Neoadjuvant Sorafenib Therapy Prior to Laser Ablation for Hepatocellular Carcinoma
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether neoadiuvant therapy with sorafenib
      increases the efficacy of thermal ablation in inducing the necrosis of hepatocellular
      carcinoma.
    

Detailed description: 
      BACKGROUND AND AIM Image-guided laser ablation (LA), minimally invasive procedure, is a
      potentially viable treatment option for achieving focal thermal destruction of hepatocellular
      carcinoma (HCC) that cannot be treated with surgery. Both techniques are effective for the
      destruction of small (<3 cm) tumors, but the success rate for index tumors larger than 4 cm
      in diameter is lower. A cause of the difficulty in treating larger tumors is represented by
      the heat-sink effect of tumor blood flow that limits the size of tumor ablation by drawing
      heat away from the tumor nodule. Surgical (Pringle maneuver) and endovascular (transarterial
      chemoembolization) techniques have been used to reduce the tumor blood flow during or before
      thermal ablation, but these techniques require invasive procedures that may decrease the
      patient acceptance and increase the risk of complications. Sorafenib is a multikinase
      inhibitor that has been approved for the treatment of advanced HCC. One of the main effect of
      this drug is to block vascular endothelial growth factor (VEGF) pathway, Flt-3, c-KIT, and
      fibroblast growth factor receptor 1, that have been shown to mediate tumor angiogenesis,
      reducing intratumoral blood flow. An experimental study in mice with renal cell carcinoma
      implanted subcutaneously, showed that treatment with sorafenib before ablation resulted in
      markedly decreased cancer microvessel density and significantly larger zones of
      radiofrequency-induced coagulation necrosis (1).

      The purpose of this study is to determine if sorafenib improves the effectiveness of laser
      ablation (LA) for the treatment of HCC larger than 4cm in size.

      1. Hakimé A, Hines-Peralta A, Peddi H, Atkins MB, Sukhatme VP, Signoretti S, Regan M,
      Goldberg SN. Combination of Radiofrequency Ablation with Antiangiogenic Therapy for Tumor
      Ablation Efficacy: Study in Mice. Radiology 2007, 244, 464-470.

      STUDY DESIGN

      Participants will be randomized to receive either sorafenib (400mg twice a day) or placebo
      continuously for 4 weeks (on days 1-28). LA will be performed on day 29. On days 0 and 28,
      and 1, 6, and 12 months after LA, patients will undergo to a physical exam. Adverse events
      will be recorded using a pre-planned questionnaire in accordance with the "common toxicity
      criteria".

      Occurrence and characteristics of postablation syndrome will also be recorded. During a
      six-month period, if clinically indicated LA procedures preceded by a four-week sorafenib
      treatment, may be repeated up to three times.

      Laboratory values will be assessed on days 0 and 28, and 1, 6, and 12 months after the first
      LA procedure.

      Upper gastrointestinal endoscopy will be done before starting drug treatment. A tumor biopsy
      will be obtained at the time of the first LA. A CT or MRI scan will be performed at the time
      of inclusion in the study, at 1, 6, and 12 months after LA.
    

Intervention name(s): Sorafenib; laser ablation (LA)
Intervention type(s): Drug; Procedure
Intervention description(s): tablets 200mg dosage: 400mg bid duration: 4 weeks; For LA, we use a commercially available system (Echolaser XVG system, Esaote El.En., Florence, Italy) and four optical fibers,inserted into the tumor through four 21-gauge needles. The tips of the needles will be positioned at a distance of 15mm from each other.
When, after LA treatments, CT or MRI findings show a residual nodule activity of 10% or less, percutaneous ethanol injection may be done. If the residual activity is of 50% or more transarterial chemoembolization may be used.
Other intervention name(s): Nexavar
Intervention MeSH terms: Sorafenib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: hepatocellular carcinoma; sorafenib; laser ablation