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Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial.
He, M, Li, Q, Zou, R, Shen, J, Fang, W, Tan, G, Zhou, Y, Wu, X, Xu, L, Wei, W, et al
JAMA oncology. 2019;(7):953-960
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Abstract
IMPORTANCE Sorafenib is the first-line treatment for hepatocellular carcinoma with portal vein invasion; however, it has shown unsatisfactory survival benefit. Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promising results for these patients in a previous phase 2 study. OBJECTIVE To investigate the efficacy and safety of sorafenib plus HAIC compared with sorafenib for hepatocellular carcinoma with portal vein invasion. DESIGN, SETTING, AND PARTICIPANTS This randomized, open-label clinical trial enrolled 818 screened patients. Of the 818 participants, 247 with hepatocellular carcinoma and portal vein invasion were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib plus HAIC or sorafenib. This trial was conducted at 5 hospitals in China and enrolled patients from April 1, 2016, to October 10, 2017, with a follow-up period of 10 months. INTERVENTIONS Randomization to receive 400 mg sorafenib twice daily (sorafenib group) or 400 mg sorafenib twice daily plus HAIC (SoraHAIC group) (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks). MAIN OUTCOMES AND MEASURES The primary endpoint was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment. RESULTS For 247 patients (median age, 49 years; range, 18-75 years; 223 men and 24 women), median overall survival was 13.37 months (95% CI, 10.27-16.46) in the SoraHAIC group vs 7.13 months (95% CI, 6.28-7.98) in the sorafenib group (hazard ratio [HR], 0.35; 95% CI, 0.26-0.48; P < .001). The SoraHAIC group showed a higher response rate than the sorafenib group (51 [40.8%] vs 3 [2.46%]; P < .001), and a longer median progression-free survival (7.03 [95% CI, 6.05-8.02] vs 2.6 [95% CI, 2.15-3.05] months; P < .001). Grade 3/4 adverse events that were more frequent in the SoraHAIC group than in the sorafenib group included neutropenia (12 [9.68%] vs 3 [2.48%]), thrombocytopenia (16 [12.9%] vs 6 [4.96%]), and vomiting (8 [6.45%] vs 1 [0.83%]). CONCLUSIONS AND RELEVANCE Sorafenib plus HAIC of FOLFOX improved overall survival and had acceptable toxic effects compared with sorafenib in patients with hepatocellular carcinoma and portal vein invasion. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02774187.
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Arsenic trioxide inhibits DNA methyltransferase and restores TMS1 gene expression in K562 cells.
Li, H, Wang, Y, Xu, W, Dong, L, Guo, Y, Bi, K, Zhu, C
Acta haematologica. 2015;(1):18-25
Abstract
BACKGROUND Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor genes in human cancers. The demethylating, dose-dependent effect of arsenic trioxide (As2O3) on several tumor-related genes has already been postulated. However, whether such a demethylating effect also applies to the TMS1 gene in chronic myeloid leukemia cell line K562 cells has not been studied so far. The aim of the present study was to detect the methylation status of the TMS1 gene in K562 cells and the demethylation effect of As2O3 on TMS1 as well as TMS1 apoptosis-associated protein Bcl-2/Bax and DNA methyltransferase (DNMT) expression. METHODS TMS1 mRNA expression in K562 cells and normal bone marrow was determined by reverse transcription (RT) polymerase chain reaction (PCR), and the DNA methylation status of the TMS1 promoter in K562 cells treated with different concentrations of As2O3 for 48 h was determined by methylation-specific PCR. RT-PCR and Western blot were used to detect TMS1 and DNMT expression. We also assessed TMS1-associated apoptosis protein Bcl-2/Bax expression by Western blot and apoptosis rates by flow cytometry using annexin V/propidium iodide double staining. RESULTS In K562 cells, TMS1 was completely methylated and both TMS1 mRNA and protein showed a low expression, but 2 μmol/l As2O3 could significantly restore the expression of the TMS1 gene both at mRNA and protein level (p < 0.01) by fully reversing DNA methylation. As2O3 decreased mRNA and protein expression of DNMT1 (p < 0.05) in a dose-dependent manner. Flow cytometry showed that in the experimental group (2 μmol/l As2O3), cell apoptosis was significantly increased compared with the control group (no As2O3; p < 0.05). In the experimental group, Western blot showed that the expression of the anti-apoptotic protein Bcl-2 was significantly decreased; however, the proapoptotic protein Bax was markedly increased and the Bcl-2/Bax ratio was markedly reduced (p < 0.01). CONCLUSIONS As2O3 could restore the expression of TMS1 by inhibiting DNMT to reverse the hypermethylation and induced apoptosis of K562 cells by downregulation of Bcl-2/Bax expression.
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Efficacy of sorafenib in advanced renal cell carcinoma independent of prior treatment, histology or prognostic group.
Tafreshi, A, Thientosapol, E, Liew, MS, Guo, Y, Quaggiotto, M, Boyer, M, Davis, ID
Asia-Pacific journal of clinical oncology. 2014;(1):60-5
Abstract
AIM: To assess the response rate and safety of sorafenib in different subpopulations of patients with advanced renal cell carcinoma (RCC). METHODS Single-arm open access trial. Key eligibility: advanced RCC with either clear-cell or non-clear-cell histopathology; progression on prior systemic chemotherapy or treatment naïve. Sorafenib was commenced at 400 mg twice daily continuously. RESULTS A total 47 participants with metastatic RCC were treated with sorafenib. Overall, 1 participant experienced complete response, 6 (13%) had documented partial response (PR) and 29 (62%) had stable disease (SD) as the best response. Eight (17%) had non-clear-cell histopathology and five (10%) had sarcomatoid features. In the non-clear-cell histopathology cohort, five participants (62.5%) had SD. Twenty-three (49%) participants were treatment naïve; of these, 1/23 showed CR, 5/23 experienced PR and 13/23 had SD (clinical benefit: 83%). Overall, 14 (30%) and 22 (47%) participants had high-risk status according to MSKCC (Memorial Sloan-Kettering Cancer Center) and Heng prognostic scores, respectively. In the MSKCC poor prognostic group (14 participants), one participant had CR, two participants showed PR and eight participants had SD (clinical benefit: 79%). In Heng poor prognostic group (22 participants), 1 participant experienced CR, 2 participants showed PR and 13 had SD (clinical benefit: 73%). Hand-foot syndrome (53%), rash (47%), fatigue (42%), nausea (40%), anorexia (34%) and diarrhea (32%) were the most common adverse events. CONCLUSIONS This study confirms the efficacy and tolerability of sorafenib in a different spectrum of advanced RCC patients including non-clear-cell histology, poor prognostic status and as first-line treatment.