The Effect of Prehabilitation on Surgical Complications Following Colon Surgery - a Prospective Randomized Study
Phase: NA
Conditions: Surgery--Complications
Sponsor: Region Skane

 
1 
 
 
2 
THE EFFECT OF 
PREHABILITATION ON 
SURGICAL COMPLICATIONS 
FOLLOWING COLON CANCER 
SURGERY – A PROSPECTIVE 
RANDOMIZED STUDY 
Does Prehabilitation Improve Outcome in Colon 
Cancer Surgery – Study 1 (PRIO01) 
Document update: 10 July, 2019 
Stefan Öberg, MD, PhD, Associate Professor 
Stefan.oberg@med.lu.se 

 
1
Research plan 
1 
 
2 
Research project title 
3 
The effect of prehabilitation on surgical complications following colon surgery – a prospective 
4 
randomized study 
5 
 
6 
Participating staff 
7 
Stefan Öberg, MD, Associate Professor, Senior Consultant. 
8 
Marcus Edelhamre, MD, PhD, Senior Consultant 
9 
Tomas Vedin, MD, PhD, Consultant. 
10 
Henrik Bergenfeldt, MD, PhD,  Resident. 
11 
Jenny Engdahl-Severin, MD, Doctoral candidate, Consultant. 
12 
Sandra Bech-Larsen, MD, Doctoral Candidate, Resident. 
13 
Lena Toft, RN, Research Nurse, Stoma thereapist and contact nurse for paitents with 
14 
colorectal cancer. 
15 
Above mentioned staff all work at the Surgical Department, Helsingborg General 
16 
Hospital, Sweden.  
17 
 
 
18 

 
2
Table of contents 
1 
Research plan ........................................................................................................................................................ 0 
2 
Research project title ......................................................................................................................................................... 1 
3 
Participating staff................................................................................................................................................................ 1 
4 
Background ............................................................................................................................................................ 4 
5 
Scientific questions ............................................................................................................................................. 5 
6 
Secondary hypotheses ........................................................................................................................................................ 5 
7 
Method ..................................................................................................................................................................... 6 
8 
Abbreviated study design ................................................................................................................................................. 6 
9 
Preoperative evaluation ................................................................................................................................................... 6 
10 
Inclusion criteria .................................................................................................................................................................. 7 
11 
Exclusion criteria ................................................................................................................................................................. 7 
12 
Randomization procedure ............................................................................................................................................... 7 
13 
Blinding procedure.............................................................................................................................................................. 7 
14 
Interrim analysis .................................................................................................................................................................. 8 
15 
Statistical calculations ....................................................................................................................................... 8 
16 
Power calculation ................................................................................................................................................................ 8 
17 
Statistical methods .............................................................................................................................................................. 8 
18 
Definitions .............................................................................................................................................................. 8 
19 
Standard care in colon cancer ....................................................................................................................................... 8 
20 
Ergospirometry ..................................................................................................................................................................... 9 
21 
Sarcopenia ............................................................................................................................................................................10 
22 
Health-related quality of life .........................................................................................................................................10 
23 
Symptoms of depression and anxiety ........................................................................................................................11 
24 
Immunonutrients ...............................................................................................................................................................11 
25 
Macronutrients ...................................................................................................................................................................11 
26 
Micronutrients ....................................................................................................................................................................12 
27 
PETH ........................................................................................................................................................................................12 
28 
Blood analysis ......................................................................................................................................................................12 
29 
Detailed description of the second part of the study ..........................................................................................13 
30 
Intervention cohort ...........................................................................................................................................................13 
31 
Exercise ..................................................................................................................................................................................13 
32 
Diet ...........................................................................................................................................................................................13 
33 
Control Group ......................................................................................................................................................................13 
34 
Operation...............................................................................................................................................................................14 
35 
Evaluation of complications ..........................................................................................................................................14 
36 
Follow-up ...............................................................................................................................................................................14 
37 

 
3
Health economics ...............................................................................................................................................................14 
1 
References ............................................................................................................................................................16 
2 
 
