage include liver transplantation, resection and percutaneous ablation. Transarterial chemoembolization (TACE) and sorafenib, classified as non-curative treatments, can improve survival for patients with intermediate and advanced tumors, respectively. Even if the incidence of HCC progressively increases with advanced age in all populations, reaching a peak at 70 years, few reports concerning correct management of HCC in elderly patients exist. Moreover, data from large randomized controlled trials (RCT) poorly reflect the elderly population that is often quantitatively and qualitatively underrepresented, as a result of the presence of tight enrolment criteria. The aim of this brief review is to highlight the main concerns, pitfalls and warnings regarding the management of HCC in elderly patients, with particular focus on systemic therapy with sorafenib.     

Iron facilitator LS081 reduces hypoxia-inducible factor-1α protein and functions as anticancer agent in hepatocellular carcinoma

Hypoxia inducible factor-1α (HIF-1α) has a central role in cellular oxygen-sensing, and its overexpression in many types of cancer is considered important in tumor progression. Thus, targeting HIF-1α production and activity has been of great therapeutic interest. In normoxic conditions, HIF-1α is hydroxylated by oxygen-dependent prolyl-hydroxylases, which require ferrous iron for its activity. The tumor suppressor protein von Hippel Lindau binds to the hydroxylated HIF-1α, which is then ubiquitinated and degraded by proteasomes. We focused on the physiological degradation machinery of HIF-1α mediated by prolyl hydroxylases. Previously, we identified a small molecule, LS081, that is capable of stimulating iron uptake into cells. In the present study, we aimed to inhibit the expression of HIF-1α protein and growth of hepatocellular carcinoma by using the iron-facilitating activity of LS081. In the human hepatocellular carcinoma cell lines Hep3B and HepG2, a combination of LS081 and ferric ammonium citrate (LS081/FeAC) inhibited HIF-1α protein expression but did not inhibit HIF-1α mRNA expression. A mutated HIF-1α protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS081 and FeAC. Furthermore, the iron-facilitating activity of LS081 resulted in Hep3B and HepG2 growth inhibition in vitro and in vivo. These results indicate that the iron-facilitating activity of LS081 inhibits HIF-1α expression through prolyl-hydroxylation of HIF-1α and might have a therapeutic effect in the treatment of hepatocellular carcinoma.     

Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells

Rho, a Ras-related small GTPase, and Rho-associated coiled coil-containing protein kinase (Rho kinase, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. Rho/ROCK kinases also play roles in proliferation, differentiation, apoptosis and oncogenic transformation. In the present study, we have shown that Rho/ROCK pathway inhibition by fasudil, an orally administered inhibitor of Rho kinases, enhanced cisplatin-induced growth inhibition and apoptosis in human ovarian cancer cell lines. Fasudil inhibited hypoxia inducible factor (HIF)-1α protein expression. Knockdown of RhoA, ROCK1 or ROCK2 also attenuated the expression of HIF-1α. Furthermore, knockdown of HIF-1α using small interfering RNA enhanced cisplatin-induced growth inhibition and apoptosis as did inhibition of the Rho/ROCK pathway by fasudil, the Rho/ROCK inhibitor Y27632, or by Rho/ROCK knockdown. Therefore, the Rho/ROCK pathway may modulate HIF-1α signal transduction and blockade of Rho/ROCK enhances the efficacy of cisplatin by inhibiting HIF-1α in ovarian cancer cells. Our findings suggested that the Rho/ROCK pathway may be a new target for molecular targeting therapies against ovarian cancer.     

No synergistic activity of epirubicin and interferon-α2b in the treatment of hepatocellular carcinoma

