Study to Evaluate a High Intensity Focused Ultrasound (HIFU) Procedure in Patient With Liver Metastases

A Phase I-II Study to Evaluate, in Patients Operated for a Hepatic Resection of Colorectal Liver Metastases, a High Intensity Focused Ultrasound (HIFU) Procedure: Feasibility, Safety and Accuracy.

The purpose of this study is to assess the feasibility, safety and efficacy of High Intensity Focused Ultrasound (HIFU) patients undergoing hepatectomy for colorectal liver metastases. This is a phase I/II study.

Justification and interest of the study:

Colorectal liver metastases (CLM) are a major public health issue (16 000 deaths each year in France). To date, complete resection of CLM offers the only potential curative approach. However, only a minority of patients (10 to 20%) is candidates. 5-year survival rates after liver resection are ranged from 20 to 35%. Consequently, alternative locally targeted therapies (radiofrequency, cryotherapy, laser, microwave) have been developed and evaluated. Their use presents many limitations: invasive procedures requiring the intraparenchymal introduction of a probe, impossibility of an accurate monitoring in real-time, small size destruction, time-consuming, high recurrence rate. The development of a non-invasive and more accurate technique combined to surgery is required.

High Intensity Focused Ultrasound (HIFU) is a new approach, which enables to generate irreversible cell death through coagulative necrosis in a few seconds. There's no cooling effect of the perfusion because of the shortness of the phenomenon.

The surgical team of the Centre Leon Berard, in collaboration with the INSERM U556 one, has undertaken a research program on CLM treatment by HIFU. A new and very powerful device, without the previously named limitations, has been developed. Preclinical studies have revealed the interest, the feasibility and the safety of this process. These results enable considering preceding the program with an early clinical study.

Experimental design:

Prospective, monocentric phase I/II study evaluating a surgical medical device (SMD).

HIFU SMD will be evaluated in clinical conditions, in patients undergoing hepatectomy for colorectal liver metastases. Several HIFU "shootings" (the number will be function of the advancement of the study) will be performed on the liver witch will be resected

Objectives and main assessment criteria:

1. st part: Phase I - on the healthy liver to remove. Feasibility 1, Safety 2, Tolerance 3. Success = 1 Ability to perform shootings, supplementary duration of intervention < 30 minutes; 2 Asepsis, absence of lesion of nearly tissues; 3 Preservation of hemodynamic and respiratory constants.

2. nd part: Phase IIa - on the healthy liver to remove, distant then close to the vascular structures of the liver.

   Ability of targeting shootings. Success = distance from the epicentre of the HIFU lesion to the mark previously positioned in the liver ≤ 5mm.

3. rd part: Phase IIb - on metastases to remove. Ability, by summation of HIFU lesions, to generate " macro-lesions " including a metastasis and insuring a sufficient safety margin in the healthy tissue.

Success = macro-lesion generated in negative margins.

Number of patients:

1. st part: The inclusion from 2 to 6 patients is required. The next step (phase II) will depend on:

   • 1st analysis after 2 patients:

     • If < 2 failures: continuation,
     • If 2 failures: cessation of the study.

   • 2nd analysis after 6 patients:

     • If < 3 failures: continuation (phase II),
     • If ≥ 3 failures: cessation.

2. nd part: Three patients will be successively included in each of the 2 landings (appendix 1):

   • If no failure: continuation (2nd landing / Phase IIb),
   • If ≤ 2 failures: + 3 patients,
   • If > 2 failures on 6 patients: cessation,
   • If ≤ 2 failures on 6 patients: continuation (2nd landing / phase IIb),
   • If 3 failures: cessation.

3. rd part:

   • p0 = 0.70 = upper limit of the success rate resulting in the inefficacy of HIFU multi-shootings.
   • p1 = 0.90 = lower limit of the success rate resulting in the efficacy of HIFU shootings.

With a 5% risk of type I error and a 80% power, 28 metastases have to be targeted by HIFU in order to conclude in one-sided situation. Taking into account that an average of 1.5 metastases will be targeted in each patient, 20 patients will be enrolled. 24 observed successes will allow concluding in the reject of H0 to accept H1.

Inclusion Criteria:

• 18 years old or more patient,
• Affected of hepatic metastasis of a colorectal cancer,
• Who must undergo a hepatectomy by laparotomy with the aim of the resection of hepatic metastasis,
• ECOG performance status (PS) = 1,
• Mandatory affiliation to a health security insurance,
• Written informed consent.

Exclusion Criteria:

• Having already undergone a major hepatic surgery (more than three segments) or biliary major (context of major iterative hepatic surgery),
• Having already undergone a major abdominal surgery with the exception of a colorectal surgery for the treatment of its primitive tumor (the surgery of the gall-bladder by laparoscopy for the deadline upper to 6 months do not constitute a criterion of not inclusion),
• Unable to be followed during the duration of the study,
• Pregnant or breast-feeding woman (a pregnancy test must be negative at the time of the inclusion in the study for the women in age to procreate; a method of reliable contraception must be used during the duration of the study).