Quantification of dynamic contrast-enhanced ultrasound in HCC: prediction of response to a new combination therapy of sorafenib and panobinostat in advanced hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Knieling F
PROVIDER: S-EPMC4544083 | biostudies-literature | 2012 Dec
REPOSITORIES: biostudies-literature
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Quantification of dynamic contrast-enhanced ultrasound in HCC: prediction of response to a new combination therapy of sorafenib and panobinostat in advanced hepatocellular carcinoma.
Knieling Ferdinand F Waldner Maximilian J MJ Goertz Ruediger S RS Strobel Deike D
BMJ case reports 20121217
Here, we report the case of a patient, who showed an antitumour response to a new combination therapy of sorafenib and the histon deacetylase inhibitor panobinostat (LBH-589). D-CEUS (Dynamic contrast-enhanced ultrasonography) was able to predict response to the new therapy regime and may be an interesting tool in the early evaluation of response to therapy. It might be especially useful to differentiate between responders and non-responders of new-targeted pharmaceuticals like multikinase inhib ...[more]
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Project description:Tumor lysis syndrome (TLS) is a life-threatening emergency that usually develops in rapidly proliferating hematologic malignancies or advanced solid tumor following cytotoxic chemotherapy or therapeutic interventions. TLS is especially rare in patients with hepatocellular carcinoma (HCC). Therefore, we present a case of a female patient with newly diagnosed advanced HCC who developed TLS and hepatic failure after receiving combination therapy of nivolumab and sorafenib. To our knowledge, this is the first case of TLS in a patient with advanced HCC owing to combination therapy of nivolumab and sorafenib. We also reviewed the literature and summarized the characteristics of TLS in patients with advanced HCC receiving various therapeutic interventions. The overall mortality rate was 63% and regarding the management, transarterial chemoembolization (TACE) was the most common etiology. TACE-related TLS developed more rapidly than sorafenib-related TLS. Furthermore, the efficacy and safety of combination therapy of nivolumab and sorafenib should be further evaluated, and TLS should still be a concern, especially in patients with large tumor burden.
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Project description:BackgroundThe mammalian target of rapamycin (mTOR) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose.MethodsWe conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint.ResultsTwenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP.ConclusionsThe combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.
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