SELective Defunctioning Stoma Approach in Low Anterior Resection for Rectal Cancer (SELSA): a Prospective Study With a Nested Randomised Clinical Trial
Phase: NA
Conditions: Rectal Cancer
Sponsor: Skane University Hospital

2023 July 1st 1 version 
Selective defunctioning stoma approach in low anterior resection for 
rectal cancer (SELSA):  a prospective study and a nested randomised 
clinical trial 
 
Authors 
Pamela Buchwald, Martin Rutegård 
Steering group 
Pamela Buchwald, Martin Rutegård, Kalle Landerholm, Josefin Segelman, Peter Matthiessen, 
Johannes Schultz, Fredrik Jörgren. 
 
Abstract 
Introduction 
Systematic use of defunctioning stoma after low anterior resection for rectal cancer has 
been shown to reduce symptomatic anastomotic leakage and associated interventions. 
However, accumulating data suggest that this comes at the price of worse bowel 
dysfunction, a higher rate of permanent stomas and kidney injury. We aim to study whether 
a selective strategy of defunctioning stoma use might lead to fewer adverse consequences, 
while still being safe for patients. 
Methods and analysis 
This is a multicentre international prospective trial including a non-blinded randomised 
clinical trial. All patients with a primary rectal cancer planned for low anterior resection with 
colorectal or coloanal anastomosis are eligible. Patients enter a prospective observational 
study, in which a randomised clinical trial is nested. Patients eligible for randomisation are 
aged below 80 years, have an American Society of Anesthesiologists’ fitness grade I or II, 
have no unresected distant disease, and have a predicted lower risk of anastomotic leakage. 
Patients will be randomised 1:1 to either an experimental arm with no defunctioning stoma 
or to a control arm with a defunctioning stoma. The randomisation is computer-generated 
with a concealed sequence and stratified by participating hospital and radiotherapy use. The 
main outcome is the composite measure of 2-year stoma-free survival without major low 
anterior resection syndrome (LARS). Secondary outcomes include anastomotic leakage, 
postoperative mortality, reinterventions, stoma-related complications, quality of life 
measures, LARS, and permanent stoma rate up to two years after index surgery. To be able 
to state superiority of any study arm regarding the main outcome, with 90% statistical 
power and assuming 25% attrition, we aim to enrol 212 patients. 
Ethics and dissemination 
This study seeks approval by the Swedish Ethical Review Authority. The results will be 
disseminated through patient associations, popular science, the broader medical 
community, and conventional scientific channels. 

Trial registration number 
This study will be registered at clinicaltrials.gov pending ethical approval. 
 
Introduction 
Background and rationale 
Low anterior resection with a defunctioning stoma is still considered the standard procedure 
for curative resection of rectal cancer where a total mesorectal excision (TME) is necessary 
for oncological reasons. Anastomotic leakage (AL) after anterior resection is common, 
amounting to 10% within 30 days  and 20% within the first postoperative years in 
population-based studies (Borstlap, Westerduin et al. 2017). AL causes morbidity and 
mortality (Bostrom, Haapamaki et al. 2019), as well as impaired bowel function (Jutesten, 
Buchwald et al. 2022) and stoma permanence (Holmgren, Kverneng Hultberg et al. 2017, 
Jutesten, Draus et al. 2019). AL prevention is therefore of utmost importance. The most 
straightforward method to abstain from an AL is a non-restorative procedure; however, 
many patients strongly wish to preserve bowel continuity. In fact, patients rank avoidance of 
a stoma as high as survival in some studies (Wrenn, Cepeda-Benito et al. 2018). Moreover, 
permanent stomas are certainly not complication-free, with short- and long-term morbidity 
such as parastomal hernias, retraction, bowel obstruction, altered self-image as well as 
associated healthcare costs. 
 
There are some well-established risk factors for AL in anterior resection whereas others 
remain debatable. Risk factors with strong support in the literature are male sex (Kang, 
Halabi et al. 2013), a distal anastomosis (Park, Choi et al. 2013), smoking (Sorensen, 
Jorgensen et al. 1999, Richards, Campbell et al. 2012), excessive alcohol consumption 
(Sorensen, Jorgensen et al. 1999), high BMI (Hu, Huang et al. 2017) and a high American 
Society of Anesthesiologists’ fitness grade (Jestin, Pahlman et al. 2008). Poor nutritional 
status and electrolyte disturbances are identified AL risk factors for colorectal surgery in 
general (McDermott, Heeney et al. 2015). In laparoscopic anterior resection, AL is commonly 
reported as related to the use of multiple firings for rectal transection (Kawada, Hasegawa et 
al. 2014, Qu, Liu et al. 2015). Corticosteroid seems related to AL whereas no clear 
relationship to nonsteroidal anti-inflammatory drugs has been shown (Klein, Gogenur et al. 
2012, Burton, Mittal et al. 2013, Kverneng Hultberg, Angenete et al. 2017). Furthermore, 
operation time, intraoperative bleeding and blood transfusion are related to AL but possibly 
serve as surrogate for poor technique or demanding surgery (Park, Choi et al. 2013, Katsuno, 
Shiomi et al. 2016, Kim, Baek et al. 2016). Whether neoadjuvant oncological treatment is a 
risk factor for AL is controversial, as an association of AL with neoadjuvant radiotherapy and 
chemoradiotherapy has been reported (Matthiessen, Hallbook et al. 2004, Park, Choi et al. 
2013, Qu, Liu et al. 2015, Sparreboom, Wu et al. 2018), but also challenged in a meta-
analysis (Hu, Huang et al. 2017).  
 
