Brian I. Carr

Safety and Efficacy of 90Y Radiotherapy for Hepatocellular Carcinoma With and Without Portal Vein Thrombosis

This study was undertaken to present data from a phase 2 study in which patients with unresectable hepatocellular carcinoma (HCC) with and without portal vein thrombosis underwent radioembolization with Yttrium (90Y) microspheres. Patients treated were stratified by Okuda, Child‐Pugh, baseline bilirubin, tumor burden, Eastern Cooperative Oncology Group (ECOG), presence of cirrhosis and portal vein thrombosis (PVT) (none, branch, and main). Clinical and biochemical data were obtained at baseline and at 4‐week intervals following treatment for up to 6 months. Tumor response was obtained using computed tomography (CT). Patients were followed for survival. One hundred eight patients were treated during the study period. Thirty‐seven (34%) patients had PVT, 12 (32%) of which involved the main PV. The cumulative dose for those with and without PVT was 139.7 Gy and 131.9 Gy, respectively. The partial response rate using world Health Organization (WHO) criteria was 42.2%. Using European Association for the Study of the Liver (EASL), the response rate was 70%. Kaplan‐Meier survival varied depending on location of PVT and presence of cirrhosis. The adverse event (AE) rates were highest in patients with main PVT and cirrhosis. There were no cases of radiation pneumonitis. Conclusion: The use of minimally embolic 90Y glass microspheres to treat patients with HCC complicated by branch/lobar PVT may be clinically indicated and appears to have a favorable toxicity profile. Further investigation is warranted in patients with main PVT. (HEPATOLOGY 2007.)

Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study.

Intrahepatic arterial yttrium 90 (90Y) microspheres have been proposed as a less toxic, less invasive therapeutic option to transhepatic arterial chemoembolization (TACE) for patients with surgically unresectable hepatocellular carcinoma (HCC). TACE has demonstrated the ability to prolong survival. However, long‐term survival remains uncertain.

Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma

The efficacy and safety of linifanib (ABT‐869), a selective inhibitor of vascular endothelial growth factor and platelet‐derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single‐arm, open‐label, multicenter trial.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: A case cohort study

Background and Aims:  A total of 967 patients with unresectable and untransplantable, biopsy‐proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death.

The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma

BACKGROUND & AIMS Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patients mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. METHODS We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia. RESULTS Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p<0.001), transarterial chemoembolization (p<0.001) and sorafenib (p<0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p<0.001). CONCLUSIONS In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. LAY SUMMARY Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC.

Economic evaluation of sorafenib in unresectable hepatocellular carcinoma.

Background and Aim:  A double‐blind, randomized phase III trial of sorafenib in advanced hepatocellular carcinoma demonstrated that sorafenib significantly prolonged overall survival compared to placebo (median overall survival = 10.7 months vs 7.9 months, P < 0.001). Sorafenib is the first and only systemic agent demonstrating survival benefit in these patients. The aim of this study was to assess the cost‐effectiveness of sorafenib versus best supportive care in the treatment of advanced hepatocellular carcinoma in the USA.

Vitamin K enhancement of Sorafenib-mediated HCC cell growth inhibition in vitro and in vivo

The multikinase inhibitor sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Apoptosis has been shown to be induced in HCC by several agents, including sorafenib as well as by the naturally occurring K vitamins (VKs). As few nontoxic agents have activity against HCC growth, we evaluated the activity of sorafenib and VKs, both independently and together on the growth of HCC cells in vitro and in vivo. We found that when VK was combined with sorafenib, the concentration of sorafenib required for growth inhibition was substantially reduced. Conversely, VK enhanced sorafenib effects in several HCC cell lines on growth inhibition. Growth could be inhibited at doses of VK plus sorafenib that were ineffective with either agent alone, using vitamins K1, K2 and K5. Combination of VK1 plus sorafenib induced apoptosis on FACS, TUNEL staining and caspase activation. Phospho‐extracellular signal‐regulated kinase (ERK) levels were decreased as was myeloid cell leukemia sequence 1 (Mcl‐1), an ERK target. Sorafenib alone inhibited growth of transplantable HCC in vivo. At subeffective sorafenib doses in vivo, addition of VK1 caused major tumor regression, with decreased phospho‐ERK and Mcl‐1 staining. Thus, combination of VK1 plus sorafenib strongly induced growth inhibition and apoptosis in rodent and human HCC and inhibited the RAF/mitogen‐activated protein kinase kinase/ERK pathway. VK1 alone activated PKA, a mediator of inhibitory Raf phosphorylation. Thus, each agent can antagonize Raf: sorafenib as a direct inhibitor and VK1 through inhibitory Raf phosphorylation. As both agents are available for human use, the combination has potential for improving sorafenib effects in HCC.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study

Objectives967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end point.ResultsWe found that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated AFP or bilirubin, or alkaline phosphatase, were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, even in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient sub groups based on liver function and tumor characteristics and found clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant factors. We also used a purely mathematical approach to derive subgroups and a prognostic model for individual patients. Interestingly, the two approaches gave similar predictive information, which opens the possibility of a more detailed mathematical analysis in the future. The results of this large dataset show that amongst non-surgical HCC patients, there are clear subsets with longer survival.ConclusionThe data supports the concept of heterogeneity of HCC. The three factors, bilirubin, AFP, and PVT predominate in prognosis.

Serum ferritin as a new prognostic factor in hepatocellular carcinoma patients treated with radiofrequency ablation

Hepatic iron accumulation is considered to be a cofactor that influences liver injury and hepatocarcinogenesis. Aim of this study is to determine whether serum ferritin (SF) levels relate to overall survival (OS) and time to recurrence (TTR) in hepatocellular carcinoma (HCC) patients treated with percutaneous radiofrequency ablation (RFA).

Angiotensin receptor blockers improve survival outcomes after radiofrequency ablation in hepatocarcinoma patients

Inhibition of angiotensin II synthesis seems to decrease hepatocellular carcinoma recurrence after radical therapies; however, data on the adjuvant role of angiotensin II receptor 1 blockers (sartans) are still lacking. The aim of the study was to evaluate whether sartans delay time to recurrence and prolong overall survival in hepatocellular carcinoma patients after radiofrequency ablation.