3 
 
4 
 
5 
 
 
6 

 
4
Background 
1 
Cancer of the large bowel and rectum is the third most common kind of cancer in 
2 
Sweden with 6500 new cases diagnosed each year. Cancer survival has improved over 
3 
the past decades and approximately 65% of the patients live beyond 5 years of 
4 
diagnosis. A great challenge of the surgical treatment is the high risk of complications 
5 
that stem from the surgery. In academic literature, this is called postoperative 
6 
complications. As many as 30% of the patients get at least one complication after 
7 
elective surgery. In certain groups of patients, such as the sick and elderly, more than 
8 
half of the patients suffer complications. These complications cause pain and suffering 
9 
and they increase the risk of dying because of surgery. Furthermore, these 
10 
complications come with prolonged hospital stay and increased costs [1, 2]. The 
11 
complications include wound infections, pneumonia, urinary tract infection, deep 
12 
venous thrombosis, pulmonary embolism, wound dehiscence, anastomotic leakage, 
13 
sepsis, myocardial infarction, stroke and death. Different types of interventions aiming 
14 
to improve the individual patient’s physical and nutritive status before surgery have 
15 
been given a lot of attention over the past years and more and more studies in this field 
16 
are being published. 
17 
 
18 
Prehabilitation encompasses all interventions that take place before a physiological 
19 
event which aim to improve the outcome of this event. These interventions include 
20 
physical training, psychological treatment and dietary improvements. 
21 
 
The conclusions that science has drawn so far regarding the effect of 
22 
prehabilitation are not  homogenous and it is still now known if preoperative 
23 
interventions aiming to improve the physical and nutritional status of the patients 
24 
actually reduces the risk of complications or affects the patient’s well-being.  
25 
 
 
26 
The effects of prehabilitation have been studied in the setting of elective abdominal 
27 
surgery in a randomized controlled trial of patients 70 years or older and/or with a 
28 
comorbidity corresponding to ASA III/IV. This study reported a 51% reduction in 
29 
postoperative complications in the group that was given prehabilitation compared to 
30 
the control group [3]. A systematic review has shown that prehabilitation of older 
31 
patients before colorectal surgery improved the patients physical status but no 
32 
statistically significant reduction of complications or hospital stay was seen. This 
33 
review article concluded that there was a lack of scientific trials studying the effects of 
34 
prehabilitation before colorectal surgery [4]. The included studies’ quality was limited 
35 
by small study populations, heterogenous control groups and poor patient compliance. 
36 
 
37 
Another study demonstrated that physical and social function was improved by 
38 
prehabilitation before colorectal surgery. However, only 71% of the patients completed 
39 
the prehabilitation and only 56% of the patients completed follow-up [5]. These 
40 
relatively low numbers constitute major scientific weaknesses. To sum up, the 
41 
conclusions in the present scientific literature are contradictory regarding the effect 
42 
prehabilitation has before surgery. Because of this, we aim to design and perform a 
43 
randomized, prospective study with adequate sample size, intervention completion and 
44 
follow-up to investigate of structured physical exercise and diet affects the outcome 
45 
regarding complications and quality of life. 
46 
 
47 

 
5
Scientific questions 
1 
 
2 
Primary hypothesis 
3 
The primary hypothesis of this study is that prehabilitation with exercise and nutritional 
4 
supplements will decreased morbidity, number of and severity of postoperative 
5 
complications.  
6 
 
7 
 
8 
Secondary hypotheses 
9 
• 
Malnourished patients have a micronutrient deficiency to a greater extent than 
10 
patients that are not malnourished.  
11 
• 
Micronutrient status can be improved with prehabilitation 
12 
• 
Prehabilitation increase the muscle mass 
13 
• 
Prehabilitation results in improved cardiopulmonary function measured with 
14 
ergospirometry (VAT ) 
15 
• 
Health-related quality of life according to SF-36 is improved with prehabilitation 
16 
• Fewer symptoms of depression and anxiety according to HADS (Hospital anxiety 
17 
and depression scale) is observed with prehabilitation 
18 
• 
Immunonutrition and protein supplement combined with exercise will result in 
19 
increased prealbumin and albumin in serum 
20 
• 
Frailty score is improved after prehabilitation 
21 
• 
Non-frail patients have fewer and less serious complications and shorter length of 
22 
stay 
23 
• 
There is a correlation between frailty score and cardiopulmonary function 
24 
measured with ergospirometry (VAT ) 
25 
• 
Frailty index can be used to predict which patients that may benefit from 
26 
prehabilitation 
27 
• 
Prehabilitation results in restored intestinal function earlier than for patients that 
28 
go through standard care 
29 
• 
Prehabilitation results in shorter length of stay 
30 
• 
An increase in muscle mass reduce the risk of postoperative complications 
31 
• 
Prehabilitation is associated with fewer readmissions 
32 
• 
Prehabilitation is associated with reduced health care costs and social costs 
33 
 