Selection of patients to restorative procedures hinges on patient fitness, i.e. ability to 
withstand an AL and predicted postoperative bowel function. The main proven alternative to 
reduce symptomatic AL and early reoperations in low anterior resection in recent decades, is 
usage of a loop defunctioning stoma (Matthiessen, Hallbook et al. 2007, Gu and Wu 2015). 
In the recent RectoLeak TENTACLE study, 24.2% of patients undergoing TME for rectal 
cancer sustained an AL within 12 months, 93.5% of whom were defunctioned at index 

operation, the vast majority with a loop ileostomy (van Workum, Talboom et al. 2021). 
Although defunctioning stoma is intended to be reversed within 3-4 months, in practice 
these temporary stomas are not reversed or have been converted to permanent colostomies 
in 18-21% of patients at two years follow-up (Gadan, Lindgren et al. 2019, Holmgren, 
Haggstrom et al. 2021). For patients having their stomas reversed, delays to such surgery is 
associated with more complications (Turner, Clifford et al. 2022), and up to 9% of patients 
return to theatre (Holmgren, Kverneng Hultberg et al. 2017). Loop ileostomies can cause 
high stoma output with a high risk of dehydration (Akesson, Syk et al. 2012, Gavriilidis, 
Azoulay et al. 2019) and subsequent acute kidney injury or even renal failure (Munshi, 
Bengtsson et al. 2020, Rutegard, Haggstrom et al. 2023), especially when not reversed in a 
timely fashion (Rutegard, Haggstrom et al. 2023). There are also accumulating data that 
defunctioning stomas may induce (Vogel, Reeves et al. 2021) low anterior resection 
syndrome (LARS), a cluster of symptoms that seem to stabilise only after 18 months 
(Varghese, Wells et al. 2022).  
 
The increased awareness of the inherent drawbacks with a defunctioning loop-ileostomy has 
questioned routine diversion after low anterior resection. Early reversal within 14 days has 
been one suggested approach to overcome this (Danielsen, Park et al. 2017). Recent data 
has suggested that stomas rather delay than prevent AL (Borstlap, Westerduin et al. 2017, 
Jutesten, Draus et al. 2019). The main advantage of faecal diversion is prevention of life-
threatening sepsis and mortality, as well as return to theatre. The issue is whether these 
short-term advantages outweigh the long-term stoma related morbidity and mortality. 
Attempts to risk-stratify patients and tailor stoma use have not been widely successful, but 
some centres have reported a selective use of stomas without obvious adverse 
consequences (Talboom, Vogel et al. 2021). There is an ongoing French prospective clinical 
trial, GRECCAR-17, where patients are randomised to routine loop-ileostomy (control arm) 
vs tailored loop-ileostomy (intervention arm) according to a risk prediction score based on 
sex, body mass index, smoking, diabetes, and tumour size after neoadjuvant treatment 
(Denost, Sylla et al. 2023). Dutch nationwide data suggest that usage of defunctioning 
stomas has decreased in later years down to 30% in 2020 (Ingwersen, van der Beek et al. 
2023), with a concurrent increase of AL rates and reinterventions with simultaneous 
reduction in postoperative mortality (Arron, Greijdanus et al. 2021). This may negate the 
fear of AL translating into fatalities. 
 
The current knowledge gap entails whether a selective approach to defunctioning stomas 
may be advantageous in a trial setting, and which of many approaches to use. As patients 
need to be selected, criteria need to be developed and agreed upon by the wider surgical 
community. Interestingly, surgeons and patients might have different thresholds for a 
defunctioning stoma in relation to anticipated AL rates, where 15 and 25%, respectively, 
would justify faecal diversion (Mackay, Clark et al. 2022). A selective approach is expected to 
increase at least early AL and reoperation rates; consequently, a corresponding readiness for 
early diagnosis and reintervention is necessary to avoid harm. The inclusion criteria and 
selection process in this study have been chosen to allow patients to tolerate an AL without 
excess mortality and also to reflect predicted AL rates below unselected usage. 

