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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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. 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. 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: 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. 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. 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.

Official Title
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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.

Conditions
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Neoplasm Metastasis

Intervention / Treatment
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* Procedure: HIFU
* Procedure: HIFU
* Procedure: HIFU


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I : HIFU<br> | Procedure: HIFU<br>* The shootings will concern the healthy liver to remove, distant to the important vascular structures and metastases. Two HIFU shootings will be made on each patient: One hurt on the surface starting from the Glisson capsule and extending to subjacent hepatic parenchyma. One hurt at given depth, at least 10 mm deeper than the hurt done on the surface NB: The shooting depth will determined for each patient at the beginning of the operation, considering preoperative exams (scans, etc.), size and location of the liver part to be resected and physical structure of the patient.<br>|
| Experimental: Phase IIa : HIFU<br> | Procedure: HIFU<br>* The shootings will concern healthy liver to be resected, distant (step 1) then close (step 2) to the important vascular structures of the liver. Several shootings HIFU will be made on each patient (ideally 4 hurts, minimum 2 hurts)<br>|
| Experimental: Phase IIb : HIFU<br> | Procedure: HIFU<br>* Shootings will concern small metastases (≤ 20 mm) and peri lesional healthy liver. They will be juxtaposed on multiple plans in order to generate a large hurt containing the metastasis targeted and guaranteeing a sufficient safety margin in healthy liver. Several metastases can be treated in the same patient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First step: Ability to shoot and supplementary duration of intervention, to use the medical device following requested asepsis procedures and no evidence of hurt on peripheral tissues and to keep vital signs stable |  | At the end of surgery (realized about 1 week after enrollment) | 
| Phase IIa - First step: accuracy of shootings on a precise area | both the distance between the hurt epicentre generated by hifu and a mark. These sizes will be measured in mm during anatomopathological exam. | At the end of surgery (realized about 1 week after enrollment) | 
| Phase IIb: possibility of ≤ 15 shootings, safety margin ≥ 5 mm in healthy liver. |  | At the end of surgery (realized about 1 week after enrollment) | 
| Phase IIa - Second step: accuracy of shootings on a zone to be spared | between the hurt limit and a vessel border previously marked. These sizes will be measured in mm during anatomopathological exam. | At the end of surgery (realized about 1 week after enrollment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: adjust the probe position to different liver segments and patient physical structure. | The aim is to be free to generate a HIFU hurt in at least 80 % of the total liver volume | At the end of surgery (realized about 1 week after enrollment) | 
| Phase I: Possibility to set a stationary mark, at given depth, echographically detectable |  | At the end of surgery (realized about 1 week after enrollment) | 
| Phase I: Possibility to spot echographically a previously Patent Blue or Methylene blue marked vessel |  | At the end of surgery (realized about 1 week after enrollment) | 
| Phase I: Mean duration to achieve each step expressed in minutes(initialization, conditioning, targeting, shooting) |  | At the end of surgery (realized about 1 week after enrollment) | 
| Phase I: description of outline during perioperative echography | diameters, depth, volume | At the end of surgery (realized about 1 week after enrollment) | 
| Phase I: description of limits during anatomopathological analysis | diameters, depth, volume | At the end of surgery (realized about 1 week after enrollment) | 
| Phase I: distance between the mark / marked vessel and the hurt limits during anatomopathological analysis | Precise measure given in mm by the anatomopathologist | At the end of surgery (realized about 1 week after enrollment) | 
| Phase II: safety of the device | no evidence of hurt on peripheral tissues (Glisson capsule on the opposite side of the HIFU shootings entrance area, retro-peritoneal, retro-hepatic tissues and diaphragm | At the end of surgery (realized about 1 week after enrollment) | 
| Phase II: assessment of vital signs during shooting phase | hemodynamic, respiratory, body temperature | At the end of surgery (realized about 1 week after enrollment) | 
| Phase IIa: correlation between hurt perioperative echographic and postoperative macroscopic, measures | hurt dimensions comparison (diameters, depth, volume, etc. - in mm), blind-measured, with echography in a first time and in a second time, right after the resection, in anatomopathology | At the end of surgery (realized about 1 week after enrollment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surgery, Ultrasonic therapy, Liver