34 
 
 
35 

 
6
Importance for health care and patient benefit 
1 
Today, the only available treatment that can cure colorectal cancer is surgery. This 
2 
require that the patients general condition allows surgery and that the patient can get 
3 
tumor free after the surgery. If preoperative intervention with exercise and diet can 
4 
improve the patients physiological condition before operation, this might lead to a 
5 
decrease of postoperative complications and a better quality of life. A reduction of the 
6 
number and severity of complications will lead to shorter length of stay and fewer re-
7 
admissions which will result, not only in a reduction of healthcare costs but also less 
8 
suffering for the specific individual.  
9 
Patients that initially are too weak to undergo surgery that go through a prehabilitation 
10 
programme, might benefit to an extent that the decision not to operate may be altered.  
11 
  
12 
 
13 
Method 
14 
 
15 
Abbreviated study design 
16 
 
17 
The study will be conducted as a single-blinded randomized controlled trial. The trial 
18 
will include patients with colon cancer scheduled for elective surgery at Helsingborg 
19 
Hospital. Patients with a newly discovered tumor of the colon will, at the time of 
20 
diagnosis, be informed of the finding and that a physician and a registered nurse from 
21 
the surgical department at Helsingborg Hospital will contact them. Patients will receive 
22 
oral and written information regarding participation in the study. In the first stage 
23 
patients will only be informed that the study aims to reduce postoperative complications 
24 
through diet and exercise. The reason for this is to avoid that patients by themselves 
25 
initiate changes in diet or exercise routines which could pollute the study design [6]. 
26 
The principal aim of the study is to evaluate if a standardized regimen combining diet 
27 
and exercise results in fewer and less serious postoperative complications compared to 
28 
conventional perioperative management consisting of a small dietician intervention if 
29 
there is clinical suspicion of malnutrition and psychosocial support through contact 
30 
nurse.  
31 
 
32 
Preoperative evaluation 
33 
All included will undergo ergospirometry, frailty screening, blood sampling and 
34 
evaluation of quality of life prior to surgery. All patients >=60 years of age who accept 
35 
inclusion and are included in the study will undergo the aforementioned testing. As 
36 
earlier studies have shown that patients with VAT<11 on ergospirometry have the 
37 
greatest potential benefit of prehabilitation these patients with low cardiopulmonary 
38 
function will be informed in writing and orally and asked to participate in the second 
39 
part of the study. Patients who accept inclusion will be randomized to two groups; an 
40 
intervention group and a control group. The intervention group will undergo 
41 
preoperative exercise and special diet intervention. The control group will undergo 
42 
conventional preoperative preparation. The study will adhere to the guidelines set forth 
43 
in the “standardized course of care” by the Swedish Association of Local Authorities 
44 
and Regions.  
45 
 
46 
Patients who undergo ergospirometry but have a cardiopulmonary function above the 
47 
threshold(i.e. VAT>11) will not be included in the study but will be followed as a 
48 

 
7
reference material(observational cohort). They will only participate in the first part of 
1 
the study and undergo frailty assessment and evaluation of health-related quality of life 
2 
and symptoms of depression and anxiety.  
3 
 
4 
As a historical comparison we will map and categorize complications after colorectal 
5 
surgery for the period 2009-2019. Patients will be identified from electronic 
6 
databases(PASIS) and through ICD-codes which identify colorectal surgical 
7 
procedures. Pertinent information will be gathered regarding: 
8 
A) Patient and disease characteristics( age, sex, present and past illness, current 
9 
medication, cardiopulmonary function, ASA-classification, Time from 
10 
diagnosis to surgery and routine labs)  
11 
B) The conducted procedure (surgeon, procedure length, blood loss, perioperative 
12 
antibiotics, bowel preparation, laparoscopy or open procedure, vascular 
13 
anatomy and technique of specimen removal) 
14 
Postoperative morbidity as defined by Clavien-Dindo and POMS (length of stay, vitals, 
15 
time to return of normal bowel function, radiologic or physiologic diagnostic 
16 
procedures undertaken, late complications and recurrence of cancer within 5 years after 
17 
surgery). 
18 
 
