Successful endoscopic treatment of hepatoduodenal fistula formed during sorafenib treatment for hepatocellular carcinoma with duodenal invasion

Objectives: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Methods: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. Results: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Conclusion: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC.

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Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03627-1 ◽

2021 ◽

Author(s):

Osman Öcal ◽

Kerstin Schütte ◽

Juozas Kupčinskas ◽

Egidijus Morkunas ◽

Gabija Jurkeviciute ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Objective Response ◽

Advanced Hepatocellular Carcinoma ◽

Sorafenib Treatment ◽

Post Hoc Analysis ◽

Y90 Radioembolization ◽

Baseline Values ◽

Post Hoc

Abstract Purpose To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Methods A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. Results Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9–8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2–4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22–7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02–4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). Conclusion IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.

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Combined Inhibition of TGF-β1-Induced EMT and PD-L1 Silencing Re-Sensitizes Hepatocellular Carcinoma to Sorafenib Treatment

Journal of Clinical Medicine ◽

10.3390/jcm10091889 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1889

Author(s):

Ritu Shrestha ◽

Prashanth Prithviraj ◽

Kim R. Bridle ◽

Darrell H. G. Crawford ◽

Aparna Jayachandran

Keyword(s):

Hepatocellular Carcinoma ◽

Combination Treatment ◽

Immune Checkpoint ◽

Post Treatment ◽

Immune Checkpoints ◽

Sorafenib Treatment ◽

Mesenchymal Transition ◽

Immune Checkpoint Molecules ◽

Tgf Β1 ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic malignancy. HCC is one of the leading causes of cancer deaths worldwide. The oral multi-tyrosine kinase inhibitor Sorafenib is the standard first-line therapy in patients with advanced unresectable HCC. Despite the significant survival benefit in HCC patients post treatment with Sorafenib, many patients had progressive disease as a result of acquiring drug resistance. Circumventing resistance to Sorafenib by exploring and targeting possible molecular mechanisms and pathways is an area of active investigation worldwide. Epithelial-to-mesenchymal transition (EMT) is a cellular process allowing epithelial cells to assume mesenchymal traits. HCC tumour cells undergo EMT to become immune evasive and develop resistance to Sorafenib treatment. Immune checkpoint molecules control immune escape in many tumours, including HCC. The aim of this study is to investigate whether combined inhibition of EMT and immune checkpoints can re-sensitise HCC to Sorafenib treatment. Post treatment with Sorafenib, HCC cells PLC/PRF/5 and Hep3B were monitored for induction of EMT and immune checkpoint molecules using quantitative reverse transcriptase (qRT)- PCR, western blot, immunofluorescence, and motility assays. The effect of combination treatment with SB431542, a specific inhibitor of the transforming growth factor (TGF)-β receptor kinase, and siRNA mediated knockdown of programmed cell death protein ligand-1 (PD-L1) on Sorafenib resistance was examined using a cell viability assay. We found that three days of Sorafenib treatment activated EMT with overexpression of TGF-β1 in both HCC cell lines. Following Sorafenib exposure, increase in the expression of PD-L1 and other immune checkpoints was observed. SB431542 blocked the TGF-β1-mediated EMT in HCC cells and also repressed PD-L1 expression. Likewise, knockdown of PD-L1 inhibited EMT. Moreover, the sensitivity of HCC cells to Sorafenib was enhanced by combining a blockade of EMT with SB431542 and knockdown of PD-L1 expression. Sorafenib-induced motility was attenuated with the combined treatment of SB431542 and PD-L1 knockdown. Our findings indicate that treatment with Sorafenib induces EMT and expression of immune checkpoint molecules, which contributes to Sorafenib resistance in HCC cells. Thus, the combination treatment strategy of inhibiting EMT and immune checkpoint molecules can re-sensitise HCC cells to Sorafenib.