Single-agent activity for anthracyclines reflected by response rates of 10%–30% has been reported in patients with advanced hepatocellular carcinoma (HCC). Preclinical data indicate that -interferon could enhance the cytotoxic activity of the anthracycline Adriamycin or its analog epirubicin. In a phase I/II study, 31 patients with biopsy-proven inoperable HCC were treated with interferon-2b given s. c. at a dose of 3×10⁶ units/m² per day for 5 days per week plus weekly epirubicin given at 25 mg/m² as an i. v. bolus. The protocol called for 4 consecutive weeks of treatment followed by 1 week off treatment. In all, 15 patients had been previously treated; 6 patients had failed hormonal therapy (tamoxifen), 5 patients had failed prior anthracycline treatment, and 4 patients had received chemoembolization of the tumor and had subsequently progressed. A total of 30 patients were evaluable for response. In all, 1 patient (3%) achieved a partial response for 8+ months and 11 patients (35%) achieved stabilization of disease. Six patients had a fall in alpha-fetoprotein (AFP) values of >50% during therapy. The median survival for all patients was 9.5 months (range, 3–34+ months). The main side effects were hematological toxicity and fever, both of which were considered tolerable. As an indicator of the immunostimulatory effects of interferon, an elevation in serum markers of inflammation [C-reactive protein (CRP), ₂-microglobulin] was found in 15%–20% of patients. All patients had measurable Mx protein production during therapy, but these effects were not correlated to the clinical response. The clinical response rate achieved in this trial indicates that the combination of interferon and epirubicin, at least when used on the schedule reported herein, is not superior to treatment with either agent alone for patients with advanced HCC. However, single patients achieved a prolonged progression-free interval (8–10+ months) on this therapy, and it may therefore be an option for patients who have failed prior hormonal or single-agent anthracycline therapy.     

Abnormal expression of hypoxia inducible factor-1α and clinical values of molecular-targeted interference in hepatocellular carcinoma

Objective  

The aim of this study was to analyze the expression features of hypoxia inducible factor-1α (HIF-1α) in hepatocellular carcinoma (HCC) and effects of HIF-1α silencing on HepG2 cells.     

Clinicopathological and prognostic significance of hypoxia-inducible factor-1α in esophageal squamous cell carcinoma: a meta-analysis

Published literatures on the prognostic value of hypoxia-inducible factor-1α (HIF-1α) overexpression in esophageal squamous cell carcinoma (ESCC) are conflicting and heterogeneous. We performed a meta-analysis to more precisely evaluate the clinicopathological and prognostic value of HIF-1α in patients with ESCC. Searches were applied to MEDLINE, Pubmed, Embase, Cochrane Library, Web of Science, and Chinese BioMedical Literature Databases until September 10, 2013, without language restrictions. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were used to estimate the effects. Twelve studies with 942 ESCC patients were selected to evaluate the correlation between HIF-1α and overall survival (OS), disease-free survival (DFS), response to chemoradiation (RC), and clinicopathological features. HIF-1α overexpression was significantly associated with poor OS (HR 1.78, 95 % CI 1.41–2.24), DFS (HR 1.91, 95 % CI 1.15–3.18), and RC (HR 3.56, 95 % CI 1.68–7.53). Besides, HIF-1α overexpression was significantly associated with stage (OR 2.90, 95 % CI 1.97–4.27), lymph node metastasis (OR 1.86, 95 % CI 1.39–2.49), depth of invasion (OR 2.45, 95 % CI 1.24–4.86), lymphatic invasion (OR 2.28, 95 % CI 1.46–3.56), distant metastasis (OR 2.04, 95 % CI 1.19–3.50), and vascular endothelial growth factor (OR 3.67, 95 % CI 1.81–7.46). Our results indicate that HIF-1α overexpression can potently predict the poor prognosis and chemoradiation resistance for ESCC. Large prospective studies with multivariable survival analyses are now needed to confirm the clinical utility of HIF-1α as an independent prognostic marker.     

A phase II study evaluating the tolerability and efficacy of CAELYX (liposomal doxorubicin, Doxil) in the treatment of unresectable pancreatic?carcinoma

