Maintenance of Sorafenib following combined therapy of three-dimensional conformal radiation therapy/intensity-modulated radiation therapy and transcatheter arterial chemoembolization in patients with locally advanced hepatocellular carcinoma: a phase I/II study

Abstract

BackgroundThree-dimensional conformal radiation therapy (3DCRT)/intensity-modulated radiation therapy (IMRT) combined with or without transcatheter arterial chemoembolization (TACE) for locally advanced hepatocellular carcinoma (HCC) has shown favorable outcomes in local control and survival of locally advanced HCC. However, intra-hepatic spreading and metastasis are still the predominant treatment failure patterns. Sorafenib is a multikinase inhibitor with effects against tumor proliferation and angiogenesis. Maintenance Sorafenib would probably prevent or delay the intrahepatic and extrahepatic spread of HCC after radiotherapy, which provides the rationale for the combination of these treatment modalities.Methods and designPatients with solitary lesion (bigger than 5 cm in diameter) histologically or cytologically confirmed HCC receive TACE (1-3 cycles) plus 3DCRT/IMRT 4-6 weeks later. Maintenance Sorafenib will be administered only for the patients with non-progression disease 4 to 6 weeks after the completion of radiotherapy. The dose will be 400 mg, p.o., twice a day. Sorafenib will be continuously given for 12 months unless intolerable toxicities and/or tumor progression. If no more than 3 patients discontinue Sorafenib treatment who experience dose-limiting toxicity after necessary dose modification and delay and/or radiation-induced liver disease in the first 15 enrolled patients, the study will recruit second fifteen patients for further evaluating safety and efficacy of treatment. Hypothesis of the current study is that Sorafenib as a maintenance therapy after combined therapy of 3DCRT/IMRT and TACE is safe and superior to radiotherapy combined with TACE alone in terms of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) in comparison to historical data.DiscussionA recent meta-analysis showed TACE in combination with radiotherapy, improved the survival and the tumor response of patients, and was thus more therapeutically beneficial. In this study, local therapy for HCC is the combination of TACE and radiotherapy. Radiation exposure as a kind of stress might induce the compensatory activations of multiple intracellular signaling pathway mediators, such as PI3K, MAPK, JNK and NF-kB. Vascular endothelial growth factor (VEGF) was identified as one factor that was increased in a time- and dose-dependent manner after sublethal irradiation of HCC cells in vitro, translating to enhanced intratumor angiogenesis in vivo. Therefore, Sorafenib-mediated blockade of the Raf/MAPK and VEGFR pathways might enhance the efficacy of radiation, when Sorafenib is followed sequentially as a maintenance modality. (ClinicalTrials.gov number, NCT00999843.)

Comparison of Chemoembolization with and without Radiation Therapy and Sorafenib for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis: A Propensity Score Analysis

“…A Chinese study of advanced-stage HCC (32) obtained promising results for the combination of sorafenib with chemoembolization compared with chemoembolization alone, and a recent study that used propensity-score methods (22) also revealed that the addition of chemoembolization to sorafenib had an impressive effect on tumor progression in these patients. An interesting phase I/II study (33) showed that maintenance therapy with sorafenib after combined treatment with RT and chemoembolization was well tolerated. The therapeutical benefit of chemoembolization plus RT in our hands may encourage other investigators to evaluate the clinical efficacy of this combination for HCC with portal invasion.…”

Molecular Biomarkers of Response to Antiangiogenic Therapy for Cancer

“…In many cancers, nuclear factor kappa B (NF-κB) is involved in tumor initiation and progression mediated via STAT3 activation [36–38]. Inflammatory cytokines induced by NF-κB pathway activation might affect angiogenesis directly via endothelial cells, or indirectly by cancer cells or recruitment and/or activation of inflammatory cells [39–46]. Interleukin (IL)-1α has a critical role by recruitment of inflammatory cells [47, 48].…”

Synergistic effects of the combination of β-ionone and sorafenib on metastasis of human hepatoma SK-Hep-1 cells

“…SF is a commonly used single agent with modest antitumor activity and safety in patients with HCC [11,12] and has been used in numerous combination chemotherapy protocols [13,14]. It has been shown that SF administrated after radiotherapy can prevent or delay the intrahepatic and extrahepatic spreading of HCC, which provides the rationale for the combination of these treatment modalities [15]. Thus, Lopez et al [1] have suggested that future studies should assess the benefits of combined molecular therapy, as opposed to SF treatment alone.…”