19 
Inclusion criteria 
20 
 
21 
Part 1 of study 
22 
- 
Suspected colon cancer 
23 
- 
Age>=60 years 
24 
 
25 
Part 2  of study 
26 
VAT<=11 at ergospirometri 
27 
 
28 
Exclusion criteria 
29 
- 
Curative treatment intent not possible as assessed by the multi-disciplinary 
30 
tumor board 
31 
 
32 
Randomization procedure 
33 
Randomization will be conducted from opaque envelopes in blocks of 10 envelopes, a 
34 
total of 180 envelopes. 
35 
 
36 
Blinding procedure 
37 
To minimize the risk of subjectivity and undue influence of postoperative patient 
38 
management due to group allocation (bias) the nursing staff and treating physicians will 
39 
have no information regarding group allocation. This will apply to all members of the 
40 
team involved in postoperative care including the physicians responsible for the study. 
41 
The only people with knowledge of group allocation will be the contact and research 
42 
nurses at the outpatient department. The contact and research nurses will not participate 
43 
in the perioperative care of the study patients, which will prevent bias regarding the 
44 
primary outcomes. The patients will be informed of the importance of not sharing 
45 
information regarding group allocation with nursing staff and physicians. If it becomes 
46 
necessary to reveal group allocation for medical reasons the research nurse will consult 
47 
the same physician in all matters. This physician, who is also the principal investigator, 
48 
will not take part in the surgical or perioperative care of the patient. 
49 

 
8
Interrim analysis 
1 
To enable evaluation of safety and, if necessary, minor changes to the study protocol 
2 
an interim analysis will be conducted after inclusion of 15 patients in each group. The 
3 
study will be prematurely terminated if there is a significant increase of serious 
4 
complications(>Clavien-Dindo 3B) in the intervention group [7]. Minor changes to the 
5 
study protocol may be made at this time if responsible researchers assess that they do 
6 
not impair the ability of the study to answer the main hypothesis. 
7 
 
8 
Statistical calculations 
9 
Power calculation 
10 
The study will be designed to identify a reduction in the prevalence of postoperative 
11 
morbidity(as assessed by postoperative morbidity survey) on the fifth day from 50 % 
12 
to 28 % with a beta-value of 0.8 and an alpha-value 0.05 based on calculations below. 
13 
 
14 
The risk reduction is estimated from Dunne et al who showed that prehabilitation 
15 
increased VAT by approximately 2 ml/kg/min which according to West et al decreases 
16 
the odds of morbidity assessed by POMS by 40 % [8, 9]. Furthermore, immunonutrition 
17 
has been shown to convey a 50 % reduction in the odds of postoperative infectious 
18 
complications [10]. When these risk reductions are combined it is considered feasible 
19 
that an intervention with diet and aerobic prehabilitation exercise will convey an 
20 
absolute reduction in the risk of postoperative morbidity of 22 percentage points. I.e. a 
21 
relative risk reduction of 44 %. For adequate statistical power 78 patients are needed in 
22 
each group. We also factor in that up to 15 % of randomized patients might not be able 
23 
to complete the study and therefore plan to include 90 patients in each group, in total 
24 
180 patients (Stata SE 13.1) 
25 
 
26 
Statistical methods 
27 
Data will be stored deidentified in an electronic database that complies with the GDPR 
28 
of the European Union and Swedish applicable laws. Analysis of parametric 
29 
distribution will be conducted by Kologorov-Smirnov test. Statistical comparisons of 
30 
group differences will be conducted by t-test for parametric variables, Kruskal-Wallis 
31 
test for non-parametric variables and Fisher’s exact test for categorical variables.  
32 
 
33 
Quantitative analysis of risk factors for complications or impaired physiological 
34 
function will be conducted by logistic regression for binary outcomes and linear 
35 
regression for continuous outcomes respectively.  
36 
 
37 
 
38 
Definitions 
39 
Standard care in colon cancer 
40 
At the first visit to the surgical outpatient clinic, the patient fillis out a form that 
41 
measures percieved health. This form encompasses physical, phsycological, social and 
42 
existential aspects. The cancer contact nurse revies this with the patient to follow-up on 
43 
any specific needs.  
44 
 
45 

 
9
Patients who have lost weight, have deviating nutritional blood work or have problems 
1 
eating recieve nutrition drinks and they are referred to the dietitian. If the patient wants, 
2 
they are referred to a therapist of even a psychologist. The cancer contact nurse contacts 
3 
the patients by phone, the week after this visit to provide phycological support and 
4 
screen for other problems that might have been missed at the first visit. The purpose of  
5 
this is to get the patient in as good shape as possible before surgery.   
6 
 
7 
At the first visit, the patient gets a file with different brochures regarding things they 
8 
can improve on their own before surgery (smoking- and alcolhol cessation) etc. 
9 
 
10 
Ergospirometry 
11 
The anaerobic threshold occurs when the muscular metabolism goes from aerobic to 
12 
anaerobic work and the pH stops dropping linearly and starts dropping exponentially, 
13 
in relation to the muscular work load. This can be measured by invasive muscle-pH 
14 
testing and a maximal exertion test. However, the Ventilatory Anaerobic Threshold 
15 
(VAT ) can be estimated by a non-invasive, non-maximal exertion test. The patient stops 
16 
biking upon perceived too big effort [11]. 
17 
 
Previous studies have shown a strong correlation between low VAT  and high risk 
18 
for postoperative complications, increased mortality and longer hospital stay [12].  In a 
19 
study of prehabilitation before liver surgery, it was been shown that the exercise regime 
20 
had good effect on cardio-pulmonary capacity, quality of life and was safe for old and 
21 
frail patients to perform [8]. 
22 
 
All included patients will go through an ergospirometri to establish VAT. The test 
23 
starts with 3 minutes of rest followed by 3 minutes of pedaling without resistance. 
24 
Following this, the resistance is progressively increased until the study person stops 
25 
pedaling by their own volition. The progressive increase of resistance occurs in steps 
26 
of 10W-25W [11]. The test is followed by 5 minutes rest. Ventilation as gas exchange 
27 
is measured by a breathing mask connected to a computer that calculates oxygen 
28 
consumption (oxygen uptake) and carbon dioxide production. Pulse, 12-lead ECG, 
29 
blood pressure and oxygen saturation of the blood is monitored during the entire session 
30 
to guarantee the patient’s safety. The protocol is described in detail by Dunne et al 
31 
(2014) [13]. 
32 
 
The ergospirometri will be performed at the department of clinical physiology it 
33 
Helsingborg General Hospital. Patients who are randomized to an exercise intervention 
34 
will perform this under supervision of a physical therapist in the hospital patient gym.  
35 
 
36 
Frailty, comorbidity and disability 
37 
Frailty is a clinical syndrome including a decreased physiological reserve and a 
38 
decreased ability to withstand physiological stressors. Frailty is often present in the 
39 
multimorbid patient with disability, but is an independent clinical syndrome including, 
40 
weightless, self-reported exhaustion, weakness, slow walking speed and low physical 
41 
activity. Many instruments to screen for frailty has been developed, but there is lack of 
42 
consensus in which instrument that is more advantageous to predict the risk for adverse 
43 
effects after surgery.  
44 
 
45 
The prevalence of frailty in patients that undergo colorectal cancer surgery has been 
46 
shown to be 40% and frail patients have an increased risk of morbidity and mortality 
47 
after surgery [14, 15]. The hypothesis is that prehabilitation can reduce the prevalence 
48 
of frailty, reduce the risk of morbidity- and mortality that is associated with frailty and 
49 

 
10
that the preoperative use of a frailty index can be used to predict the risk of 
1 
complications in patients with VAT<11 that are planned for colorectal surgery. 
2 
 
3 
• Frailty will be assessed using:  
4 
o Frailty Phenotype,  
5 
o Edmonton frail scale 
6 
o RAI-score (Risk-analysis-index) 
7 
o  
8 
• Disability will be assessed using:  
9 
o ADL 
10 
o IADL 
11 
 
12 
Comorbidity will be assessed using the Charlson comorbidity index. 
13 
 
14 
 
15 
Sarcopenia 
16 
Sarcopenia, (low muscle mass), has a prevalence of up to 40% in colorectal cancer 
17 
patients. It is associated with an increased risk of postoperative complications [16]. Fat 
18 
free mass will be measured with bioelectrical impedance to examine if prehabilitation 
19 
affects the muscle mass.  
20 
 
21 
 
22 
Health-related quality of life 
23 
It has been shown that colorectal cancer surgery reduces quality of life [17]. Our 
24 
hypothesis is that prehabilitation eliminate or at least decrease the reduction in health-
25 
related quality of life after surgery.  
26 
 
27 
Health-related quality of life is reduced after planned colorectal surgery. The SF-36 
28 
(short-form 36 Health Survey) is a generic self-reported health-related quality of life 
29 
questionnaire that is available in a Swedish validated and reliability-tested version [18]. 
30 
The SF-36 questionnaire consists of 35 individual questions divided into eight 
31 
subscales that represent eight domains of health. The scores on items pertaining to the 
32 
same dimension are then aggregated to generate a score for each of the eight domains 
33 
of health (physical functioning, role physical, pain, social functioning, role emotional, 
34 
vitality, mental health, and general health perception). The numerical answers are then 
35 
recorded according to a pre-specified algorithm to yield scores ranging for 0 to 100 for 
36 
each domain. It takes 8 minutes to answer the questions [10].  
37 
 
38 
It’s been shown that scores on six of eight domains deteriorated after colorectal cancer 
39 
surgery and improved to baseline thereafter. Scores on all subscales but mental health 
40 
and general health perception were significantly lower than baseline at 1 month 
41 
postoperatively and at 2 months, the score for role physical remained significantly 
42 
below baseline [17]. 
43 
No studies on the potential effect of prehabilitation on health-related quality of life in 
44 
colorectal cancer surgery exist. In this study, The SF-36 will be used to measure health-
45 
related quality of life in all the included patients before randomization, before 
46 
operation, 30 days postoperatively, 3 and 6 months postoperatively, and 1,3 and 5 years 
47 
postoperatively.   
48 
 
49 

 
11
Symptoms of depression and anxiety 
1 
Approximately 30% of patients with cancer are affected with symptoms of anxiety and 
2 
depression [19]. Prehabilitation has been shown to reduce these symptoms in patients 
3 
suffering from colon cancer [20]. Previous studies that have shown a reduction of these 
4 
symptoms have had psychological support as a part of the prehabilitation program. Our 
5 
hypothesis is that prehabilitation in this study will result in reduced anxiety and 
6 
depression even though the patients won’t receive professional psychological support, 
7 
other than the support provided in the standard care program, which include counselling 
8 
if necessary. 
9 
 
10 
HAD (hospital anxiety and depression scale) is a questionnaire used to measure 
11 
symptoms of depression and anxiety in an in- or outpatient setting. HAD has been tested 
12 
in older populations and seem to have a good accordance compared to other 
13 
questionnaires [21, 22]. It takes 3-5 minutes to complete the test. An advantage with 
14 
this form compared to other questionnaires is that it covers not only symptoms of 
15 
depression but also symptoms of anxiety.  
16 
 
17 
 
18 
Immunonutrients 
19 
Immunonutrition can be defined as intake of a diet rich in glutamin, arginin and Omega-
20 
3 fatty acids during a period of 5-7 days prior to operation. A metanalysis of 14 
21 
randomized controlled studies in patients that underwent colorectal surgery showed that 
22 
immunonutrition significantly reduced the frequency of complications [10]. It is 
23 
however unclear if immunonutrition combined with exercise and protein supplement 
24 
further can reduce the frequency of complications. 
25 
 
26 
Macronutrients 
27 
Our hypothesis is that protein supplement combined with exercise can improve patients 
28 
physical level of function and reduce the risk of postoperative complications. Older 
29 
individuals are particularly dependent of an adequate intake of protein (20-30grams per 
30 
meal) to maintain a normal muscle protein synthesis [23]. European Society of Clinical 
31 
Nutrition and Metabolism recommend a protein intake of 2 grams per kilo per day for 
32 
patients with cancer. The intake of protein in patients with acute or chronic kidney 
33 
failure should be limited to 1 gram per kilo per day.  
34 
A low albumin (<35g/L) has been shown to be a better marker to predict postoperative 
35 
morbidity than weight loss and BMI in patients with colorectal cancer [24]. Even 
36 
though albumin is a useful marker to predict surgical complications, it is a flawed 
37 
marker to indicate malnutrition. Prealbumin (transthyretin) might be a favorable marker 
38 
since the half-life is shorter than for albumin (2-3 days). This may be more useful for 
39 
detecting acute changes in nutritional status to the recognition of rapid nutritional 
40 
changes  [25]. 
41 
 
42 
Protein supplement as a part of a prehabilitation intervention has previously been 
43 
examined in a study randomizing patients to structured prehabilitation before surgery 
44 
or structured rehabilitation after surgery [20]. The study showed that prehabilitation 
45 
resulted in better physical level of functioning, but no difference in number and severity 
46 
of complications were observed. Protein supplement with no other interventions have 
47 
shown to improve the walking capacity compared to placebo in patients who will have 
48 
surgery for colorectal cancer [26].  
49 
 
50 

 
12
 
1 
Micronutrients 
2 
A number of micronutrients (Zink, Iron, Copper, Calcium, Selenium, Vitamins A, C 
3 
and D, folate, cobalamin) are essential to adequate muscle protein synthesis, 
4 
postoperative wound healing and adequate immune response after surgery. It is 
5 
therefore theoretically possible that these substances can affect the results of 
6 
prehabilitation and also reduce the risk of postoperative complications. Several studies 
7 
have shown a correlation between protein intake, micronutrient reserves, muscle 
8 
strength and frailty [27]. Up to 30% of patients with colorectal cancer have shown 
9 
suffer from malnutrition [24]. It is not known if or to what extent these malnourished 
10 
individuals also suffer from a micronutrient deficiency. Furthermore, there are no 
11 
studies that have explored if micronutrient deficiency  can affect the result of 
12 
prehabilitation or increase the risk for postoperative complications.  
13 
 
14 
PETH 
15 
PETH (Phosphatedylethanol) is a validated laboratory method to quantify alcohol 
16 
intake with 100% specificity. Alcohol intake has proven to increase the risk of surgical 
17 
and affects cardiac function, immune defense and hemostasis [28]. To avoid 
18 
confounding, it is necessary to quantify the patients’ alcohol. 
19 
 
20 
Blood analysis 
21 
A broad spectrum of blood analyses will be performed. Patients will be samples before 
22 
the CT (sampling 1), preoperatively (sampling 2) and postoperatively (sampling 3).  
23 
 
24 
If there are pathological samples at sampling 3, patients will be followed by the surgical 
25 
outpatient clinic in Helsingborg of cared for by primary care.  
26 
 
27 
Laboratory analysis will be performed by the department of clinical chemistry at 
28 
Helsingborg General Hospital. Included patients will have the same patient insurance 
29 
as all patients cared for by Region Skåne. 
30 
 
31 
 
32 
 
33 
Samplings 1, 2, och 3: 
34 
• S-Cu 
• S-Ceruloplasmine 
• S-Selenium 
• S-Ascorbic acid 
• P-Cobolamin 
• P-Folate 
• P-Homocystein 
• S-Mettylmalonate 
• Zink 
• P-albumine 
• P-2-makroglobuline 
• S-Fe 
• S-Ferritin 
• S-Hepcidin 
• S-sTfR 
• S-TIBC 
• MCH 
• MCV 
• Calcidiol(25(OH)D) 
• S-Ca 
• S-Ca2+ 
• S-PTH 
• S-Retinol 
• P-Mg 
• Omega-3 
• SuPAR 
• Peth

 
13
Detailed description of the second part of the 
study 
 
Intervention cohort 
Patients who accept participation and have VAT<11 will be randomized to either the 
control group or the intervention group. 
 
Exercise  
Based on the subject's cardiopulmonary function (VAT), an interval training program 
will be designed. The training will be conducted 4 times a week (Monday, Tuesday, 
Thursday and Friday). Patients will be included and begin interval training as soon as 
a legit referral of a suspected colon cancer is present at the Surgical Department at 
Helsingborg Hospital. If the patients meet the listed criteria for inclusion in the study 
the patients will be enrolled in the training program and trained until 3 days prior to 
surgery. The reason for this is purely practical in order to allow the patient to rest at 
least one day before cycle test 2 and one day further before surgery. The training is 
done on an ergometer and takes a total of about 60 minutes at a time where 15 minutes 
is warm up, 30 minutes is interval training of 60-90% of VAT and 15 minutes is cool 
down. The training is performed in accordance with Dunne et al (2016) [8]. The training 
will be performed in a room at the hospital. It will, when possible, be performed in 
groups and will be led by a physical therapist. Patients will be offered free transport to 
and from the hospital as well as lunch in connection with the training. 
 
