Clinical trial NCT06236633: Safety & Efficacy of Ischemic Preconditioning by Embolization of the Inferior Mesenteric Artery in Surgery for Tumors of Lower and Middle Rectum
Official title: Evaluation of the Safety and Efficacy of Ischemic Preconditioning by Embolization of the Inferior Mesenteric Artery in Oncologic Surgery for Tumors of the Lower and Middle Rectum. Bicentric Exploratory Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cancer, Rectal
Keywords: Ischemic preconditioning surgery
Cancer, Rectal
Inferior Mesenteric Artery Embolus
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
First posted: 2024-02-01
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pilot exploratory descriptive prospective bicentric study to evaluate the safety and efficacy of an innovative procedure: inferior mesenteric artery embolization prior to rectal cancer surgery involving 2 groups: one with standard treatment and the other with inferior mesenteric artery embolization.
Primary purpose: TREATMENT

Brief summary: The present study will investigate the safety of inferior mesenteric artery embolization prior to rectal surgery, according to IDEAL recommendations (Lancet 2009). It aims to assess the safety of endovascular embolization of the inferior mesenteric artery prior to surgery in patients with rectal tumors, and estimate the potential benefits in terms of time to surgery and the occurrence of post-operative fistulas.The study will also assess the impact of subacute ischemia induced by IMA embolization on colonic vasculature remodeling, colonic ischemic suffering, altered hemostasis and initiation of neo-angiogenesis through blood sampling kinetics.The hypothesis is that ischemic preconditioning by inferior mesenteric artery embolization prior to rectal cancer resection surgery is safe and will result in a decrease in acute relative colon ischemia and a reduction in the rate of fistulas and post-surgical complications. Indeed, we believe that the beneficial effects of the ischemic preconditioning of IMA will be due to better blood perfusion of the colon at 3 weeks, which is apparently linked to remodeling and/or the development of collateral vascularization.

Detailed description: Anastomotic fistulas are the main cause of morbidity and mortality in colorectal surgery. They are responsible for septic complications, leading to increased mortality, local recurrence, repeat surgery and impaired sexual, urinary and digestive function. Fistulas are multifactorial; among the causes, colonic vascularization seems to be a major one. Ligation of the inferior mesenteric artery during rectal surgery has been shown to reduce intraoperative colonic perfusion flow. The left colon is then vascularized only by the colonic border arcade, perfused by the superior mesenteric artery. Ischemic pre-conditioning of the arterial network prior to surgery should ensure better vascularization by developing arterial collaterality and increasing perfusion flow in the colonic border arcade. In view of major advances in interventional radiology, this preconditioning could be achieved by endovascular ligation of the inferior mesenteric artery (IMA), based on the same principle as during surgery: proximal occlusion of the inferior mesenteric artery (IMA), using embolization material (plug or coils), 3 weeks before surgery, to allow the colonic border arcade to develop. We carried out a single-center pilot study (AMIREMBOL 1, NIMAO 2017; Frandon et al. 2022) to assess the feasibility of ischemic preconditioning of the colon for patients with rectal or sigmoid cancer. The study included 10 patients, randomized into two groups: the control group, with preoperative arteriography and standard management and the "embolization" group, with embolization of the IMA three weeks prior to surgery. IMA embolization was successfully performed in all 5 patients in the embolization group, with no major complications. The effect on colonic perfusion, measured by intraoperative Doppler directly on the border arch, with recording of resistance indexes (independent of measurement angle), showed a drop in resistance indexes in the control arm, after ligation of the IMA, which persisted after 5 minutes. In the "Embolization" arm, no drop in this index was reported during surgery, reflecting good development of vascular collaterality and at least relative acute ischemia of the colon after IMA ligation during surgery. Finally, in the "control" group, one anastomotic fistula was reported after surgery and required re-operation. There were no fistulas in the embolization group.