Objectives 
We hypothesise that the long-term effects will favour the selective approach, as many 
patients are likely to avoid having a stoma at all and thus without impairment of bowel 
function. The primary aim is to evaluate which of the approaches is superior when 
considering stoma-free survival at two years, without major LARS. The secondary objectives 
include anastomotic leakage, reinterventions, stoma-related complications, quality of life 
measures, major LARS, bowel continuity, patient reported recovery and permanent stoma, 
up to two years after surgery. 
Trial design 
This is a multicentre international prospective observational study including a nested non-
blinded randomised clinical trial. The SELlective defunctioning Stoma Approach in low 
anterior resection for rectal cancer (SELSA) trial is designed as a pragmatic randomised, 
controlled, open label, non-blinded, multicentre superiority trial with two parallel groups 
and a primary outcome of stoma-free survival without major LARS at 2 years after surgery. 
Patients are block-randomised intraoperatively with a 1:1 allocation, stratified for centre and 
radiotherapy. The protocol was drafted in accordance with the SPIRIT 2013 statement 
(Standard Protocol Items: Recommendations for Interventional Trials) (Chan, Tetzlaff et al. 
2013). 
 
Methods and analysis 
Participations, interventions, outcomes 
Study setting 
This is a multicentre prospective study conducted in Nordic hospitals that perform low 
anterior resection for rectal cancer. 
Eligibility criteria 
Inclusion criteria 
● Adult patients with rectal cancer planned for a low anterior resection with 
anastomosis by TME with any surgical approach 
Exclusion criteria 
● Insufficient command of Swedish, Norwegian, Danish or English to understand 
questionnaires or consent 
● Emergency rectal resection (tumour resection due to large bowel obstruction, 
perforation, etc) 
● Pregnancy or breastfeeding 
Additional inclusion criteria for randomised part of the study 
● Patients aged less than 80 years 
● Patients with American Society of Anesthetists’ (ASA) fitness grade I or II as 
determined by the anaesthesiologist or the surgeon 
● Patients without clear radiological signs of distant disease before rectal cancer 
surgery (previous metastatic surgery is no exclusion criterion) 

● Anastomotic leak risk score of 0-1 
● Willingness to be randomised 
Additional exclusion criteria for randomised part of the study 
● Previous pelvic irradiation (due to e.g. gynaecological or urological cancer) 
● Preoperative tumour perforation or pelvic sepsis 
● Beyond TME surgery and/or concurrent resection of other organ 
● Concurrent corticosteroid treatment (prednisone-equivalent dosage ≥10 mg daily) 
● Planned postoperative chemotherapy 
Intraoperative exclusion criteria for randomised part of the study 
● >2 staple firings for rectal transection 
● Intraoperative blood loss ≥700 ml 
● More than one intraabdominal anastomosis performed 
● Incomplete doughnuts 
● Air-leak test positive 
● Any significant intraoperative adverse event at the discretion of the operating 
surgeon (e.g. ureterotomy, bowel or tumour perforation, major medical event – 
pulmonary embolism, cardiac arrhythmia) (Gawria, 2022 ) 
● TME with anastomosis ultimately not done 
Trial centre requirements 
Centres can participate provided that the centre: 
● Performs low anterior resection, regardless of approach 
● Has resources to perform necessary trial measurements 
● Has resources to provide timely reintervention for suspected anastomotic leak 
● Has at least one local investigator in charge 
Interventions 
Preoperative measures 
Stoma site is marked preoperatively by a specialised nurse. Mechanical bowel preparation is 
employed at all centres, where formulations vary according to local routines. Preoperative 
antimicrobial prophylaxis is administered according to local guidelines. Patients will be 
managed according to the principles outlined in the Enhanced Recovery After Surgery 
guidelines for rectal surgery (Gustafsson, 2019). 
Low anterior resection 
Any surgical approach, whether open, robotic-assisted or with conventional laparoscopy, is 
allowed. Splenic flexure mobilisation, left colic artery preservation, use of descending or 
sigmoid colon as conduit, or anastomotic configuration is at the discretion of the operating 
surgeon. TME should be conducted according to the principles of dissection in embryological 
planes as proposed by Heald (Heald, 1982) down to the pelvic floor. Adjuncts such as near-
infrared indocyanine green assessment are allowed, but only to influence decision-making 
prior to construction of the anastomosis. After construction of anastomosis by any method, 
the integrity of the doughnuts should be evaluated, and an air-leak test should be 
performed. Agreement with the anaesthetics team should be sought to determine 
intraoperative blood loss; if this is 700 ml or more, more than two stapler firings have been 

