Multi-Interventional program for prevention and early Management of Anastomotic leakage
after total mesorectal excision in Rectal cancer patIents, IMARI-trial

Problem:
Anastomotic leakage (AL) is one of the most feared complications after rectal
cancer surgery. AL leads to a significant increase of postoperative morbidity,
long-term surgical complications, negative impact on quality of life, higher
permanent stoma rates and impaired oncological outcome.
Our research group recently published a cross-sectional study of outcomes after
rectal cancer surgery in the Netherlands with a long-term incidence of AL of
20%. The current management of AL usually involves a deviating ileostomy, if
not performed primarily, in combination with *passive* drainage of the abscess
cavity via transanal or transcutaneous route. The cross-sectional study showed
that almost half of the leaks do not heal and may require major salvage surgery.

Solution:
Numerous risk factors have been identified for AL. Modifiable surgical factors
include tension on the anastomosis and anastomotic perfusion. A more recently
described pathophysiological mechanism relates to the intestinal microbiome.
Given the multifactorial etiology, a multi-interventional program is required
for the prevention of AL. Mechanical bowel preparation (MBP) with oral
antibiotics can lead to a reduction in AL by reduction of
the fecal bulk and bacterial load. Splenic flexure mobilization (SFM) optimizes
a tension-free anastomosis, particularly for the most distal rectal cancers.
Intraoperative real-time fluorescence angiography (FA) using indocyanine green
(ICG) assesses perfusion, thereby enabling precise
delineation of bowel transection and final anastomotic vitality. Routine use of
this technology has been associated with reduced AL rates.
If AL occurs, early diagnosis and *active* treatment allows for optimal control
of pelvic sepsis, anastomotic healing and stoma reversal. No international
consensus exists on a diagnostic pathway for early detection of AL, even though
evidence is building for the use of C-reactive protein (CRP) in the early
postoperative period. Considering *active* treatment our research group
investigated the impact of endoscopic vacuum-assisted drainage (EVAC) of the
abscess cavity in combination with early transanal closure of the anastomotic
defect. In the IMARI-trial we want to address all the interventions mentioned
above within existing institutional enhanced recovery programs and
prehabilitation initiatives (i.e. correction of anemia, optimization of
nutritional status, cessation of smoking).

To increase the one year anastomotic integrity rate in patients undergoing
total mesorectal excision (TME) for rectal cancer by the routine and quality
controlled implementation of a multi-interventional program, which includes:
1. MBP with oral antibiotics
2. Tailored full SFM
3. Intraoperative FA using ICG
4. Routine CRP-measurement at day three postoperatively, CT-scan with rectal
contrast on
indication
5. EVAC with early transanal closure of the anastomotic defect

This is a multicenter prospective clinical effectiveness trial, whereby current
local practice (control cohort) will be evaluated, and subsequently compared to
the results after implementation of the multiinterventional program
(intervention cohort). Hospitals that apply up to three interventions in the
routine care pathway comprise the control cohort. After finishing accrual of
the control cohort, the full multi-interventional program will be implemented
and checked for quality over a three month period in all participating
hospitals, followed by accrual in the intervention cohort. Anastomotic
integrity at one year will be determined by a CT-scan in all included patients.
In the setting of a classical randomized controlled trial, contamination is
likely to occur in the control arm. We consider this also as a downside of a
stepped wedge cluster randomized trial design. For this reason, a comparative
cohort design has been chosen.

The quality controlled implementation of a multi-interventional program to
increase the one year anastomotic integrity rate in patients undergoing total
mesorectal excision (TME) for rectal cancer, includes:
1. MBP with oral antibiotics
2. Tailored full SFM
3. Intraoperative FA using ICG
4. Routine CRP-measurement at day three postoperatively, CT-scan with rectal
contrast on
indication
5. EVAC with early transanal closure of the anastomotic defect

Of this program, fluorescence angiography using ICG is an intraoperative tool
and an investigational intervention.

Patients are asked to fill in questionnaires before surgery and 90 days and 1
year after the operation. Furthermore, patients are asked to submit faecal
material for microbiota-analysis before surgery, and 4 days post-operative.
Drain fluid will be collected on day 1 postoperative (when a postoperative
drain is placed during surgery) and each subsequent day until the drain is
removed. Drain fluid collection will only be performed in Amsterdam UMC
locations and OLVG. Blood samples will be taken peri-operatively and on day 3
after surgery. When patients develop AL, an additional swab will be taken from
the presacral cavity.

At one year a CT-scan will be performed to assess the primary endpoint