Neoadjuvant Sorafenib Therapy Prior to Laser Ablation for Hepatocellular Carcinoma (LANEX)

• Effectiveness of sorafenib in increasing the effectiveness of laser ablation (LA) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Measures: complete tumor ablation rate (according to the mRECIST), time-to-recurrence (in complete response subgroup), time-to-progression (in partial response subgroup).
  
  

• Safety of sorafenib treatment prior to LA. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  Measure: incidence and grade of adverse events in patients treated with sorafenib (group B)
  
  
• Survival in the two treatment groups [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Measured from the date of LA until the date of death or last visit
  
  

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.