used, the doughnuts are incomplete, or a major intraoperative adverse event has taken 
place as judged by the operating surgeon, the patient will be excluded from the randomised 
part of the study and will be provided with either a defunctioning stoma or no anastomosis 
at all. Drains will be used at the discretion of the operating surgeon, but are generally 
discouraged. Anastomotic height is measured by digital rectal exam/rigid sigmoidoscopy and 
noted. 
Experimental arm: selective approach to defunctioning stoma 
With randomisation to this experimental arm (selective approach), no defunctioning stoma 
is constructed. 
Control arm: systematic approach to defunctioning stoma 
With randomisation to this control arm (systematic approach), a defunctioning stoma is 
constructed using the marked stoma site. A loop ileostomy is fashioned using an ileal loop 
close to the ileocecal valve, while a loop colostomy can be derived from either the 
transverse or a redundant left colon. 
Postoperative surveillance 
Patients will be surveyed according to the national guidelines concerning their oncological 
follow-up. In Sweden, this typically involves computerised tomography (CT) of the chest, 
abdomen, and pelvis at 1 and 3 years. Carcinoembryonic antigen (CEA) will be analysed at 
these time points as well, while a colonoscopy is provided at 3 years and subsequently at 
every 5 years. Any recurrences will be managed according to the local multidisciplinary team 
(MDT) and will be registered and ascertained via the Swedish Colorectal Cancer Registry 
(SCRCR) as well as to an eCRF. Other participating countries will have similar but slightly 
different follow-up, where participating centres will report to an eCRF.  
 
Defunctioning stoma reversal will be performed according to local and national routines and 
guidelines regarding timing and operative procedure and will not be mandated by the trial 
itself. The integrity of the anastomosis is often determined by endoscopy and/or CT with 
water soluble contrast enema, prior to closure. Typically, stoma reversal is planned 3-6 
months after index surgery as long as no anastomotic leak or other complications have taken 
place; in cases with adjuvant chemotherapy, stoma reversal is planned after completion of 
treatment and will therefore usually take place 9-12 months after the index surgery. 
Adherence assessment 
As this is a pragmatic trial of already established surgical techniques, no adherence 
assessment is planned. 
Concomitant therapy 
Preoperative as well as postoperative radiotherapy and chemotherapy, as well as other 
oncological agents, can be used according to the MDT. 
Outcomes 
The primary outcome is a hybrid so-called textbook outcome; stoma-free survival at two 
years without major LARS, reflecting a functionally appropriate outcome after low anterior 
resection for rectal cancer. The summary measure is the proportion of patients fulfilling this 
composite outcome: no extant stoma, alive, and a LARS score at 30 or less at the time point 

two years after the anterior resection. This time point is chosen as most stomas are 
considered permanent two years after surgery, whereas bowel function has stabilised as 
well for those without a stoma in situ. 
 
The secondary outcomes along with measurement variables, analysis metrics, aggregation 
methods and measurement time points, are presented in Table 1. 
 
Table 1. Secondary outcomes in the SELSA trial 
Secondary outcome Measurement variable Analysis metric 
Summary 
measure 
Time point 
(months) 
Anastomotic leakage ISREC grading 
Final value 
Proportion 
1, 3, 12, and 
24 
Complications 
Clavien-Dindo grade 
Final value 
Proportion 
1, 3, 12 and 
24 
Length of hospital 
stay 
Total days in-hospital 
Final value 
Median 
At discharge 
Postoperative 
mortality 
Clinical assessment 
categorisation 
Final value 
Proportion 
3 
Major LARS 
LARS domain score 
Change from baseline and  
spot measure 
Proportion 
12 and 24 
Quality of life 
EORTC-C30 domain 
scores 
Change from baseline and 
spot measure 
Median 
12 and 24 
Quality of life 
EORTC-CR29 domain 
scores 
Change from baseline and 
spot measure 
Median 
12 and 24 
QoR15swe 
Total QoR15 score 
Change from baseline 
Median 
1 
Adjuvant 
chemotherapy for 
high-risk patients 
Clinical assessment 
categorisation 
Final value 
Proportion 
12 
Renal function 
Creatinine (mg/L) 
Change from baseline and  
spot measure 
Median 
12 and 24 

Stay out of hospital 
Total days out of 
hospital and alive 
Final value 
Median 
24 
Stoma in situ 
Clinical assessment 
categorisation 
Final value 
Proportion 
24 
Recurrence (local 
and distant) 
Clinical assessment 
categorisation 
Final value 
Proportion 
36 and 60 
Overall survival 
Clinical assessment 
categorisation 
Final value 
Proportion 
36 and 60 
 
 
Measures of complications 
Anastomotic leakage 
Anastomotic leakage is defined according to the INternational Study Group of REctal Cancer 
(ISREC) consensus definition (Rahbari, 2010), which states that any communication between 
intra- and extraluminal compartments is considered a leakage. This includes fistulae as well 
as isolated pelvic abscesses, without evidence of direct communication. Leakage will be 
categorised into three levels: grade A denotes a leak without need for reintervention, 
typically asymptomatic and detected radiologically at follow-up; grade B means a leak 
requiring reintervention without a formal reoperation, ranging from antibiotics to 
percutaneous or transanal drains or vacuum-treatment or similar procedures; grade C 
denotes a leak necessitating formal laparotomy or laparoscopy under general anaesthesia. 
 
