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

Phase 2
18 Years
85 Years
Open (Enrolling)
Hepatocellular Carcinoma

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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.


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

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.

Inclusion Criteria:

- Age 18-80 years

- ECOG = 0 or 1

- No liver decompensation (Child-Pugh <8), bilirubin <3mg/dL

- Patients with unresectable HCC or who refused surgery

- Confirmed HCC by pathology or by AASLD imaging guidelines

- At least one HCC nodule (index tumor) accurately measured as 4-8cm in diameter on
baseline imaging

- No prior therapy for the index tumor

- No prior systemic treatment for HCC within 4 weeks of study entry

- LA clinically indicated for index tumor

- Hemoglobin >9.0 g/dl; Platelet count correctable to >50,000/mm3; INR correctable to

Exclusion Criteria:

- Other severe concomitant diseases that may reduce life expectancy

- Participants currently receiving any other study agents

- Cancer vascular invasion or extrahepatic metastasis

- Uncontrolled hypertension

- Thrombotic events or myocardial infarction within the past 6 months

- Hemorrhage/bleeding event within 4 weeks

- Evidence of severe or uncorrectable bleeding diathesis or coagulopathy

- Contraindication to or inability to undergo the LA procedure

- Human immunodeficiency virus (HIV) infection

- Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

- Any condition that is unstable or which could jeopardize the safety of the patient
and his/her compliance in the study.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Effectiveness of sorafenib in increasing the effectiveness of laser ablation (LA)

Outcome Description:

Measures: complete tumor ablation rate (according to the mRECIST), time-to-recurrence (in complete response subgroup), time-to-progression (in partial response subgroup).

Outcome Time Frame:

1 year

Safety Issue:



Italy: The Italian Medicines Agency

Study ID:




Start Date:

January 2012

Completion Date:

January 2015

Related Keywords:

  • Hepatocellular Carcinoma
  • hepatocellular carcinoma
  • sorafenib
  • laser ablation
  • Carcinoma
  • Carcinoma, Hepatocellular