Safety & Efficacy of Ischemic Preconditioning by Embolization of the Inferior Mesenteric Artery in Surgery for Tumors of Lower and Middle Rectum

Not Applicable

Recruiting

• Conditions: Cancer, Rectal
• Interventions: Procedure: Ischemic preconditioning; Procedure: Arteriogram

• Registration Number: NCT06236633
• Lead Sponsor: Centre Hospitalier Universitaire de Nīmes

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.

Study Timeline

• Study First Submitted: 2024-01-24
• Study First Submitted QC: 2024-01-31
• Study First Posted: 2024-02-01
• Status Verified: 2024-08
• Study Start: 2024-08-02
• Last Update Submitted: 2024-08-02
• Last Update Posted: 2024-08-05
• Primary Completion: 2025-08-01
• Study Completion: 2026-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ischemic preconditioning group	Ischemic preconditioning	In the experimental group, patients will undergo preoperative arteriography and ischemic preconditioning One blood sample will be taken before and two samples taken after embolization of the IMA. These patients will receive a phone call on Day 7 post embolization. A blood sample will also be taken at the time of surgery.
Ischemic preconditioning group	Arteriogram	In the experimental group, patients will undergo preoperative arteriography and ischemic preconditioning One blood sample will be taken before and two samples taken after embolization of the IMA. These patients will receive a phone call on Day 7 post embolization. A blood sample will also be taken at the time of surgery.

Primary Outcome Measures

Name	Time	Method
Safety of endovascular inferior mesenteric artery embolisation prior to surgical resection of the rectum in patients with tumours of the lower and middle rectum.	Day 7 post embolization (performed 3 weeks before surgical resection of the rectum)	Percentage of patients with a complication (any grade) within 7 days after embolisation of the inferior mesenteric artery according to the classification of the International Society of Interventional Radiology assessed during the follow-up telephone consultation by the interventional radiologist.; Complications will be classified as minor (Grades A and B) or Major (grades C to F).; Grade A = No therapy, no consequence Grade B = Nominal therapy, no consequence. Includes overnight admission for observation only Grade C = Requires therapy, minor hospitalization (\<48 hours) Grade D = Requires major therapy. Unplanned increase in level of care. Prolonged hospitalization (\>48 hours) Grade E = Permanent adverse sequelae Grade F= Death