Leakage will be characterised by day of diagnosis, leak grade, type of leak, modalities used to 
make the diagnosis, and management of the leak itself, including subsequent reoperations 
and other measures. This will be included in an eCRF attached to the conventional SCRCR 
registration and will be registered at several time points. In particular, a postoperative 
examination using flexible sigmoidoscopy or contrast enema is required in order to detect 
even asymptomatic leaks. 
 
Complications 
Measures of complications will be registered and ascertained using an eCRF at all time 
points. Study-specific variables include stoma-related complications (high-output stoma, 
admission for dehydration, kidney injury, stoma retraction, stoma prolapse, symptomatic 
parastomal hernia, peristomal skin irritation, stoma leaks, stoma reversal complications). 
 
Safety measures, early postoperative complications, and other clinical adverse events 
A safety analysis will be carried out after recruitment and 90-day follow-up of 40 patients 
(see paragraph monitoring and quality control). Serious adverse events, e.g. admission to 
the intensive care unit or mortality will be reported to PIs. 

 
Participant timeline 
Patients in the SELSA trial will be screened for inclusion at each participating centre’s local 
MDT. At the preoperative visit, after completion of potential neoadjuvant treatment, 
patients will be assessed for eligibility, informed of the study and informed consent will be 
provided. Baseline measurements include biochemical tests, quality of life and functional 
measures; these measures will be repeated at postoperative month one, at one year, and at 
two years. At these time points, an eCRF detailing postoperative complications will be filled 
in. Of importance, an examination at 1–3 months after surgery is scheduled, using flexible 
sigmoidoscopy or contrast enema. A schedule of study events is displayed in Table 2. 
 
Table 2. Schedule of study events in the SELSA trial. 
 
Study events 
Inclusion 
Surgery 
(day 0) 
Follow-up 
(month 1) 
3 
months 
Year 1 
Year 2 
Patient 
information 
x 
 
 
 
 
 
Signed consent 
x 
 
 
 
 
 
Confirmation of 
eligibility 
x 
 
 
 
 
 
Clinical 
examination 
x 
 
x 
 
 
 
eCRF 
x 
x 
x 
x 
x 
x 
Biochemical 
tests 
x 
 
 
x 
x 
x 
Contrast enema 
and/or flexible 
sigmoidoscopy 
 
 
x 
x (if not 
done) 
x 
 
QLQ-C30 & 
QLQ-CR29 
x 
 
x 
 
x 
x 
QoR-15 
x 
 
x 
 
 
 
LARS 
x 
 
x 
 
x 
x 
Clavien-Dindo 
 
 
x 
 
x 
x 
Serious adverse 
event 
x 
x 
x 
x 
x 
x 
Blood sample 
(translational 
study) 
x 
 
 
 
 
 
 
Clinical examination: preop – digital rectal exam, review ASA grade, body mass index; postop 
– chart review (eCRF) Biochemical tests: C-reactive protein, albumin, hemoglobin, creatinine 
and electrolytes. 
 

Some patients will be eligible for the randomised part. The study variables are the same for 
the prospective and the nested randomised trial. All data will be used up to the point of 
discontinuation unless the reason for discontinuation is withdrawal of consent (Figure 1). 
 
 
Figure 1. Study flowchart. ASA = American Society of Anaesthesiologists’ fitness grade; LARS 
= Low anterior resection syndrome. 
 
The anastomotic leak risk score is derived from SCRCR data on low anterior resections during 
2007–2020. Using established risk factors for anastomotic leakage such as male sex, 
elevated body mass index (BMI), and receipt of radiotherapy, a risk prediction model was 
constructed and tested in an independent multicentric cohort with chart-reviewed leakage 
data (RectoLeak cohort: 2014–2018). This risk score model, or a similar but improved one, 
will be used to stratify risk of anastomotic leakage and is presented below in Table 3. 
 
Table 3. Risk prediction modelling including male sex +1, BMI >30 +1, and radiotherapy +1 in 
patients with AL within ≤30 days in SCRCR 2007-2020 and ≤30 days RectoLeak cohort 2014-
2018. All patients undergoing TME, <ASA 3, age ≤80 years and perioperative bleeding ≤700 
ml. In the SCRCR cohort tumour height is 5-10 cm instead of TME. 
 
