Trial Information

Randomized Controlled Phase II Trial Of Neoadjuvant Sorafenib Therapy Prior to Thermal Ablation for Hepatocellular Carcinoma More Than 4 cm in Size

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.