The present study (AMIREMBOL 2) will investigate the safety of IMA embolization prior to rectal surgery, according to IDEAL recommendations (Lancet 2009). Its aim is to assess the safety of endovascular embolization of the IMA prior to surgery in patients with rectal tumors, and to estimate the potential benefits in terms of time to surgery and the occurrence of post-operative fistulas.

The study will also assess the impact of subacute ischemia induced by IMA embolization on colonic vasculature remodeling, colonic ischemic suffering, altered hemostasis and initiation of neo-angiogenesis through blood sampling kinetics.

The hypothesis is that ischemic preconditioning by inferior mesenteric artery (IMA) embolization prior to rectal cancer resection surgery is safe and will result in a decrease in acute relative colon ischemia and a reduction in the rate of fistulas and post-surgical complications. The hypothesis is that the beneficial effects of the ischemic preconditioning of IMA will be due to better blood perfusion of the colon at 3 weeks, which is apparently linked to remodeling and/or the development of collateral vascularization.

Eligibility criteria: Inclusion Criteria:

* Patients with cancer of the lower or middle rectum, eligible for surgical treatment requiring ligation at the origin of the inferior mesenteric artery.
* Patients with free, informed consent.
* Patients affiliated to or benefiting from a health insurance plan.

Exclusion Criteria:

* Patients with history of abdominal surgery.
* Patients with occlusion of the superior mesenteric artery or stenosis of more than 50%, visible on the CT scan performed as part of conventional management during extension workup.
* Patients with occlusion of the IMA on the extension scan.
* Patients with a systemic disorder responsible for haemostasis (haemophilia, Willebrand's disease, thrombocytopenia) and on anticoagulant therapy.
* Patients taking corticosteroids or immunosuppressants leading to an unacceptable surgical risk.
* Patients with renal insufficiency with clearance \< 30mL/min.
* Patients with an allergy to iodine.
* Patients who has had treatment of the abdominal aorta or its branches.
* Patients participating in an interventional study.
* Patients in an exclusion period determined by another study.
* Patients under court protection, guardianship or curatorship.
* Patients unable to give consent.
* Patients for whom it is impossible to provide informed information.
* Pregnant or breast-feeding patients.