Risk Score 
SCRCR 
AL (%) 
RectoLeak 
Early AL (%) 
RectoLeak – study 
criteria applied 
early AL (%) 
0 
4.3 
5.2 
5.3 
1 
7.2 
17.0 
13.2 
2+ 
12.0 
20.8 
17.2 
 
                                          
                           
                         
                  
                    
                 
                                    
               stoma freesurvivalwithoutma or LARS
                                    
               stoma freesurvivalwithoutma or LARS
                  
 
<3 staple rings
 
 loodloss <700 ml
 
 otmorethan1 anastomosis
 
Completestaplerdoughnuts
 
Air leaktest nega ve
 
 o signi cantadverseevent
 
TME withanastomosisdone
 
Anastomo cleakrisk score <2
 
Age <80years
 
ASA <III
 
 o cor costeroidtreatment
 
 o plannedpostopera vechemotherapy
 
 o unresectedmetasta cdisease
 
 opreviouspelvicirradia on
 
 o preopera vetumourperfora on sepsis
 
 o beyondTME surgery
 
Pa entwillingto berandomised
                        
 o
 es

Sample size 
The sample size is considered in relation to proving superiority of the experimental no stoma 
arm to the control stoma arm in terms of the primary outcome stoma-free survival without 
major LARS at two years. The sample size is calculated with the following assumptions: 
 
● Mortality at two years is estimated to be 4% in both groups 
● Proportion of patients with stoma-free survival without major LARS is estimated at 
65% in the experimental no stoma group 
● Proportion of patients with stoma-free survival without major LARS is estimated at 
40% in the control stoma group 
● The loss of data due to for example, non-adherence to study protocol, is anticipated 
to be 25% 
 
With the above assumptions, a total of 158 randomised patients (79 in each arm) are 
needed for 90% statistical power and a significance level of 5%. Considering attrition and 
missing data, this means 212 patients. 
 
The first 100 included patients will be regarded feasibility, and after inclusion of 100 patients 
assumptions will be checked descriptively and sample size may be adjusted accordingly.  
 
The prospective part will approximately contain 500 patients. 
Recruitment considerations 
We anticipate that study recruitment can take place within 3 years, assuming that at least 12 
Nordic centres with different caseloads include on average 6 patients per year eligible for 
randomisation. Given successful grant applications, reimbursement for recruitment may be 
considered. 
Assignment of interventions 
Allocation 
After written consent has been provided, eligibility for the prospective or the randomised 
part of the study is confirmed. The actual randomisation occurs intraoperatively after 
construction of the anastomosis and air leak test, making sure that no intraoperative 
exclusion criteria have been fulfilled for patients eligible for randomisation. 
 
The randomisation will be done online via a web application (https://www.randomizer.at/) 
or within RedCAP. Participants will be randomly assigned to either the control or the 
experimental arm with a 1:1 allocation. Permuted blocks are used and the computerised 
randomisation is stratified by centre and radiotherapy use. The size of the randomisation 
blocks will vary by chance within predefined concealed limits. 
Concealment mechanism 
The randomisation will be centralised to prevent influence on the randomisation process.   

Blinding 
Blinding in surgical studies is difficult to accomplish. This study is performed without 
attempts for blinding and thus the healthcare workers and the patient do not have to be 
blinded. This may cause detection bias by the assessors, a bias which is partly reduced by the 
use of validated outcome scales and questionnaires. 
Data collection, management and analysis 
Data collection methods 
The trial data will be collected as part of the routine registration in the SCRCR, but also by 
using study-specific eCRFs and questionnaires. Surgeons, and nurses participating in this trial 
are asked to provide baseline data, intraoperative data, and postoperative visit data 
including surveillance (as specified in Table 2 above). Patients will provide patient-reported 
outcomes using questionnaires, which will be administered in paper form and collected by 
study nurses. 
Compliance and retention 
To improve compliance, there will be an option to allow the central administration of the 
study to administer 1-year and 2-year questionnaires, including reminders. Periodical 
reminders to participating centres will be issued to fill in eCRFs. Prestudy meetings to explain 
study logistics will be held. 
Statistical methods: outcomes, additional analyses, analysis population and missing data 
Analysis principles 
All primary analyses in this study will be performed according to the intention-to-treat (ITT) 
principle, that is, patients will be allocated to treatment groups corresponding to their 
assigned treatment, even if the patient does not receive the correct treatment. 
The ITT population will consist of all patients who are operated with low anterior resection 
and eligible for study inclusion, subsequent randomisation and with complete data for the 
primary outcome. 
Patient discontinuations 
Reasons for discontinuations in the study will be compared between the two treatment 
groups. Tables or a CONSORT diagram (Moher, 2012) will reveal the number and proportion 
of patients who have completed the study as well as patients that have discontinued, 
grouped by reason for discontinuation. 
Primary outcome analysis 
The main analysis in this trial consists of a comparison of the proportion of patients that are 
stoma-free, alive and without ma or LARS at 2 years after surgery; the χ2 test will be used in 
an ITT analysis. A sensitivity analysis will be conducted, with adjustment for centre as well as 
preoperative variables indicating a high risk of anastomotic leakage and permanent stoma, 
such as sex, age, ASA fitness grade, radiotherapy, and clinical tumour stage. These 
adjustments, using binomial regression, are done in order to alleviate the impact of chance 
confounding, as this is a relatively small trial; estimates of relative risk ratios and absolute 
risk differences with 95% confidence intervals will be produced. 

