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Long-lasting remission in a metastatic hepatocellular carcinoma patient after combined regorafenib therapy and surgery.

ABSTRACT: Aims:The therapeutic scenario of systemic treatments for hepatocellular carcinoma (HCC) is rapidly changing. There is much interest in the possibility of combining new therapies with surgery, but clinical data is lacking. We aimed to provide an example of such integration. Patients & methods:We report a patient with metastatic HCC who received regorafenib in the setting of the RESORCE trial. Results:A brilliant response led to a tumor downstaging and a subsequent adrenal metastasectomy with radical intent. Conclusions:New agents will change the therapeutic perspectives in advanced HCC and lead to a higher rate of objective responses, with possibilities of associating systemic therapy and surgery. Thus, the management of HCC will require more and more of an integrated, multidisciplinary and personalized approach.

SUBMITTER: Goio E

PROVIDER: S-EPMC7399611 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Long-lasting remission in a metastatic hepatocellular carcinoma patient after combined regorafenib therapy and surgery.

Goio Elisabetta E Ielasi Luca L Benevento Francesca F Renzulli Matteo M Tovoli Francesco F

Hepatic oncology 20200703 3

<h4>Aims</h4>The therapeutic scenario of systemic treatments for hepatocellular carcinoma (HCC) is rapidly changing. There is much interest in the possibility of combining new therapies with surgery, but clinical data is lacking. We aimed to provide an example of such integration.<h4>Patients & methods</h4>We report a patient with metastatic HCC who received regorafenib in the setting of the RESORCE trial.<h4>Results</h4>A brilliant response led to a tumor downstaging and a subsequent adrenal me ...[more]

PMID: 32774834

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Project description:BackgroundThe treatment of advanced hepatocellular carcinoma (HCC) is challenging. The positive effect of gelatin sponge microparticles for transarterial chemoembolization (GSMs-TACE) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage C and large HCC has been confirmed by previous studies. This study initially explored the efficacy and safety of GSMs-TACE combined with regorafenib in patients with unresectable HCC who failed first-line sorafenib and/or lenvatinib therapy.MethodsThis retrospective study collated the data of patients who presented at the Affiliated Zhongshan Hospital of Dalian University between December 2018 and June 2021. Patients were treated with GSMs-TACE, followed by regorafenib 1 week later. Follow-up was conducted every 3 to 5 weeks after combination therapy. If the treatment was changed due to disease progression, the patients were followed up every 3 months to obtain overall survival (OS) time. The OS, progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) was used to evaluate the efficacy of the treatment, while adverse events (AEs) was used to assess its safety.ResultsA total of 47 patients were included in the study. The age of patients was 64.4±6.8 years; There were 43 (91.5%) males and 4 (8.5%) females; the number of Child-Pugh grade A was 22 (46.8%) and B was 25 (53.2%); the longest tumor diameter was 5.1 cm [interquartile range (IQR), 3.8, 8.9 cm]; the number of BCLC grade B was 14 (29.8%) and grade C was 33 (70.2%). The median follow-up time was 11.6 months [95% confidence interval (CI): 10.8 to 14.0 months]. The median number of GSMS-TACE sessions was 3. The initial doses of regorafenib were 80 mg/d (n=17, 36.2%), 120 mg/d (n=23, 48.9%), and 160 mg/d (n=7, 14.9%). The median PFS was 6.0 months (95% CI: 4.5 to 7.5 months), and the median OS was 14.3 months (95% CI: 11.8 to 16.8 months). The ORR and DCR were 21.3% and 85.1%, respectively. The incidence of grade 3/4 AEs was 8 out of 47 patients (17.0%).ConclusionsThe study indicated that GSMs-TACE combined with regorafenib may be efficient and safe in patients with unresectable HCC. Future prospective large-scale studies should be conducted to verify these results.

Project description:Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

Dataset Information

Long-lasting remission in a metastatic hepatocellular carcinoma patient after combined regorafenib therapy and surgery.

Publications

Long-lasting remission in a metastatic hepatocellular carcinoma patient after combined regorafenib therapy and surgery.

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