Primary outcomes:
measure: Safety of endovascular inferior mesenteric artery embolisation prior to surgical resection of the rectum in patients with tumours of the lower and middle rectum.
timeFrame: Day 7 post embolization (performed 3 weeks before surgical resection of the rectum)
Secondary outcomes:
measure: Technical success of the embolization procedure
timeFrame: Day 0, on the day of embolization
measure: Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade I
timeFrame: Post-operative Day 30
measure: Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade II
timeFrame: Post-operative Day 30
measure: Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IIIa
timeFrame: Post-operative Day 30
measure: Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IIIb
timeFrame: Post-operative Day 30
measure: Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IVa
timeFrame: Post-operative Day 30
measure: Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IVb
timeFrame: Post-operative Day 30
measure: Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade V
timeFrame: Post-operative Day 30
measure: Rate of fistulas up to 30 days after surgery
timeFrame: Day 0
measure: Rate of fistulas up to 30 days after surgery
timeFrame: Post-operative Day 30
measure: Duration of post-surgical hospitalization
timeFrame: Up to 30 days after rectal surgery
measure: Degree of difficulty experienced by the visceral surgeon during surgery
timeFrame: Week 3 to 4 on the day of rectal surgery
measure: Systemic inflammation markers: Pro-inflammation cytokines
timeFrame: Day 0 (on the day of inclusion)
measure: Systemic inflammation markers: Pro-inflammation cytokines
timeFrame: 25 minutes before embolization
measure: Systemic inflammation markers: Pro-inflammation cytokines
timeFrame: 60 minutes after embolization
measure: Systemic inflammation markers: Pro-inflammation cytokines
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Systemic inflammation markers: Complement protein C3
timeFrame: Day 0 (on the day of inclusion)
measure: Systemic inflammation markers: Complement protein C3
timeFrame: 25 minutes before embolization
measure: Systemic inflammation markers: Complement protein C3
timeFrame: 60 minutes after embolization
measure: Systemic inflammation markers: Complement protein C3
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Anti-inflammation markers:
timeFrame: Day 0 (on the day of inclusion)
measure: Anti-inflammation markers:
timeFrame: 25 minutes before embolization
measure: Anti-inflammation markers:
timeFrame: 60 minutes after embolization
measure: Anti-inflammation markers:
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Hemostasis markers : Von Willebrand factor
timeFrame: Day 0 (on the day of inclusion)
measure: Hemostasis markers : Von Willebrand factor
timeFrame: 25 minutes before embolization
measure: Hemostasis markers : Von Willebrand factor
timeFrame: 60 minutes after embolization
measure: Hemostasis markers : Von Willebrand factor
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Hemostasis markers : coagulation factor V
timeFrame: Day 0 (on the day of inclusion)
measure: Hemostasis markers : coagulation factor V
timeFrame: 25 minutes before embolization
measure: Hemostasis markers : coagulation factor V
timeFrame: 60 minutes after embolization
measure: Hemostasis markers : coagulation factor V
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Hemostasis markers : D-dimers
timeFrame: Day 0 (on the day of inclusion)
measure: Hemostasis markers : D-dimers
timeFrame: 25 minutes before embolization
measure: Hemostasis markers : D-dimers
timeFrame: 60 minutes after embolization
measure: Hemostasis markers : D-dimers
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Hemostasis markers : platelet-activating factor (PAF)
timeFrame: Day 0 (on the day of inclusion)
measure: Hemostasis markers : platelet-activating factor (PAF)
timeFrame: 25 minutes before embolization
measure: Hemostasis markers : platelet-activating factor (PAF)
timeFrame: 60 minutes after embolization
measure: Hemostasis markers : platelet-activating factor (PAF)
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Hemostasis markers : prostaglandin E4
timeFrame: Day 0 (on the day of inclusion)
measure: Hemostasis markers : prostaglandin E4
timeFrame: 25 minutes before embolization
measure: Hemostasis markers : prostaglandin E4
timeFrame: 60 minutes after embolization
measure: Hemostasis markers : prostaglandin E4
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Hemostasis markers : Thromboxane B2
timeFrame: Day 0 (on the day of inclusion)
measure: Hemostasis markers : Thromboxane B2
timeFrame: 25 minutes before embolization
measure: Hemostasis markers : Thromboxane B2
timeFrame: 60 minutes after embolization
measure: Hemostasis markers : Thromboxane B2
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of tissue inflammation: Blood pH
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of tissue inflammation: Blood pH
timeFrame: 25 minutes before embolization
measure: Markers of tissue inflammation: Blood pH
timeFrame: 60 minutes after embolization
measure: Markers of tissue inflammation: Blood pH
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of tissue inflammation: ischemia-modified albumin
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of tissue inflammation: ischemia-modified albumin
timeFrame: 25 minutes before embolization
measure: Markers of tissue inflammation: ischemia-modified albumin