Missing data 
Every effort will be made to ensure that missing data is kept at a minimum. As the primary 
outcome is dependent on several parameters, one of which is derived from the LARS 
questionnaire, multiple imputation by chained equations is planned to impute missing data 
for the 24-month assessment, using available data on perioperative and functional 
information from other time points.  
Secondary analyses 
Comparison between proportions in study arms will be made with the χ2 test or the Fisher’s 
exact test, while comparisons of continuous variables will be made with the Student’s t-test 
or Mann-Whitney U test, post hoc Bayesian analysis as appropriate. The pertinent outcomes 
and time points are outlined in Table 1. The following comparisons between study arms will 
be conducted: 
 
● Anastomotic leakage 
● Leakage grading 
● Stoma-related complications 
● Length of hospital stay 
● Postoperative mortality 
● Incidence of major LARS 
● Quality of life measured with QLQ-C30 and QLQ-CR29 
● Postoperative recovery measured with QoR15Swe 
● Adjuvant chemotherapy receipt in patients deemed high-risk for recurrence 
● Renal function 
● Days out of hospital during study period 
● Stoma in situ 
 
These secondary outcome analyses are deemed exploratory.  
 
Registry-based comparison 
The trial participants can be seen as nested in a larger, population-based study based on the 
prospectively collected SCRCR data. This data collection can be used to provide external 
validation of effectiveness, where defunctioning stoma use or no use is treated as exposure 
and anastomotic leak as well as stoma-free survival can be seen as outcome. The relevant 
data can be derived from the SCRCR, where patients not included in the trial, but who could 
have been, are evaluated, using the same inclusion and exclusion criteria as far as possible. 
Translational sub study 
Participating centres may collect preoperative blood samples from all patients for later 
molecular analysis of predictors for anastomotic leakage. Previous research has indicated 
that chemokines CXCL6 and CLL11 might be strong predictors of anastomotic leakage in 
rectal cancer patients, but these findings require external validation (Holmgren, 2022). 
 
Blood samples are collected the day before or on the day of surgery. The blood sampling 
includes EDTA plasma and serum. The aim is to have a time of less than 4 h between blood 
sampling and obtaining frozen aliquots. Fractions are stored in 0.5-ml microvials (Micronic, 
Lelystad, The  etherlands) and preserved at  −80°C. Local biobanks need to be employed. 

 
The frozen samples will be transported to the analysis company Olink (Uppsala, Sweden), 
where the bespoke protein panel Olink Insight will be used. In this panel, proteins have been 
selected reflecting both the aforementioned chemokines CXCL6 and CLL11 as well as other 
proteins with high significance clinically and statistically with regards to leakage 
development. The panel proteins are summarised below in Table 4. 
 
Table 4. Selected proteins of interest in the translational substudy on prediction of anastomotic 
leakage. 
Assay name 
UniProt ID 
Gene 
Eotaxin 
P51671 
CCL11 (SCYA11) 
Eukaryotic translation initiation factor 4E 
P06730 
EIF4E (EIF4EL1 EIF4F) 
C-C motif chemokine 8 
P80075 
CCL8 (MCP2 SCYA10 
C-X-C motif chemokine 11 
O14625 
CXCL11 (ITAC SCYB11 
Tumor necrosis factor ligand superfamily 
member 14 
O43557 
TNFSF14 (HVEML LIGHT) 
Tumor necrosis factor receptor 
superfamily member 9 
Q07011 
TNFRSF9 (CD137 ILA) 
Adenosine deaminase 
P00813 
ADA (ADA1) 
C-C motif chemokine 25 
O15444 
CCL25 (SCYA25 TECK) 
STAM-binding protein 
O95630 
STAMBP (AMSH) 
Caspase-8 
Q14790 
CASP8 (MCH5) 
Leukemia inhibitory factor receptor 
P42702 
LIFR (CD118) 
Interleukin-6 
P05231 
IL6 (IFNB2) 
C-X-C motif chemokine 6 
P80162 
CXCL6 (GCP2 SCYB6) 
Interleukin-8 
P10145 
CXCL8 (IL8) 
Vascular endothelial growth factor A 
P15692 
VEGFA (VEGF) 
Matrilysin 
P09237 
MMP7 (MPSL1 PUMP1) 
Growth-regulated alpha protein 
P09341 
CXCL1 (GRO GRO1 
Interleukin-7 
P13232 
IL7 
C-C motif chemokine 20 
P78556 
CCL20 (LARC MIP3A 
Hepatocyte growth factor 
P14210 
HGF (HPTA) 
Kit ligand 
P21583 
KITLG (MGF SCF) 
 