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Impact of more detailed categorization of shrinkage or progression ratio at initial imaging response after sorafenib treatment in advanced hepatocellular carcinoma patients

OncoTargets and Therapy ◽

10.2147/ott.s94246 ◽

2015 ◽

pp. 3193

Author(s):

Yoshiyuki Wada ◽

Yuko Takami ◽

Masaki Tateishi ◽

Tomoki Ryu ◽

Kazuhiro Mikagi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Advanced Hepatocellular Carcinoma ◽

Sorafenib Treatment ◽

Initial Imaging ◽

Imaging Response

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Experience With Early Sorafenib Treatment With mTOR Inhibitors in Hepatocellular Carcinoma Recurring After Liver Transplantation

Transplantation Journal ◽

10.1097/tp.0000000000002955 ◽

2020 ◽

Vol 104 (3) ◽

pp. 568-574 ◽

Cited By ~ 4

Author(s):

Federica Invernizzi ◽

Massimo Iavarone ◽

Claudio Zavaglia ◽

Stefano Mazza ◽

Umberto Maggi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Mtor Inhibitors ◽

Sorafenib Treatment

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Evaluation of sorafenib treatment and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: a comparative study using the propensity score matching method

Cancer Medicine ◽

10.1002/cam4.476 ◽

2015 ◽

Vol 4 (8) ◽

pp. 1214-1223 ◽

Cited By ~ 10

Author(s):

Kotaro Fukubayashi ◽

Motohiko Tanaka ◽

Kazuhiro Izumi ◽

Takehisa Watanabe ◽

Satomi Fujie ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Propensity Score ◽

Comparative Study ◽

Hepatic Arterial Infusion ◽

Advanced Hepatocellular Carcinoma ◽

Matching Method ◽

Arterial Infusion ◽

Sorafenib Treatment ◽

Arterial Infusion Chemotherapy ◽

Infusion Chemotherapy

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Sorafenib treatment in Child–Pugh A and B patients with advanced hepatocellular carcinoma: safety, efficacy and prognostic factors

Investigational New Drugs ◽

10.1007/s10637-015-0237-3 ◽

2015 ◽

Vol 33 (3) ◽

pp. 729-739 ◽

Cited By ~ 41

Author(s):

Sadahisa Ogasawara ◽

Tetsuhiro Chiba ◽

Yoshihiko Ooka ◽

Naoya Kanogawa ◽

Tomoko Saito ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Advanced Hepatocellular Carcinoma ◽

Sorafenib Treatment

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Combination Therapy after TACE for Hepatocellular Carcinoma with Macroscopic Vascular Invasion: Stereotactic Body Radiotherapy versus Sorafenib

Cancers ◽

10.3390/cancers10120516 ◽

2018 ◽

Vol 10 (12) ◽

pp. 516 ◽

Cited By ~ 2

Author(s):

Lujun Shen ◽

Mian Xi ◽

Lei Zhao ◽

Xuhui Zhang ◽

Xiuchen Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stereotactic Body Radiotherapy ◽

Vascular Invasion ◽

Progression Free Survival ◽

Sorafenib Treatment ◽

Free Survival ◽

Sorafenib Group ◽

Treatment Responses ◽

Hepatic Lesions ◽

Macroscopic Vascular Invasion

Stereotactic body radiotherapy (SBRT) has shown promising results in the control of macroscopic vascular invasion in patients with hepatocellular carcinoma (HCC); however, its efficacy in comparison to sorafenib when combined with transarterial chemoembolization (TACE) remains to be determined. Between 2009 and 2017, 77 HCC patients with macroscopic vascular invasion receiving TACE–SBRT or TACE–sorafenib combination therapies were enrolled. The best treatment responses, overall survival (OS), and progression-free survival (PFS) of the two treatment arms were compared. Of the patients enrolled, 26 patients (33.8%) received TACE–SBRT treatment, and 51 (66.2%) received TACE–sorafenib treatment. The patients in the TACE–SBRT group were more frequently classified as elder in age (p = 0.012), having recurrent disease (p = 0.026), and showing lower rates of multiple hepatic lesions (p = 0.005) than patients in TACE–sorafenib group. After propensity score matching (PSM), 26 pairs of well-matched HCC patients were selected; patients in the TACE–SBRT group showed better overall response rates in trend compared to those in the TACE–sorafenib group. The hazard ratio (HR) of OS to PFS for the TACE–SBRT approach and the TACE–sorafenib approach was 0.36 (95% CI, 0.17–0.75; p = 0.007) and 0.35 (95% CI, 0.20–0.62; p < 0.001), respectively. For HCC patients with macrovascular invasion, TACE plus SBRT could provide improved OS and PFS compared to TACE–sorafenib therapy.

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