timeFrame: 60 minutes after embolization
measure: Markers of tissue inflammation: ischemia-modified albumin
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of tissue inflammation:intestinal fatty acid-binding protein (I-FABP)
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of tissue inflammation:intestinal fatty acid-binding protein (I-FABP)
timeFrame: 25 minutes before embolization
measure: Markers of tissue inflammation:intestinal fatty acid-binding protein (I-FABP)
timeFrame: 60 minutes after embolization
measure: Markers of tissue inflammation:intestinal fatty acid-binding protein (I-FABP)
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of tissue inflammation: L-lactate
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of tissue inflammation: L-lactate
timeFrame: 25 minutes before embolization
measure: Markers of tissue inflammation: L-lactate
timeFrame: 60 minutes after embolization
measure: Markers of tissue inflammation: L-lactate
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of tissue inflammation: D-lactate
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of tissue inflammation: D-lactate
timeFrame: 25 minutes before embolization
measure: Markers of tissue inflammation: D-lactate
timeFrame: 60 minutes after embolization
measure: Markers of tissue inflammation: D-lactate
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of tissue inflammation: Lactate dehydrogenase
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of tissue inflammation: Lactate dehydrogenase
timeFrame: 25 minutes before embolization
measure: Markers of tissue inflammation: Lactate dehydrogenase
timeFrame: 60 minutes after embolization
measure: Markers of tissue inflammation: Lactate dehydrogenase
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of neoangiogenesis : CD34
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of neoangiogenesis : CD34
timeFrame: 25 minutes before embolization
measure: Markers of neoangiogenesis : CD34
timeFrame: 60 minutes after embolization
measure: Markers of neoangiogenesis : CD34
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of neoangiogenesis : transcription factor HIF1-α
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of neoangiogenesis : transcription factor HIF1-α
timeFrame: 25 minutes before embolization
measure: Markers of neoangiogenesis : transcription factor HIF1-α
timeFrame: 60 minutes after embolization
measure: Markers of neoangiogenesis : transcription factor HIF1-α
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of neoangiogenesis : Growth factors
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of neoangiogenesis : Growth factors
timeFrame: 25 minutes before embolization
measure: Markers of neoangiogenesis : Growth factors
timeFrame: 60 minutes after embolization
measure: Markers of neoangiogenesis : Growth factors
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 2
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 2
timeFrame: 25 minutes before embolization
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 2
timeFrame: 60 minutes after embolization
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 2
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 9
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 9
timeFrame: 25 minutes before embolization
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 9
timeFrame: 60 minutes after embolization
measure: Markers of epithelial-mesenchymal transition : matrix metallo-protease - 9
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
measure: Markers of epithelial-mesenchymal transition : transcription factors
timeFrame: Day 0 (on the day of inclusion)
measure: Markers of epithelial-mesenchymal transition : transcription factors
timeFrame: 25 minutes before embolization
measure: Markers of epithelial-mesenchymal transition : transcription factors
timeFrame: 60 minutes after embolization
measure: Markers of epithelial-mesenchymal transition : transcription factors
timeFrame: Week 3 to 4 after patient induction just before rectal surgery
Other outcomes:
measure: Gender
timeFrame: Day 0, on the day of inclusion
measure: Age
timeFrame: Day 0, on the day of inclusion
measure: Height
timeFrame: Day 0, on the day of inclusion
measure: Tumor stage
timeFrame: Day 0, on the day of inclusion
measure: Tumor, Node and Metastasis staging (TNM)
timeFrame: Day 0, on the day of inclusion
measure: Circumferential resection margin
timeFrame: Week 3 or 4 on the day of surgery
measure: Distance from the lower pole of the tumor relative to the upper edge of the anal sphincter
timeFrame: Week 3 or 4 on the day of surgery
measure: Bi-ischial diameter
timeFrame: Week 3 or 4 on the day of surgery
measure: Bi-uterine diameter
timeFrame: Week 3 or 4 on the day of surgery
measure: Mesorectal area
timeFrame: Week 3 or 4 on the day of surgery
measure: Type of surgery
timeFrame: Week 3 or 4 on the day of surgery
measure: Cardiovascular risk factors
timeFrame: Day 0 on the day of inclusion
measure: Presence of the border arcade, occlusion of the mesenteric artery during arteriography.
timeFrame: Day 0 on the day of inclusion
measure: Operative data
timeFrame: Week 3 or 4 on the day of surgery
Locations:
city: Montpellier
country: France
facility: Hôpital Saint-Eloi
city: Montpellier
country: France
facility: Institut du Cancer de Montpellier
city: Nîmes
country: France
facility: CHU de Nîmes
Study officials:
References: