The EDFI-Cohort: Determining Early Development of Faecal Incontinence and Anorectal Muscle Function After Curative Surgery for Rectal Cancer.
Conditions: Rectum Cancer, Quality of Life, Faecal Incontinence, Low Anterior Resection Syndrome
Sponsor: Slagelse Hospital

 
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Original titel (dansk) 
EDFI-Kohorten: 
Et 
kohortestudie 
om 
udviklingen 
af 
afføringsinkontinens 
og 
endetarmens 
lukkemuskelsfunktion, hos personer opereret for endetarmskræft. 
 
Project title 
The EDFI-Cohort: Determining early development of faecal incontinence and anorectal muscle function after 
curative surgery for rectal cancer. 
 
Background 
Patients who have been diagnosed with rectal cancer and treated with curative rectal surgery (low anterior 
resection (LAR)) have a high chance of survival (about 60% are alive after 5 years). [1] There is increasing 
focus on quality of life for these survivors. A stigmatized problem that more than a third of patients surgically 
treated for rectal cancer develop is faecal incontinence also known as the low anterior resection syndrome 
(LARS) [2-7], that has significant impact on quality of life. [8, 9]  There is limited knowledge on why some 
patients develop major LARS. Some of the known exposures that increases the risk of developing major LARS 
are; age at surgery, gender, tumor height, pre-operative radiotherapy and surgical technique. The choice of 
surgical procedure is likely to play an important role in developing LARS, but has primarily been evaluated in 
smaller longitudinal studies with few patients (mean n ≈ 18 patients, range 3-100 patients). [10, 11] 
Other factors that are likely to play a role in developing major LARS, has to our knowledge not yet been 
studied. In order to evaluate the underlying mechanisms of LARS, and in the future provide effective 
treatments, it is central to evaluate the anorectal muscle function. Anorectal muscle function has been 
evaluated with anorectal manometry in patients who have been treated with low anterior resection at a 
median of 6 weeks (range 4-40 weeks) [12] and at a mean of 23 months (range 6-106 months) [13, 14] after 
surgery. Despite variations in methodology, these studies had similar findings with anorectal resting pressure 
of 20-40 mmHg and maximal squeeze pressure of 80-140 mmHg, which is half the pressure performed by 
continent controls [12-16]. These studies have also measured rectal capacity. They found a maximal tolerated 
volume of 95-140 mL and around 200 mL measured in continent controls. Additionally, a conscious rectal 
sensitivity threshold of 35-44 mL was measured in both patients and continent controls. [12-16] Despite 
these findings, there is limited knowledge of the relationship between severity of faecal incontinence and 
pelvic floor muscle function in patients surgically treated for rectal cancer [17]. 
Despite LARS being a central factor for reducing quality of life, other factors are likely to play an important 
role as well. Dysfunctions such as sexual dysfunction, urinary incontinence and feacal incontinence are 
present in patients with rectal cancer as long after surgery as 4 years, therefore it is important to determine 
when these symptoms develop and how they are related to each other in patients treated for rectal cancer. 
[18] Other factors likely to reduce quality of life are problems with fatique, physical inactivity and finding 
meaning in life. To our knowledge, no records exist on these relationships from prior to surgery to 2 years 
after. These softer factors are central to include when developing effective treatments strategies for this 
patient group. 
 
To guide the choice of surgical technique outcomes of mortality, adverse events and self-reported quality of 
life are important to report. As before mentioned LARS has significant impact on quality of life and is thus 
important to study. In order to evaluate the underlying mechanisms of LARS, and in the future provide 
effective treatments, it is central to evaluate the anorectal muscle function. Anorectal muscle function has 
been evaluated with anorectal manometry in patients who have been treated with low anterior resection at 
a median of 6 weeks (range 4-40 weeks) [12] and at a mean of 23 months (range 6-106 months) [13, 14] after 
surgery 
Sexual dysfunction, urinary incontinence and feacal incontinence are present in patients with rectal cancer 
as long after surgery as 4 years, therefore it is important to determine if when these symptoms develop and 
how they are related to each other in patients treated for rectal cancer. [18] To our knowledge, no records 
exist on these relationships from prior to surgery to 2 years after low anterior resection. This type of 
information is central to the future design and conduct of expensive randomized trials. 
 

 
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Purpose 
The primary purpose of the EDFI-Cohort study is to determine how several baseline variables (surgical 
technique, anorectal muscle function, faecal incontinence, urinary incontinence, sexual dysfunction, fatigue, 
physical activity, meaning in life and physical functioning) develop over time and predicts quality of life, and 
secondary how it predicts LARS-score in patients with rectal cancer from prior to surgery to 2 years after 
primary treatment. 
 
Hypothesis 
A priori, we determined the following major hypotheses for this study to be (with corresponding null 
hypotheses): 
 
1. We expect to see poorer quality of life in patients with a higher LARS-score 
2. Overall we expect to see poorer quality of life in patients with poor anorectal muscle function, faecal 
incontinence, urinary incontinence, sexual dysfunction, fatigue, low physical activity, low meaning in 
life and physical functioning.  
3. We expect to a difference in quality of life and LARS-scores between surgical technique. We expect 
that PME will lead to fewer symptoms and TA-TME to worse symptoms compared with other 
techniques. 
4. We expect to see no differences in mortality rate and adverse events between the different baseline 
variables. 
 
Method 
Subjects for the EDFI-Cohort study will be recruited during 2019 and 2020 from Department of Surgery, 
Slagelse, and Zealand University Hospital, Køge. Subjects need to be diagnosed with rectal cancer and have 
received curative surgery (low anterior resection) with/without adjuvant (radiation/chemo) therapy. 
Subjects for this study are to meet the following inclusion criteria: Low anterior resection (e.g. not limited to 
total mesorectal excision (TME) or partial mesorectal excision (PME)), ability to communicate in Danish, 
adults (> 18 years of age), and American Society of Anaesthesiologists (ASA) score: I-IV. Exclusion criteria are: 
ASA score of: V-VI. 
 
Prior to inclusion, subjects must provide written informed consent to participate in this study. 
Subjects for the EDFI-Cohort study will be identified through surgical codes at Slagelse Hospital and Zealand 
University Hospital, Køge, Denmark. Eligible subjects will primarily be invited to participate in this study prior 
to discharge with oral and written information, provided in person by a health professional from the research 
group. Alternatively eligible subjects will be sent a letter after discharge. The letter and written information 
contain information on the study, the right to say no to the study, the right to 24 hours reflection time and 
the right to bring next of kin or another person of the subject’s choice with him/her to the inclusion meeting. 
Potential subjects that are only invited by letter are asked to contact the research group for further 
information. A second letter will be sent to potential subjects whom have not contacted the research group 
within two weeks, and 2-3 weeks after the second letter has been sent, subjects will be contacted once by 
phone. Verbal and written information will be provided by a health professional from the research group at 
a meeting in an undisturbed examination room at Slagelse Hospital or Zealand University Hospital, Køge, 
Denmark. 
 
 
 
 
 
 
 
 
 

 
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Sample size: 
The cohort will recruit all eligible patients from summer 2019 to April 2020. I this time period we estimate to 
recruit 70 patients to the EDFI cohort. A total of 86 patients were surgically treated for rectum cancer in 2017 
at Slagelse Hospital and Zealand University Hospital, Køge. 
The minimal clinically important difference on the EORTC QLQ-C30 subscale Global Health Status is 
considered to be 7-12 points for a variety of cancer types (rectal cancer not studied). [19-22] Thus, with the 
estimated recruitment flow; we will have a power of 0.98 for a two-sample pooled t-test of a normal mean 
difference with two-sided significance level of 0.05 (p ≤0.05), assuming a common SD of 22 EORTS QLQ-C30 
points to detect a mean difference of 10 points between groups with different surgical techniques or with 
high or low anorectal muscle function (primary study purpose 1). 
Additionally, we will have a power of 0.99 for a two-sample pooled t-test of a normal mean difference with 
two-sided significance level of 0.05 (p ≤0.05), assuming a common SD of 12 LARS points [3] to detect a mean 
difference of 6 LARS points between groups with different surgical techniques or with high or low anorectal 
muscle function (study purpose 2). 
Whether or not we are able to reach sufficient numbers within the 1 year timeframe, recruitment will end in 
April 2020. 
 
Outcomes: 
Outcomes is to be obtained from patient records, self-reported questionnaires and objective measures. For 
full list of outcomes to be collected and time points, see table 1. 
 
Patient records: 
In order to identify and invite eligible subjects, information on diagnosis, type of surgery, admission and 
contact information will be collected from patient records and given to the research group, prior to 
acceptance to participate in the study. After acceptance to participate in this study the following 
descriptive information will be collected from patient records (including electronic patient journals): Age at 
surgery (years), time of surgery (weeks), type of surgery, surgical complications, gender (male/female), 
tumor height (cm from anal verge), tumor stage (UICC), involvement of lymph nodes (N stage), additional 
radiotherapy/chemotherapy, surgical technique, anastomosis, ASA grade (I-IV), time with temporary stoma, 
and if available data from pre-surgery manometric examination, digital examination, Six-Minute Walk test 
(6MWT) and mortality status. This information will be used to adequately describe patient characteristics, 
cancer treatment, surgical outcome and mortality status. Additionally the acceptance to participate in this 
study allows the research group and relevant control agency direct access to collect information on health 
status in relation to quality control. 
 
Self-reported outcomes: 
Information on education level, work status and civil status will be obtained through self-reported 
questionnaires at 3 weeks. The remaining self-reported outcomes is collected with a series of validated 
questionnaires that subjects will be asked to complete 6 times during the two year study, see table 1. 
 
Quality of life of cancer patients (primary outcome) is assessed with questionnaires developed by the 
European Organisation for Research and Treatment of Cancer (EORTC). EORTC has developed and validated 
a generic core set (EORTC QLQ-C30) for assessing quality of life. [23] [24] As recommended by the EORTC, 
have added symptom specific module (EORTC QLQ-CR29) [23] and fatique module (EORTC QLQ-FA12). [25] 
[26] 
 
Bowel related quality of life (secondary outcome) is quantified with the Low Anterior Resection Symptom 
score (LARS-score), which is a validated score to group subjects into either no/low LARS or major LARS. [9] 
The items included in the LARS-score have been selected and weighted to reflect bowel related quality of 
life. [9] [27] 
  

 
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Faecal incontinence is also quantified with the St. Marks Incontinence score (also known as the Vaizey score), 
which is a validated instrument for assessing severity of faecal incontinence. [28] 
 
Urinary incontinence is assessed with questionnaires developed by the workgroup International 
Consultation on Incontinence Modular Questionnaire (ICIQ). ICIQ has developed and validated a generic 
core set (ICIQ-UI) for assessing urinary incontinence. [29] Additionally, we use symptom specific modules 
also developed and validated by ICIQ. The modules assess urinary symptoms in males and females and 
sexual matters in males and females. 
 
Physical activity level is quantified as done in the Danish National Health Profile – Health of the Danish People, 
which is a nationwide questionnaire answered by more than 180.000 Danish people in 2017. [30, 31] 
 
Sources of meaning and meaningfulness is assessed with Sources of Meaning and Meaning in Life 
Questionnaire (SoMe), which is a self-reported measure of meaningfulness and crisis of meaning reported 
on two separate scales, enabling further analysis and comparisons of positive and negative aspects of 
meaning in life. The questionnaire has been validated in a Danish population. [32] [33] 
 
Objective measures 
All objective measures are to be collected at Slagelse Hospital and Zealand University Hospital, Køge, at 6 
weeks, 6 months, 12 months and 24 months. 
 
Digital examination of anorectal muscle function is an easy-to-use and cheap assessment tool readily 
available in a clinical setting. When using the Digital Rectal Examination Scoring System (DRESS) that ranges 
0-5 (lowest to highest), the digital examination showed very high agreement with manometry pressures 
(Spearman rank correlation coefficients 0.81-0.82). [34] Digital examination involves inserting a finger in the 
anal canal.  
 
High-Resolution AnoRectal Manometry (HR-ARM) is considered state of art in measuring anorectal muscle 
function and has shown to have moderate to high reliability in adults with or without faecal incontinence, 
with intra-individual correlations (ICC) for resting pressure (ICC 0.60-0.91) [35] [36] [16], squeezing pressure 
(ICC 0.49-0.95) [35] [36] [16] and rectal perception (ICC 0.75-0.92) [36] [16]. HR-ARM involves a narrow 
catheter being inserted in the anal canal that measures pressure with strain gauges several times throughout 
the anal canal. Rectal perception is measured by inflating a balloon in the rectal canal. 
 
The Six-Minute Walk test (6MWT) is a widely used measure of submaximal exercise capacity in populations 
with and without pathology. [37] The 6MWT has shown to be correlated to maximum exercise capacity 
(r=0.67) and to perceived physical function (EORTC QLQ-C30 physical function subscale) (r=0.55) in cancer 
patients. [38] A systematic review has recommended that a minimal clinically important difference of ≥ 30.5 
m for the 6MWT can be considered clinically meaningful for patients with a variety of pathology. [39] 6MWT 
involves the patient walking as far as possible in 6 minutes indoor. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 1: Full list of outcomes. 
Patient records at hospital 
Items that is obtained 
Time point 
Descriptive information: 
Age at surgery (years) 
Time of surgery (weeks) 
Gender (male/female) 
Tumor height (cm from anal verge) 
Tumor stage (UICC) 
Involvement of lymph nodes (N stage) 
Additional radiotherapy/chemotherapy 
Surgical technique 
Anastomosis 
ASA grade (I-IV) 
Time with temporary stoma 
Manometric examination (if available) 
Digital examination (if available) 
Six-Minute Walk test (if available) 
At identification of relevant 
patients  
Adverse events from surgery 
Hospitalisation 30 days after surgery 
Surgical complications 
30 days after surgery 
Mortality (and at the National 
Patient Registry) 
Is the subject deceased? 
If no answer is obtained 
through questionnaires or no 
show at clinical examination. 
 
 
 
Self-reported outcomes: 
Questionnaire 
Time point 
Education level, work status and 
civil status 
Non standardized questionnaire  
3 weeks 
Bowel related quality of life 
Low anterior resection symptom – score (LARS-
score) 
3, 6, 12, 26, 52 and 104 
weeks 
Faecal incontinence 
St. Marks Incontinence score (Vaizey-score) 
3, 6, 12, 26, 52 and 104 
weeks 
Quality of life of cancer patients: 
EORTC QLC-C30 
3, 6, 12, 26, 52 and 104 
weeks 
 
Colorectal 
EORTC QLQ-CR29 
3, 6, 12, 26, 52 and 104 
weeks 
 
Fatique 
EORTC QLQ-FA12 
3, 6, 12, 26, 52 and 104 
weeks 
 
Information about disease 
and treatment 
EORTC QLQ-INFO25 
3, 6, 12, 26, 52 and 104 
weeks 
Urinary Incontinence 
International Consultation on Incontinence 
Modular Questionnaire (ICIQ) - Urinary 
Incontinence Short Form (ICIQ-UI SF) 
3, 6, 12, 26, 52 and 104 
weeks 
 
Urinary symptoms, males 
ICIQ-Male Lower Urinary Tract Symptoms 
(ICIQ-UI MLUTS) 
3, 6, 12, 26, 52 and 104 
weeks 
 
Urinary symptoms, females 
ICIQ-Female Lower Urinary Tract Symptoms 
(ICIQ-UI FLUTS) 
3, 6, 12, 26, 52 and 104 
weeks 
Sexual dysfunction 
 
 

 
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Sexual dysfunction, males 
ICIQ-Male Sexual Matters associated with 
Lower Urinary Tract Symptoms (ICIQ-UI 
MLUTSsex) 
3, 6, 12, 26, 52 and 104 
weeks 
 
Sexual dysfunction, females 
ICIQ-Female Sexual Matters associated with 
Lower Urinary Tract Symptoms (ICIQ-UI 
FLUTSsex) 
3, 6, 12, 26, 52 and 104 
weeks 
Physical activity level 
physical activity section of the Danish 
National Health Profile 
3, 6, 12, 26, 52 and 104 
weeks 
Sources of meaning and 
meaningfulness 
Sources of Meaning and Meaning in Life 
Questionnaire (SoMe) 
3, 6, 12, 26, 52 and 104 
weeks 
 
 
 
Objective measure: 
Units: 
Time point 
Anorectal muscle function (digital 
examination) 
 
 
 
Maximal resting pressure 
Maximal squeeze pressure 
Endurance squeeze - max 
squeeze pressure or longest 
time 
 
Latency (rate of force 
development), number of 
rectal muscle 
contractions/squeezes in 15 
sec test. 
0-5 (DRESS) (lowest to highest) 
 
0-5 (DRESS) (lowest to highest) 
0-5 (DRESS) and s, maximum of 60 s. 
 
 
 
n  
6, 26, 52 and 104 weeks 
Anorectal muscle function (High-
Resolution AnoRectal 
Manometry) 
 
 
 
Pressure measurements: 
Maximal resting pressure 
Maximal squeeze pressure 
Maximal squeeze pressure 
duration 
 
mmHg 
mmHg 
s 
6, 26, 52 and 104 weeks 
 
Volume capacity 
measurements: 
Maximal tolerated volume 
Conscious rectal sensitivity 
threshold 
Conscious rectal sensitivity 
Constant sensation 
 
 
mL 
mL 
 
% of maximal volume 
mL 
6, 26, 52 and 104 weeks 
Physical Performance 
 
 
 
6-Minute Walk test 
M 
6, 26, 52 and 104 weeks 
 
Statistical analysis 
We plan to analyze the EDFI-Cohort study as repeated measures with both simple and multiple linear 
regression models for the continuous data. We plan to adjust for the following known confounders: patient 
characteristics: age at surgery, gender, tumor height, tumor stages and variables related to treatment: 
surgical complications (e.g. nerve damage, sphincter rupture), additional radiotherapy/chemotherapy, time 
with stoma. 
 
Patient involvement 
Prior to planning of the EDFI-Cohort study, we have performed a single case-study (spring 2016) on 
examination procedure, questionnaires and pelvic floor muscle rehabilitation. This case provided us with 
valuable information on testing and possible evaluation of treatment effect. In the winter of 2017-18, we 

 
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interviewed subjects on their perspective on this study design and examination load. In the same time-
period, we did pilot testing on the clinical examinations.  
 
Research ethics 
Examinations included in this study are all associated with very few, if any, adverse events, except from the 
mild discomfort related to the clinical anorectal examination itself. Subjects included in this study will receive 
four examinations, whereas care as usual at Slagelse and Køge Hospital usually include one 
examination/contact to the local LARS clinic with no anorectal examination. This, included subjects are more 
closely monitored and, if need be, might receive relevant treatment earlier compared to care as usual 
patients. 
 
Future implications 
Results from the EDFI-Cohort study will help guide the design of randomized controlled trials on treatments 
of faecal incontinence in subjects who have been surgically treated for rectal cancer. With emphasis on 
establishing the role of anorectal muscle function in the development of faecal incontinence. 
 
Applicability of registrations and approvals 
A prior version of the EDFI-Cohort study protocol has been approved by the regional research ethics 
committee of Region Zealand and The Data Protection Agency journal number: REG-130-2017. This project 
adhere to the General Data Protection Regulation and Data Protection Act. The regional research ethics 
committee and data protection agency will need to approve the new version of the study protocol prior to 
project start. Finally, the project will, prior to start, be registered at ClinicalTrials.gov. This study is part of the 
patient compensation scheme (patienterstatningsordningen). 
 
Study economy 
This study is partially funded. Funding has so far come from the local research fund of NSR hospitals (DKK 
968,000) and The Association of Danish Physiotherapists (DKK 82,000). The Department of Physiotherapy 
and Occupational Therapy at Slagelse Hospital provides access to facilities and offices. None of the funding 
agencies have any influence on study design or reporting of data. Further funding will be applied for from 
public and private foundations.  
To reduce unnecessary inconvenience for subjects, we have planned the study test sessions on same days as 
subjects are to meet in the LARS outpatient clinics.  
 
Dissemination of study results: 
The EDFI-Cohort study is expected to be presented at several conferences for health professionals and the 
public and to provide 4 international peer-reviewed scientific papers on the findings whether they are 
positive, negative or inconclusive. All reporting of the EDFI-Cohort study will comply with the STROBE-
guidelines [40, 41]. 
 
The first publication (paper 1) will report on associations between quality of life and LARS-score, adjusted for 
baseline variables (surgical technique, anorectal muscle function, faecal incontinence, urinary incontinence, 
sexual dysfunction, fatigue, physical activity, meaning in life and physical functioning) from prior to curative 
surgery until 12 weeks after surgery. 
 
The second publication (paper 2) will report on the development of quality of life and LARS-score, stratified 
based on choice of surgical technique prior to curative surgery until 6 months after surgery. 
 
The third publication (paper 3) will report on associations between quality of life and LARS-score, adjusted 
for baseline variables (surgical technique, anorectal muscle function, faecal incontinence, urinary 
incontinence, sexual dysfunction, fatigue, physical activity, meaning in life and physical functioning) from 
prior to curative surgery until 2 years after surgery. 
 

 
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The fourth publication (paper 4) will report on mortality rate and adverse events adjusted for baseline 
variables (surgical technique, anorectal muscle function, faecal incontinence, urinary incontinence, sexual 
dysfunction, fatigue, physical activity, meaning in life and physical functioning) from prior to curative surgery 
until 2 years after surgery. 
 
 

 
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