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

• ClinicalTrials.gov Identifier: NCT01489787
• Recruitment Status: Unknown
• First Posted: December 12, 2011
• Last Update Posted: January 29, 2018
• Sponsor: Centre Leon Berard
• Collaborators: National Cancer Institute, France; Cancéropôle Lyon Auvergne Rhône-Alpes
• Information provided by (Responsible Party): Centre Leon Berard

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Neoplasm Metastasis	Procedure: HIFU	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 38 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: March 2010
• Estimated Primary Completion Date: October 2019
• Estimated Study Completion Date: December 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase I : HIFU	Procedure: HIFU; 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.
Experimental: Phase IIa : HIFU	Procedure: HIFU; 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)
Experimental: Phase IIb : HIFU	Procedure: HIFU; 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

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
2. Phase IIa - First step: accuracy of shootings on a precise area [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   both the distance between the hurt epicentre generated by hifu and a mark. These sizes will be measured in mm during anatomopathological exam.
3. Phase IIb: possibility of ≤ 15 shootings, safety margin ≥ 5 mm in healthy liver. [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
4. Phase IIa - Second step: accuracy of shootings on a zone to be spared [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   between the hurt limit and a vessel border previously marked. These sizes will be measured in mm during anatomopathological exam.

Secondary Outcome Measures :

1. Phase I: adjust the probe position to different liver segments and patient physical structure. [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   The aim is to be free to generate a HIFU hurt in at least 80 % of the total liver volume
2. Phase I: Possibility to set a stationary mark, at given depth, echographically detectable [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
3. Phase I: Possibility to spot echographically a previously Patent Blue or Methylene blue marked vessel [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
4. Phase I: Mean duration to achieve each step expressed in minutes(initialization, conditioning, targeting, shooting) [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
5. Phase I: description of outline during perioperative echography [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   diameters, depth, volume
6. Phase I: description of limits during anatomopathological analysis [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   diameters, depth, volume
7. Phase I: distance between the mark / marked vessel and the hurt limits during anatomopathological analysis [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   Precise measure given in mm by the anatomopathologist
8. Phase II: safety of the device [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   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
9. Phase II: assessment of vital signs during shooting phase [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
   hemodynamic, respiratory, body temperature
10. Phase IIa: correlation between hurt perioperative echographic and postoperative macroscopic, measures [ Time Frame: At the end of surgery (realized about 1 week after enrollment) ]
    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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Contacts

Contact: Séverine METZGER; +33 478 78 27 86; severine.metzger@lyon.unicancer.fr

Locations

France

Centre Léon Bérard; Recruiting

Lyon, France, 69373

Contact: Michel RIVOIRE +33 478 78 28 28 michel.rivoire@lyon.unicancer.fr

Principal Investigator: Michel RIVOIRE

Sponsors and Collaborators

Centre Leon Berard

National Cancer Institute, France

Cancéropôle Lyon Auvergne Rhône-Alpes

Investigators

• Principal Investigator: Michel RIVOIRE; Centre Léon Bérard, LYON, FRANCE

More Information

Publications:

Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006 Aug;244(2):254-9.

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Mulier S, Ni Y, Jamart J, Ruers T, Marchal G, Michel L. Local recurrence after hepatic radiofrequency coagulation: multivariate meta-analysis and review of contributing factors. Ann Surg. 2005 Aug;242(2):158-71. Review.

Rivoire M, De Cian F, Meeus P, Négrier S, Sebban H, Kaemmerlen P. Combination of neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma. Cancer. 2002 Dec 1;95(11):2283-92.

Antoniou A, Lovegrove RE, Tilney HS, Heriot AG, John TG, Rees M, Tekkis PP, Welsh FK. Meta-analysis of clinical outcome after first and second liver resection for colorectal metastases. Surgery. 2007 Jan;141(1):9-18. Epub 2006 Nov 17.

Pawlik TM, Schulick RD, Choti MA. Expanding criteria for resectability of colorectal liver metastases. Oncologist. 2008 Jan;13(1):51-64. doi: 10.1634/theoncologist.2007-0142. Review.

Garcea G, Lloyd TD, Aylott C, Maddern G, Berry DP. The emergent role of focal liver ablation techniques in the treatment of primary and secondary liver tumours. Eur J Cancer. 2003 Oct;39(15):2150-64. Review.

Seifert JK, Morris DL. Indicators of recurrence following cryotherapy for hepatic metastases from colorectal cancer. Br J Surg. 1999 Feb;86(2):234-40.

Coleman DJ, Lizzi FL, Driller J, Rosado AL, Burgess SE, Torpey JH, Smith ME, Silverman RH, Yablonski ME, Chang S, et al. Therapeutic ultrasound in the treatment of glaucoma. II. Clinical applications. Ophthalmology. 1985 Mar;92(3):347-53.

Valtot F, Kopel J, Petit E, Moulin F, Haut J. [Treatment of refractory glaucoma with high density focused ultrasonics]. J Fr Ophtalmol. 1995;18(1):3-12. Review. French.

Chapelon JY, Margonari J, Vernier F, Gorry F, Ecochard R, Gelet A. In vivo effects of high-intensity ultrasound on prostatic adenocarcinoma Dunning R3327. Cancer Res. 1992 Nov 15;52(22):6353-7.

