Targeted agents for the systemic treatment of advanced hepatocellular carcinoma

The prognosis for advanced hepatocellular carcinoma is poor and systemic therapy has historically been of limited benefit. However, novel targeted agents offer promise in improving patient outcomes. In a recent phase III study the oral multi-tyrosine kinase inhibitor sorafenib was demonstrated to have a survival advantage over a placebo in advanced hepatocellular carcinoma. Similar efficacy was demonstrated in a phase III trial limited to an Asian–Pacific group of patients. While these results are encouraging, it is vital to make further progress. In this review we examine current knowledge of targeted agents in advanced hepatocellular carcinoma. We also address some of the key issues that require exploration regarding the use of targeted agents in advanced hepatocellular carcinoma.     

Genetic predisposition of hand‐foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma

BACKGROUND:

Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand‐foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib‐induced HFSR and genetic polymorphisms in Korean patients with HCC.

METHODS:

For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor‐alpha (TNF‐α) were measured using enzyme‐linked immunosorbent assays before therapy and 1 month after therapy.

RESULTS:

During a median treatment period of 18 months, 55 patients (93%) developed sorafenib‐induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF‐α ?308GG, VEGF ?94GG, VEGF 1991CC, VEGF IVS3‐28CC, and uridine diphosphate glucuronosyltransferase 1 family‐polypeptide A9 (UGT1A9) IVS1‐37431AA were associated significantly with the development of high‐grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF‐α ?308GG (odds ratio, 44.1), and UGT1A9 IVS1‐37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high‐grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF‐α level measured 1 month after sorafenib therapy was correlated significantly with the development of high‐grade HFSR (odds ratio, 3.56; P = .026).

CONCLUSIONS:

Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF‐α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF‐α after sorafenib therapy. Cancer 2013. © 2012 American Cancer Society.     

VEGF及其受体与肝细胞癌血管生成和抗血管治疗研究进展

肝细胞癌(hepatocellular carcinoma,HCC)发生发展与肿瘤血管生成密切相关,而血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体能直接或间接参与肝癌血管生成,且具有很强的促进作用,在肝癌的发生、发展及预后中扮演着极其重要的角色。近年来,以VEGF及其受体为靶点的肿瘤抗血管治疗是HCC治疗研究的热点。本文复习近十年相关文献,对VEGF及其受体与HCC肿瘤血管生成和HCC抗血管治疗相关研究进展作简要综述。     

Phase 2 trial of linifanib (ABT-869) in patients with advanced renal cell cancer after sunitinib failure

Purpose

This study assessed the efficacy and safety of linifanib in patients with advanced renal cell carcinoma (RCC) who were previously treated with sunitinib.

Materials and methods

This open-label, multicentre, phase 2 trial of oral linifanib 0.25 mg/kg/day enrolled patients who had prior nephrectomy and adequate organ function. The primary end-point was objective response rate (ORR) per response evaluation criteria in solid tumors (RECIST) by central imaging. Secondary end-points were progression-free survival (PFS), overall survival (OS) and time to progression (TTP). Safety was also assessed.

Results

Fifty-three patients, median age 61 years (range 40-80) were enrolled (August 2007 to October 2008) across 12 North-American centres. Median number of prior therapies was 2 (range 1-4); 43 patients (81%) had clear-cell histology. ORR was 13.2%, median PFS was 5.4 months (95% Confidence Interval (CI): 3.6, 6.0) and TTP was the same; median OS was 14.5 months (95% CI: 10.8, 24.1). The most common treatment-related adverse events (AEs) were diarrhoea (74%), fatigue (74%) and hypertension (66%), and the most common treatment-related Grade 3/4 AE was hypertension (40%).

Conclusions

Linifanib demonstrated clinically meaningful activity in patients with advanced RCC after sunitinib failure. At 0.25 mg/kg/day, significant dose modifications were required. An alternative, fixed-dosing strategy is being evaluated in other trials.     

Pro‐angiogenic TIE‐2‐expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma

Sorafenib, a multi‐kinase inhibitor, inhibits tumor angiogenesis and is the first‐line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE‐2‐expressing monocytes (TEMs) to predict the response in sorafenib‐treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51–48.16, p = 0.015] and Child‐Pugh class (HR = 5.59, 95% CI = 1.06–29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib‐treated patients with advanced HCC.     

Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer

BACKGROUND:

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC).

METHODS:

Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2‐stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point.