Diet 
• Assessment of the study dietician regardless of clinical nutritional status. 
o diet anamnesis; "48-recall", i.e. complete review of the intake of food in the last 48 
hours. 
o Length, weight, weight change, body composition 
o Albumin, Prealbumin (S-Transthyretin - TTR), C-Reactive Protein 
• Target caloric intake is set to 30-35 kcal / kg / day and for protein is set to 2g / kg / 
day  
• Supplementation with nutritional drink Fresubin Protein Energy Drink, 2-3 pcs daily 
on dietary suspicion of insufficient protein energy intake. If additional protein is 
needed, Fresubin protein powder is given. 
• Supplementation with dietary supplements in the absence of micronutrients in blood 
sampling 1 according to appendix 1. 
• Immunonutrition from 7 days preoperatively with Nestlé Oral Impact 3x300ml 
 
Control Group 
Patients randomized to this group will follow pre and postoperative standard routines 
for elective abdominal cancer surgery at Helsingborg Hospital. This means, among 
other things, psychosocial support via contact nurse and curator if needed. Dietician on 
clinical suspicion of nutritional problems and mobilization with the help of paramedical 
staff in the postoperative department. 
 
 
 

 
14
Operation  
All included patients will be operated according to standard and generally accepted 
colorectal cancer surgical techniques. The procedure is performed by consultant 
surgeons specially trained for colon cancer surgery. The operation will either be 
performed as minimal invasive surgery with or without robot or conventional open 
surgery. Regardless of the surgical method, the procedure is done according to a 
standard procedure, which involves dissecting the intestine in embryological planes 
ensuing best oncological outcome for each patient. This technique removes the cancer 
with a good margin, which has been shown to lead to fewer relapses and better survival 
for the patient. 
 
The staff and the surgeon are only aware that the patient is included in the study. 
 
Evaluation of complications 
Postoperative Morbidity Survey (POMS) is an instrument developed to identify 
complicated postoperative procedures that result in extended care time. POMS assess 
the incidence of morbidity in 8 domains (Renal, Cardiovascular, Pulmonary, Infectious, 
Neurological, Hematological, Gastrointestinal, Wound Related and Pain) regardless of 
etiology. POMS can be used both retrospectively and prospectively and has low 
interindividual variance [29, 30]. 
 
Clavien-Dindo is a scale developed to classify the severity of a complication based on 
which therapeutic consequence is needed. According to Clavien-Dindo, complications 
are graded on a five-degree scale from complications that did not require active 
treatment to fatal complications [7]. Together, POMS and Clavien-Dindo provides a 
picture of the incidence of complications as well as the severity. 
 
Follow-up 
The follow-up will be done with registration of post-operative complications, time to 
restored bowel function on a daily basis and total days of admission will be registered. 
After 30 days post operatively the chart will be checked again for further postoperative 
complications, re-admission.  The patient will also perform SF-36 and HAD on day 30 
postoperatively. 
 
Thereafter SF-36 and HAD as well as studies of the patient chart will be carried out 
after 3 and 6 months, and after 1, 3 years and 5 years postoperatively. 
 
Patients excluded before randomization will be followed up as mentioned above until 
day 30 post operatively. 
 
Health economics 
Health economics is a discipline that analyzes health and medical care from an 
economics perspective. As the resources of society are limited and the demand for care 
is increasing, methods are needed to be able to make priorities in the healthcare sector. 
Our hypothesis is that preoperative intervention with exercise and diet improves the 
patient's physiological conditions before surgery, which can lead to reduced 
postoperative complications and improved quality of life and thus lower costs for 
healthcare and society at large. 
 

 
15
Some studies have shown that the mean cost for a complication is around SEK 120.000, 
which corresponds to a doubling of the cost of care for these patients. And in these 
studies one-third of the investigated unit's budget was used to fund the management of 
complications [31, 32]. 
Within the tenets of this study, we intend to calculate costs for hospital care and for 
society at large, and in what way these are affected by post-operative complications. 
Our hypothesis is that prehabilitation reduces the costs of secondary postoperative 
complications. 
 
 

 
16
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