Poissonnier L, Chapelon JY, Rouvière O, Curiel L, Bouvier R, Martin X, Dubernard JM, Gelet A. Control of prostate cancer by transrectal HIFU in 227 patients. Eur Urol. 2007 Feb;51(2):381-7. Epub 2006 May 2.

Kinsey AM, Diederich CJ, Rieke V, Nau WH, Pauly KB, Bouley D, Sommer G. Transurethral ultrasound applicators with dynamic multi-sector control for prostate thermal therapy: in vivo evaluation under MR guidance. Med Phys. 2008 May;35(5):2081-93.

Madersbacher S, Pedevilla M, Vingers L, Susani M, Marberger M. Effect of high-intensity focused ultrasound on human prostate cancer in vivo. Cancer Res. 1995 Aug 1;55(15):3346-51.

Vallancien G, Harouni M, Guillonneau B, Veillon B, Bougaran J. Ablation of superficial bladder tumors with focused extracorporeal pyrotherapy. Urology. 1996 Feb;47(2):204-7.

Wu F, Wang ZB, Cao YD, Zhu XQ, Zhu H, Chen WZ, Zou JZ. "Wide local ablation" of localized breast cancer using high intensity focused ultrasound. J Surg Oncol. 2007 Aug 1;96(2):130-6.

Melodelima D, Prat F, Fritsch J, Theillere Y, Cathignol D. Treatment of esophageal tumors using high intensity intraluminal ultrasound: first clinical results. J Transl Med. 2008 Jun 5;6:28. doi: 10.1186/1479-5876-6-28.

Wu F, Wang ZB, Chen WZ, Zhu H, Bai J, Zou JZ, Li KQ, Jin CB, Xie FL, Su HB. Extracorporeal high intensity focused ultrasound ablation in the treatment of patients with large hepatocellular carcinoma. Ann Surg Oncol. 2004 Dec;11(12):1061-9. Epub 2004 Nov 15.

Vaezy S, Fujimoto VY, Walker C, Martin RW, Chi EY, Crum LA. Treatment of uterine fibroid tumors in a nude mouse model using high-intensity focused ultrasound. Am J Obstet Gynecol. 2000 Jul;183(1):6-11.

Marquet F, Pernot M, Aubry JF, Montaldo G, Marsac L, Tanter M, Fink M. Non-invasive transcranial ultrasound therapy based on a 3D CT scan: protocol validation and in vitro results. Phys Med Biol. 2009 May 7;54(9):2597-613. doi: 10.1088/0031-9155/54/9/001. Epub 2009 Apr 8.

Uchida T, Ohkusa H, Nagata Y, Hyodo T, Satoh T, Irie A. Treatment of localized prostate cancer using high-intensity focused ultrasound. BJU Int. 2006 Jan;97(1):56-61.

Melodelima D, N'Djin WA, Parmentier H, Chesnais S, Rivoire M, Chapelon JY. Thermal ablation by high-intensity-focused ultrasound using a toroid transducer increases the coagulated volume. Results of animal experiments. Ultrasound Med Biol. 2009 Mar;35(3):425-35. doi: 10.1016/j.ultrasmedbio.2008.09.020. Epub 2008 Dec 10.

Parmentier H, Melodelima D, N'Djin A, Chesnais S, Chapelon JY, Rivoire M. High-intensity focused ultrasound ablation for the treatment of colorectal liver metastases during an open procedure: study on the pig. Ann Surg. 2009 Jan;249(1):129-36. doi: 10.1097/SLA.0b013e31818c70b6. Erratum in: Ann Surg. 2009 Sep;250(3):506. Hubert, Parmentier [corrected to Parmentier, Hubert]; David, Melodelima, David [corrected to Melodelima, David]; Apoutou, N'Djin [corrected to N'Djin, Apoutou]; Sabrina, Chesnais [corrected to Chesnais, Sabrina]; Yves, Chapelon Jean [corrected to Chapelon,.

N'Djin WA, Melodelima D, Parmentier H, Chesnais S, Rivoire M, Chapelon JY. Utility of a tumor-mimic model for the evaluation of the accuracy of HIFU treatments. results of in vitro experiments in the liver. Ultrasound Med Biol. 2008 Dec;34(12):1934-43. doi: 10.1016/j.ultrasmedbio.2008.04.012. Epub 2008 Jul 14.

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dupré A, Melodelima D, Pérol D, Chen Y, Vincenot J, Chapelon JY, Rivoire M. First clinical experience of intra-operative high intensity focused ultrasound in patients with colorectal liver metastases: a phase I-IIa study. PLoS One. 2015 Feb 26;10(2):e0118212. doi: 10.1371/journal.pone.0118212. eCollection 2015. Erratum in: PLoS One. 2015;10(3):e0123751.

• Responsible Party: Centre Leon Berard
• ClinicalTrials.gov Identifier: NCT01489787
• Other Study ID Numbers: HIFU; ET2009-068 ( Other Identifier: Sponsor number )
• First Posted: December 12, 2011
• Last Update Posted: January 29, 2018
• Last Verified: January 2017

Keywords provided by Centre Leon Berard:

Surgery; Ultrasonic therapy; Liver

Additional relevant MeSH terms:

Neoplasm Metastasis; Neoplastic Processes; Neoplasms; Pathologic Processes