RESULTS:

Twenty‐seven patients with advanced HCC (median age, 60 years) were enrolled in this multi‐institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8‐7.1). Median survival time was 9.5 months (95% CI, 7.1‐17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea.

CONCLUSIONS:

In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression‐free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. Cancer 2012. © 2011 American Cancer Society.     

Urocortin's inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2

Urocortin (UCN) functions via corticotrophin-releasing factor receptors (CRFRs), CRFR1 & 2. CRFR2 is reported to be a tonic suppressor of vascularization, implying its role in tumor angiogenesis. Here, it was found that UCN inhibited the growth of hepatocellular carcinoma (HCC) and reduced tumor microvessel density in nude mice. Hepatoma cells didn't express CRFRs whereas vessels expressed CRFRs, mainly CRFR2. In vitro three-dimensional culture assay showed UCN inhibited angiogenesis, this effect was abolished by CRFR2 antagonist, anti-sauvagine-30, demonstrating involvement of CRFR2. Furthermore, UCN inhibited the proliferation and promoted the apoptosis of endothelial cells and down-regulated VEGF expression in vivo via CRFR2.     

Vascular endothelial growth factor in the management of hepatocellular carcinoma

The importance of tumor angiogenesis in tumor biology is now widely accepted. Hepatocellular carcinoma (HCC) is a highly vascular tumor, and angiogenesis is believed to play a considerable role in its development and progression. The authors reviewed the role of circulating vascular endothelial growth factor (VEGF) in screening for HCC and in risk stratification and treatment monitoring. They searched the world medical literature by accessing MEDLINE and PubMed for articles on: 1) the utility of circulating VEGF for HCC screening in patients with cirrhosis; 2) the role of circulating VEGF as a predictor of the invasive potential of HCC; and 3) monitoring anti‐HCC treatment effects by serial measurements of circulating VEGF. They found evidence to support a potential role for VEGF in screening and surveillance of HCC. They also found support for developing the use of VEGF in the monitoring of treatment outcomes. Several studies suggested that the circulating VEGF level may be an independent prognostic marker in HCC. Further studies are needed to determine the utility of circulating VEGF in screening of patients with cirrhosis and to determine its potential role as a prognostic and predictive biomarker in patients with HCC. Cancer 2009. © 2009 American Cancer Society.     

Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma

BACKGROUND: Growth factor overexpression, including epidermal growth factor receptor (EGFR) expression, is common in hepatocellular cancers. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR. The primary objective of this study was to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression-free (PFS) at 16 weeks of continuous treatment. METHODS: Patients with unresectable HCC, no prior systemic therapy, performance status (PS) of 0, 1, or 2, and Childs-Pugh (CP) cirrhosis A or B received oral erlotinib 150 mg daily for 28-day cycles. Tumor response was assessed every 2 cycles by using Response Evaluation Criteria in Solid Tumors (RECIST; National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Md) criteria. Patients accrued to either "low" or "high" EGFR expression cohorts; each cohort had stopping rules applied when there was a lack of efficacy. RESULTS: Forty HCC patients were enrolled. Median age was 64 years (range, 33-83 years), sex distribution was 32 males and 8 females, performance scores were 40% PS 0, 55% PS 1, Childs-Pugh distribution was 75% A and 20% B. There were no complete or partial responses; however, 17 of 40 patients achieved stable disease at 16 weeks of continuous therapy. The PFS at 16 weeks was 43%, and the median overall survival (OS) was 43 weeks (10.75 months). No patients required dose reductions of erlotinib. No correlation between EGFR expression and outcome was found. CONCLUSIONS: Results of this study indicated that single-agent erlotinib is well tolerated and has modest disease-control benefit in HCC, manifested as modestly prolonged PFS and OS when compared with historical controls.     

Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma

BACKGROUND: Epidermal growth factor receptor (EGFR) and ligand expression is frequently seen in hepatocellular carcinoma (HCC). A phase 2 study was performed with cetuximab, a chimeric monoclonal antibody that binds specifically to EGFR, in patients with advanced HCC. METHODS: Eligibility criteria included unresectable or metastatic measurable HCC, an Eastern Cooperative Oncology Group performance status 相似文献   

Dickkopf-1 promotes angiogenesis by upregulating VEGF receptor 2-mediated mTOR/p70S6K signaling in hepatocellular carcinoma

The expression of Dickkopf-1 (DKK1), a negative regulator of the Wnt/β-catenin signaling pathway, is upregulated in hepatocellular carcinoma (HCC). Here, we investigated the tumorigenic and angiogenic potential of DKK1 in HCC. Stable cell lines were established using the clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease 9 (CRISPR/Cas9)-based DKK1 knock-out system in Hep3B cells and the tetracycline-based DKK1 inducible system in Huh7 cells. Multicellular tumor spheroids (MCTSs) were cultured using Hep3B stable cells. We also employed xenografts generated using Hep3B stable cells and transgenic mouse models established using hydrodynamic tail vein injection. The angiogenic potential increased in HUVECs treated with CM from Huh7 stable cells with high DKK1 expression and Hep3B wild-type cells. DKK1 accelerated the downstream molecules of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated mTOR/p70 S6 kinase (p70S6K) signaling. MCTSs generated using Hep3B wild-type cells promoted compact spheroid formation and increased the expression of CD31 and epithelial-mesenchymal transition (EMT) markers, and increased the VEGFR2-mediated mTOR/p70S6K signaling, compared to the controls (all P<0.01). Xenograft tumors generated using Hep3B cells with DKK1 knock-out (n=10) exhibited slower growth than, the controls (n=10) and the expression of Ki-67, VEGFR2, CD31 and EMT markers decreased (all P<0.05). In addition, forced DKK1 expression with HRAS in transgenic mouse livers (n=5) resulted in the formation of more tumors and increased expression of downstream molecules of VEGFR2-mediated mTOR/p70S6K signaling pathway as well as Ki67, CD31 and EMT markers (P<0.05), compared to that of the controls (n=5). Our findings indicate that DKK1 facilitates angiogenesis and tumorigenesis by upregulating VEGFR2-mediated mTOR/p70S6K signaling in HCC.     

Relationship of ethnicity and overall survival in patients treated with sorafenib for advanced hepatocellular carcinoma

Background

Although both the SHARP and the Asian-Pacific trials showed improved overall survival (OS) for sorafenib, the magnitude of benefit was substantially less for Asians, who have a higher prevalence of hepatitis B viral (HBV) infection. Whether the worse prognosis is related to ethnicity or to the etiology of hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to identify prognostic factors among patients with HCC who received sorafenib in British Columbia (BC), which has a sizeable Asian population.

Methods

A total of 255 consecutive patients with advanced HCC who initiated sorafenib from January 2008 to February 2013 were identified using our pharmacy database. Clinicopathological variables and outcomes were retrospectively collected. Prognostic factors were assessed by univariate and multivariate analyses.

Results

Median age was 63 years, 80.2% were men, and 38% were Asian. Among them, 34.5% had HBV and 29.8% had hepatitis C viral (HCV) infection. In addition, 68.6% had cirrhosis and 45.9% had liver-limited disease. Median progression-free and OS were 3.7 [95% confidence interval (CI): 3.3-4.2] and 7.5 months (95% CI: 5.7-9.2), respectively. On multivariate analysis, Eastern Cooperative Oncology Group performance status (ECOG PS) and HCV positivity correlated with better OS (P<0.001 and 0.04, respectively), but ethnicity did not (P=0.622).

Conclusions

When treated with sorafenib at the same institution, Asians and Caucasians with advanced HCC had similar OS. ECOG PS and HCV were the only significant prognostic factors. A higher proportion of HCV positivity might explain why the SHARP trial achieved better OS when compared to the Asian-Pacific trial.     

Sorafenib continuation or discontinuation in patients with unresectable hepatocellular carcinoma after a complete response

Aims

To assess the efficacy of continued administration of sorafenib for patients with unresectable hepatocellular carcinoma (HCC) treated with local regional therapy (LRT) after a complete response (CR), also, the adverse events of sorafenib after discontinuation of administration were observed.

Methods

Between April 2008 and May 2012, 956 consecutive patients with unresectable HCC treated with LRT (transarterial chemoembolization, radiofrequency ablation) combined with sorafenib were retrospectively investigated. Of these, 157 patients with a CR were enrolled: 102 of them continued to receive sorafenib (test group) and the other 55 stopped receiving sorafenib (control group).

Results

The median recurrence-free survival (RFS), post-complete response overall survival (pOS) and overall survival (OS) in the test and control groups were 11 months (95% CI: 6.1, 15.9), 25 months (95% CI: 20.7, 29.3) and 33 months (95% CI: 29.2, 36.8) and 12 months (95% CI: 10.4, 13.6), 28 months (95% CI 24.2, 31.8) and 34 months (95% CI: 30.8, 37.2) respectively. The differences in RFS, pOS and OS between the groups were not significant (P = 0.768, 0.797 and 0.730, respectively). The adverse events related to sorafenib resolved after discontinuation of administration and the quality of life (QoL) scores improved.

Conclusions

Patients with unresectable HCC who achieved a CR did not benefit from continued sorafenib in terms of RFS, pOS or OS. The adverse events of sorafenib were reversible, and discontinuation of sorafenib may improve the QoL of patients who have achieved a CR.     

Radioembolization with Yttrium-90 microspheres for patients with unresectable hepatocellular carcinoma

Background

Hepatocellular carcinoma (HCC) is aggressive primary malignancy of the liver that most commonly presents late in the disease course. As a result, the majority of patients are not candidates for curative therapies. Locoregional therapies including Yttrium-90 (Y-90) radioembolization play an important role in management of the vast majority of patients with HCC.

Methods

Patients with unnresectable HCC (n=17) treated with Y-90 radioembolization from 2005 to 2014 were evaluated retrospectively. Data was abstracted from medical records including patient charts, laboratory data, and imaging. Toxicities were recorded using Common Terminology Criteria 3.0. Response was recorded according to modified RECIST (mRECIST) criteria.

Results

Seventeen patients received 33 treatments with Y-90 radioembolization. A majority (65%) received TheraSphere with a minority (35%) receiving SIR-Spheres. The median treatment activity delivered was 1.725 gBq (range, 1.4-2.5 gBq). The median treatment dose delivered was 100 Gy (range, 90-120 Gy). The median lung shunt fraction was 2.02% (range, 1.5-4.1%). The most common clinical toxicity among all patients was nausea and vomiting (59%), primarily grade 1 and 2. Other post-treatment findings included abdominal pain (29%), fatigue (53%), and weight loss (18%). One patient developed a grade 5 gastric ulcer after the treatment. A clinical benefit, defined as patients achieving complete response (CR), partial response (PR) or stable disease (SD), was seen in 48% of patients. PR was seen in 24% of cases; progressive disease (PD) was noted in 35%. Patients survived for a median of 8.4 months (range, 1.3 to 21.1 months) after the first radioembolization treatment. Median survival after Y-90 treatment was 8.4 months among patients treated TheraSphere as compared with 7.8 months in patients treated with SIR-Spheres. The mean overall survival from the time of diagnosis was 11.7 months (range, 3.4 to 43.2 months).

Conclusions

For patients with unresectable HCC, Y-90 radioembolization is a safe and well-tolerated procedure. Our experience suggests that a significant percentage of patients achieve clinical benefit including many with PR. Survival after treatment from this single-center, transplant center is in line with prior reports. Prospective, randomized data is required to compare radioembolization with other therapies including chemoembolization and systemic therapy with sorafenib.     

Phase 2 trial of concurrent bevacizumab and transhepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma

BACKGROUND:

Vascular endothelial growth factor is up‐regulated in hepatocellular carcinoma (HCC) and is further up‐regulated after transhepatic arterial chemoembolization. The authors of this report conducted a phase 2 trial to evaluate the safety and efficacy of bevacizumab combined with chemoembolization in patients with unresectable HCC.

METHODS:

Patients who had an Eastern Cooperative Oncology Group performance of status 0 to 2, a Child‐Pugh score of A or B, and Barcelona Clinic Liver Cancer stage B or C HCC were eligible. Treatment consisted of bevacizumab every 2 weeks and chemoembolization during the third week of a 6‐week cycle for up to 3 cycles over 6 months. The primary endpoints were safety and efficacy.

RESULTS:

Twenty‐five patients received chemoembolization and bevacizumab. The most common grade 3 and 4 events after the first treatment cycle were leukocytopenia (12%), fatigue (12%), and hyponatremia (12%). Serious toxicities that had a known association with bevacizumab were observed in 4 patients. Thirty‐day mortality was 0%. The median time to tumor progression for the targeted lesions was not reached, and overall survival was 10.8 months. The objective response rate was 60% using enhancement response evaluation criteria, and the disease control rate was 100%.

CONCLUSIONS:

Concurrent treatment with bevacizumab and chemoembolization was safe in carefully selected patients and demonstrated antitumor activity in patients with unresectable HCC. These results support the further development of bevacizumab combined with chemoembolization as a treatment for unresectable HCC. Cancer 2013. © 2012 American Cancer Society.