Secondary Outcome Measures

Name	Time	Method
Technical success of the embolization procedure	Day 0, on the day of embolization	A control arteriogram of the inferior and superior mesenteric arteries will be carried out at the end of the embolisation procedure: intravascular injection into the inferior mesenteric artery and control of the resumption of vascularisation of the distal inferior mesenteric artery by the border arcade by injecting into the superior mesenteric artery.; If embolisation fails, the patient will continue the study.; The number of failures will be converted into a percentage
Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade II	Post-operative Day 30	Percentage of patients presenting a post-operative complication according to the Clavien-Dindo Classification within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.; The Clavien-Dindo classification (Dindo et al 2004, Dindo D. 2004) classifies surgical complications into 7 categories (I, II, IIIa, IIIb, IVa, IVb and V)
Anti-inflammation markers:	Week 3 to 4 after patient induction just before rectal surgery	IL-10 and Transforming Growth Factor-β will be measured as percentages
Markers of neoangiogenesis : CD34	Week 3 to 4 after patient induction just before rectal surgery	CD34 will be measured
Markers of neoangiogenesis : transcription factor HIF1-α	Week 3 to 4 after patient induction just before rectal surgery	Transcription factor HIF1-α will be measured
Markers of neoangiogenesis : Growth factors	Week 3 to 4 after patient induction just before rectal surgery	Growth factors and their receptors, notably vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) and platelet-derived growth factor (PDGF) and platelet-derived growth factor receptor (PDGFR) will be measured
Markers of epithelial-mesenchymal transition : transcription factors	Week 3 to 4 after patient induction just before rectal surgery	Transcription factors SNAI2 (SLUG), SNAIL (SNAI1) and zinc-finger E-box binding homeobox (ZEB-1) will be measured
Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade I	Post-operative Day 30	Percentage of patients presenting a post-operative complication according to the Clavien-Dindo Classification within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.; The Clavien-Dindo classification (Dindo et al 2004, Dindo D. 2004) classifies surgical complications into 7 categories (I, II, IIIa, IIIb, IVa, IVb and V)
Rate of fistulas up to 30 days after surgery	Post-operative Day 30	Percentage of patients with a fistula within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.A fistula will be identified either on the basis of clinical criteria (presence of pus or enteric contents in the drains, leakage of contrast medium through the anastomosis, anastomotic dehiscence during a repeat operation), or on the basis of radiological criteria (presence of an abdominal or pelvic collection in the area of the anastomosis on CT scan) if there is clinical doubt or if a CT scan is carried out for another reason (before stoma closure, for example).
Hemostasis markers : D-dimers	Week 3 to 4 after patient induction just before rectal surgery	D-dimers will be measured
Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IIIa	Post-operative Day 30	Percentage of patients presenting a post-operative complication according to the Clavien-Dindo Classification within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.; The Clavien-Dindo classification (Dindo et al 2004, Dindo D. 2004) classifies surgical complications into 7 categories (I, II, IIIa, IIIb, IVa, IVb and V)
Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IVa	Post-operative Day 30	Percentage of patients presenting a post-operative complication according to the Clavien-Dindo Classification within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.; The Clavien-Dindo classification (Dindo et al 2004, Dindo D. 2004) classifies surgical complications into 7 categories (I, II, IIIa, IIIb, IVa, IVb and V)
Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IVb	Post-operative Day 30	Percentage of patients presenting a post-operative complication according to the Clavien-Dindo Classification within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.; The Clavien-Dindo classification (Dindo et al 2004, Dindo D. 2004) classifies surgical complications into 7 categories (I, II, IIIa, IIIb, IVa, IVb and V)
Hemostasis markers : Von Willebrand factor	Week 3 to 4 after patient induction just before rectal surgery	Von Willebrand factor will be measured.
Hemostasis markers : prostaglandin E4	Week 3 to 4 after patient induction just before rectal surgery	Prostaglandin E4 will be measured
Markers of tissue inflammation: L-lactate	Week 3 to 4 after patient induction just before rectal surgery	L-lactate will be measured
Markers of tissue inflammation: D-lactate	Week 3 to 4 after patient induction just before rectal surgery	D-lactate will be measured
Hemostasis markers : platelet-activating factor (PAF)	Week 3 to 4 after patient induction just before rectal surgery	Platelet-activating factor (PAF) will be measured
Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade IIIb	Post-operative Day 30	Percentage of patients presenting a post-operative complication according to the Clavien-Dindo Classification within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.; The Clavien-Dindo classification (Dindo et al 2004, Dindo D. 2004) classifies surgical complications into 7 categories (I, II, IIIa, IIIb, IVa, IVb and V)
Systemic inflammation markers: Pro-inflammation cytokines	Week 3 to 4 after patient induction just before rectal surgery	Pro-inflammation cytokines (IL-1β, IL-6, IL-8, Tumor Necrosis Factor-α and Interferon-ɣ) will be measured as percentages
Markers of tissue inflammation: Blood pH	Week 3 to 4 after patient induction just before rectal surgery	Blood pH will be measured
Markers of tissue inflammation:intestinal fatty acid-binding protein (I-FABP)	Week 3 to 4 after patient induction just before rectal surgery	intestinal fatty acid-binding protein (I-FABP) will be measured
Markers of tissue inflammation: Lactate dehydrogenase	Week 3 to 4 after patient induction just before rectal surgery	Lactate dehydrogenase will be measured
Markers of epithelial-mesenchymal transition : matrix metallo-protease - 2	Week 3 to 4 after patient induction just before rectal surgery	Matrix metallo-protease - 2 will be measured
Post-surgical complications up to 30 days after surgery. Clavien-Dindo Grade V	Post-operative Day 30	Percentage of patients presenting a post-operative complication according to the Clavien-Dindo Classification within 30 days of rectal surgery, assessed during hospitalization and at the 1-month post-surgical consultation, according to standard management.; The Clavien-Dindo classification (Dindo et al 2004, Dindo D. 2004) classifies surgical complications into 7 categories (I, II, IIIa, IIIb, IVa, IVb and V)
Duration of post-surgical hospitalization	Up to 30 days after rectal surgery	Length of hospital stay (number of days)
Systemic inflammation markers: Complement protein C3	Week 3 to 4 after patient induction just before rectal surgery	Complement protein C3 will be measured as a percentage
Markers of tissue inflammation: ischemia-modified albumin	Week 3 to 4 after patient induction just before rectal surgery	Ischemia-modified albumin will be measured
Degree of difficulty experienced by the visceral surgeon during surgery	Week 3 to 4 on the day of rectal surgery	Surgeon's assessment of degree of difficulty using a 4-point Likert scale after each operation as follows : 1= Dissection of the inferior mesenteric artery was standard 2 = Dissection of the inferior mesenteric artery was more complicated than expected 3 = Dissection of the inferior mesenteric artery was much more complicated than expected; 4 = Dissection of the inferior mesenteric artery was Very difficult.
Hemostasis markers : coagulation factor V	Week 3 to 4 after patient induction just before rectal surgery	Coagulation factor V will be measured.
Hemostasis markers : Thromboxane B2	Week 3 to 4 after patient induction just before rectal surgery	Thromboxane B2 will be measured.
Markers of epithelial-mesenchymal transition : matrix metallo-protease - 9	Week 3 to 4 after patient induction just before rectal surgery	Matrix metallo-protease - 9 will be measured

Trial Locations

Locations (3)

CHU de Nîmes; 🇫🇷 Nîmes, France

Hôpital Saint-Eloi; 🇫🇷 Montpellier, France

Institut du Cancer de Montpellier; 🇫🇷 Montpellier, France