Area under the curve with receiver operating characteristics will be derived for each protein 
as well as selected combinations (CXCL6 + CLL11). Thresholds to optimise subsequent 
diagnosis of anastomotic leakage will be calculated. 
Monitoring and quality control 
A safety monitoring board will be appointed with the task to contact each centre annually 
and ask for unforeseen adverse events and problems. If severe adverse events occur the PI 
and the monitoring board have the responsibility to decide whether the study can continue 
or should be stopped after a safety analysis – such a safety analysis will be executed after 

recruitment and 90-day follow-up of 40 patients. Difference in reoperation rate, anastomotic 
leakage, intensive care unit admission, and mortality will be analysed. 
 
A higher reoperation rate is anticipated in the experimental group, where earlier data 
suggest that this should be up to three times as likely. If a safety analysis would indicate a 
risk increase higher than this, early termination will be considered. 
 
Interim analyses are planned according to the statistics paragraph. All safety analyses will be 
performed based on the intent-to-treat population. All statistical tests of safety will be 
conducted with a two-sided test, using an alpha level of 0.05. 
Quality assurance 
To ensure accurate and reliable data the study administration will do the following: 
● Instigate start-up training and meetings with investigators 
● Be available for consultation 
● Regular communication to investigators with data on recruitment 
● Conduct quality review of the database (a monitor may be sent to participating 
centres) 
 
Monitoring of the study interventions while the trial is underway is planned, conditioned on 
funding, where monitors will conduct regular site visits. Individual surgical teams and 
centres are responsible to adhere to the protocol, nevertheless. 
Ethics and dissemination 
Ethical review 
This study will be conducted in accordance with the ethical principles stated in the most 
recent version of the declaration of Helsinki or the applicable guidelines on good clinical 
practice, whichever represents the greater protection of the individual. National ethical 
approval will be sought from the relevant authorities. 
 
Informed consent 
The informed consent document (supp file: informed consent) with study information will be 
used to explain in simple terms to patients what participation in the study means for the 
patient. The patient will receive information of the risks, benefits, and potential alternatives. 
 
It is the investigators’ responsibility to ensure that informed consent is obtained from each 
patient study inclusion. The informed consent document must be signed, dated and 
subsequently stored in an archive at each participating centre. The signed document may 
also be photo-scanned to an electronic document and included in the hospital electronic 
patient file. 
Patient and public involvement 
The protocol has been developed in conjunction with national and international patient 
representatives. Lay men will be involved in the approval by the Swedish Ethical Review 
Authority. 

Confidentiality 
The study participants’ data are entered into eCRF in RedCap or attached to the patient’s 
SCRCR record. Each participant is deidentified, using a linking code, which is separate from 
the database server; the code is encrypted, stored on a universal serial bus device and kept 
in a locked office space. Code access is limited to the PI and the independent observer, if 
need be. Only deidentified data is shared with co-investigators. 
Access to data 
The full dataset will only be accessible by the PI and the co-investigators who are involved in 
the analysis part of the drafted manuscripts. 
Compensation for damage incurred 
Every participant in the study may be compensated for damage incurred, by the regular 
insurance policy for patients as provided by the appropriate legal bodies in Sweden. 
Publication policy 
Every attempt will be made to reduce to a minimum the time interval between data 
collection completion and the release of study results. After data collection is finalised, we 
expect that a time period of at least 6 months is needed to compile the results and submit 
the findings to an appropriate journal. All results will be disseminated to the site 
investigators, patients and the general medical community. 
 
At least two publications including study protocol and main finding will be submitted. The 
translational part will be published separately. Most likely several spinoff papers including 
sub-group outcomes and long-term outcomes will be published. 
 
Authorship rules 
We aim to recruit co-authors for the reports of this study among the investigators in 
participating centres. One site investigator from each centre will be offered co-authorship as 
long as patients are eventually recruited, while other participants with a substantial 
contribution will be denoted collaborators. 
Acknowledgments 
The authors would like to acknowledge Per Johansson (ILCO), Fredrik Hopfgarten (Mag- och 
tarmförbundet), Sue Blackwell (European Society of Coloproctology patient representative), 
and Anna Åkesson (statistician Forum Söder). 
 
Appendix 
 
SELSA estimated time plan. 
 

 
 
 
 
 
 
 

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