Background:Preclinical studies of liposomal doxorubicin(CAELYX^TM) have demonstrated significant inhibition of growthof human pancreatic cancer explants in nude mice. This study evaluatedthe efficacy of CAELYX^TM in chemotherapy-naïve patientswith unresectable, histologically confirmed pancreatic carcinoma.Secondary endpoints were quality of life (QOL), time to progression andoverall survival. Patients and methods:Twenty-twopatients (median age 65) were enrolled. CAELYX^TM wasadministered to the first five patients at a dose of 30 mg/m²three-weekly. Two of these patients were dose escalated to 50mg/m² four-weekly. Subsequent patients were all treated onthe latter schedule. Results:Two patients died afterconsenting to enter the study but before treatment was commenced and arenot included in the analysis. Sixteen patients were evaluable forresponse. No objective responses were seen. Six patients had stabledisease. One patient experienced grade 4 toxicity with palmar plantardysaesthesia (PPE), but continued treatment after dose reduction anddelay. Four patients experienced grade 3 stomatitis and two grade 3nausea. Median survival from time of starting chemotherapy was 3.2months (range 21 days to 19 months) and one year survival was10%. Eight patients completed at least two EORTC QLQ C-30questionnaires. There was no significant change in either global QOL orin any functional or symptom subscale score. Conclusion:No objective responses were seen with CAELYX in this study.CAELYX^TM was however associated with stable disease, but datawere inconclusive with regard to clinical benefit. It warrants furtherinvestigation in the context of combination trials.     

No association of the hypoxia-inducible factor-1α gene polymorphisms with survival in patients with colorectal cancer

Hypoxia-inducible factor-1 (HIF-1) is the key regulator of cellular response to hypoxia and presumably plays a central role in the control of tumor growth. The present study analyzed polymorphisms of HIF-1α gene and their impact on the prognosis for patients with colorectal cancer. Four hundred and forty-five consecutive patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue, and 2 polymorphisms of HIF-1α gene (HIF-1α C1772T and HIF-1α G1790A) determined using a real-time PCR genotyping assay. The 2 HIF-1α gene polymorphisms were successfully amplified, and the frequencies of each genotype are as follows: [C1772T: CC (92.1%), CT (7.9%); G1790A: GG (93.0%), GA (7.0%)]. Survival analysis including stage, age, site of disease, and CEA level showed that these polymorphisms were not associated with survival. For the clinicopathologic parameters, CEA level and TNM stage were significant prognostic factors in a Cox model for survival. HIF-1α gene polymorphisms investigated in this study were not found to be an independent prognostic marker for Korean patients with surgically resected colorectal cancer. However, further studies are warranted to clarify the role of HIF-1α gene polymorphisms as a prognostic biomarker for colorectal cancer patients.     

Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

Introduction: The increasing knowledge of the genomic landscape of hepatocellular carcinoma (HCC) and the development of molecular targeted therapies are a promising background for increasing the number of effective drugs for HCC patients. In recent years, many new drugs have been tested as an alternative to sorafenib or after sorafenib failure.

Areas covered: In this review, our aim is to describe the randomized trials recently conducted in HCC patients, in order to understand the main reasons potentially related to the failures of many drugs. In addition, we briefly describe the main ongoing trials, that could potentially change the scenario of HCC treatment in the next years.

Expert commentary: Heterogeneity of study populations, lack of understanding of critical drivers of tumor progression, risk of liver toxicity associated with experimental agents, ?aws in trial design and marginal antitumoral potency can be considered the main reasons for failure of phase III clinical trials in HCC. Most ongoing trials are conducted without any molecular selection criteria, although many drugs could be probably better tested in a molecularly selected population. The knowledge of potential predictive factors for drug efficacy in patients with advanced HCC could improve the chance of obtaining positive results in clinical trials.     

The efficacy of combined treatment with recombinant human tumor necrosis factor-α and 5-fluorouracil is dependent on the development of capillaries in tumor

The antitumor effects of recombinant/human tumor necrosis factor-α (rTNF-α) and 5-fluorouracil (5-FU) in combination treatment were examined on Meth A fibrosarcoma implanted intradermally in mice. Growth of the tumor was inhibited when rTNF-α was given i.v. on day 7 or 11 after implantation, but the effect was countered when 5-FU was additionally given i.p. once a day on days 1–4 after implantation. Conversely, 5-FU given on days 5–8 after implantation augmented the antitumor effects of rTNF-α. Injection of carbon particles showed that fine capillaries did not develop in the tumors of mice treated with 5-FU on days 1–4 after implantation, but that a delicate network of capillaries developed in the tumors of both the mice treated with 5-FU on days 5–8 after implantation and the controls given saline. The results show that the timing of 5-FU treatment is important when attempting to enhance the antitumor effects of rTNF-α, and suggest that these effects are directly associated with newly formed fine capillaries in the tumor.