Nutritional status assessment
In this study we will use several methods to analyze patients’ nutritional status. The NRS-2002 is a screening tool designed to assess the risk of malnutrition, as shown in Table 1 [25]. It takes into account BMI, weight loss during the past three months, food consumption during the past week, the severity of the illness and age under/over 70. Maximum points are 7. Patients who scored 0 are not at a nutritional risk, patients who scored 1–2 are at a low nutritional risk, and patients who scored 3–4 are at a moderate risk of malnutrition. A score of 5 or more indicates a severe risk of malnutrition. In our study, each patient will be scored a minimum 2 points at baseline and at the one-month follow-up visit because of their disease severities since these patients have local cancer and an upcoming or recent major abdominal operation.
Bioimpedance analysis has been shown to be reliable in analyzing the nutritional status and body composition of a patient with a cancer [26], [27]. It measures body tissue resistance and reactance, giving an estimate of total body water. When the patient’s height is known, the estimation of fat-free mass can be calculated [28], [29].
A reliable estimation of physical strength can be measured by the handgrip strength. It has also been proven to be a method for screening malnutrition, and it was also shown that patients who were at risk of malnutrition according to NRS-2002 had a lower handgrip strength [30], [31]. A low handgrip strength has been associated with increased mortality [32].
Laboratory markers have been considered an easy method for assessing malnutrition. Traditionally, the laboratory parameters albumin, CRP and total lymphocyte count have been used [33] .
Computed tomography (CT) can be used to assess body composition and lean body mass. Lean body mass is described as the sum of fat-free mass. The cross-sectional area of muscle and fat at the level of L3 has been shown to correlate with the volume of tissues in the whole body [34]. Sarcopenia and myosteatosis can be calculated with a CT scan. Sarcopenia is defined as a skeletal muscle index (SMI) < 41cm2/m2 for women, 43cm2/m2 for men with BMI < 25kg/m2 and 53 cm2/m2 for men with BMI ≥ 25kg/m2 [35]. Myosteatosis is defined as a Hounsfield unit (HU) < 41 for patients with BMI < 25kg/m2 and HU < 33 for patients with BMI ≥ 25kg/m2 [35].
Table 1: NRS-2002 screening tool
- Nutritional situation
|
|
|
Points
|
|
BMI
|
<18.5
|
3
|
|
|
18.5-20.5
|
2
|
|
|
>20.5
|
0
|
|
Weight loss during last 3 months
|
weight loss <5%
|
0
|
|
|
weight loss 5-10%
|
1
|
|
|
weight loss 10.1-15% (or >5%/2 months)
|
2
|
|
|
weight loss >15% (or>5%/1 month)
|
3
|
|
Food amount last week
|
ate normal amount
|
0
|
|
|
ate over 50% of normal
|
1
|
|
|
ate approximately 50% or less of normal
|
2
|
|
|
ate very sparingly
|
3
|
|
|
|
max points 3
|
- Severity of disease nutritionally
|
|
normal situation (no significant disorders)
|
0
|
|
|
mild
patient on his/her feet despite of deteriorated overall condition
chronically sick patient staying in hospital due to comorbidities
chronic wound below 25 cm2
local cancer
alcohol or drug problem
|
1
|
|
|
moderate
bedridden patient
ambulatory patient with, e.g., widespread cancer, severe inflammatory bowel disease, recent major abdominal operation, repeated operations, recent stroke, severe infection, burn injury, pressure ulcer, widespread chronic wound, hip fracture, multiple traumas, acute leukemia
|
2
|
|
|
severe
intensive care
head injuries
stem cell transplantation
anorexia nervosa
|
3
|
- Influence of age
|
Age
|
<70
|
0
|
|
|
≥ 70
|
1
|
Abbreviations: BMI, Body Mass Index;
Surgery
Standard treatment of colon adenocarcinoma includes either a left or right hemicolectomy depending on the location of the tumor. Most operations for colon cancer are accomplished by laparoscopic techniques with the exception of T4 tumors and tumors of the transverse colon, of which a laparotomy is used. If the lymph node status is positive, or there are any other signs of a high risk of recurrence, a patient is considered for adjuvant therapy by an oncologist.
Perioperative care includes the assessment and optimization of medical risk factors, thromboprophylaxis with low-molecular weight heparin and elastic compression stockings, standard anesthesia with epidural analgesia, avoidance of hypothermia and increased oxygen concentrations. Mechanical bowel preparation will be performed according to local hospital policies. In perioperative care the Enhanced Recovery after Surgery (ERAS) protocol will be followed.
Data collection
All data will be collected prospectively using an electronic database designed for this study. The reasons for withdrawal, if any, will be documented. All data will be handled confidentially and pseudonymously.
For each participant, data collection will proceed as follows. The height and weight will be measured. BMI will be calculated. At baseline, the body weights three and six months previously will be obtained from the patients. The American Society of Anesthesiologists (ASA), WHO classification and Charlson Comorbidity Index will be recorded. History of smoking, comorbidities, additional supplement use and the patient’s medication will be recorded. The patient’s symptoms, date of first symptoms and date of diagnosis will be recorded. Whole-body computed tomography will be performed to assess the possibility of metastases or locally spread cancer and also to measure body composition. Colonoscopy findings will also be recorded.
The NRS-2002 score will be calculated on each time point. Each patient will score 2 points for disease severity at randomization and at the one-month follow-up visit because they have local cancer and upcoming or recent major abdominal operation. Bioimpedance analysis will be performed (Tanita 980) and the handgrip strength will be measured. Patients will keep a food diary for four days before the surgery and for four days at both one- and three- month time points after the operation to assess the energy and nutrient consumption. The actual consumption of the ONS will be recorded in both groups before and after the surgery.
Laboratory parameters including leukocytes, hemoglobin, C-reactive protein (CRP), carcinoembryonic antigen (CEA), creatinine and albumin concentrations will be measured. Cytokine levels will be examined. Samples of plasma, serum and whole blood will be saved at -80°C for later analyses.
The surgical specimen will all be analyzed by a pathologist, and study pathologists will review the cancer type, grade and classification of malignant tumors (pTNMs) according to TNM8. In addition, the degree of inflammatory reaction at the tumor margin will be recorded using the Klintrup-Mäkinen score [38] , and the number of lymphoid structures will be measured according to Väyrynen et al.’s method [39]. The number of intraepithelial lymphocytes and the SMI status will be recorded. The amount of tissue necrosis will be recorded [39]. Samples of subcutaneous and visceral fat tissue, rectus abdominis muscle, liver, tumor, healthy-looking bowel wall (including all layers), peritumoral bowel wall and stool samples will bw collected during the operation. Samples will be taken for histological and biochemical analyses. In right-sided cancers, a sample from the terminal ileum will also be taken. The sample´s warm and cold ischemia times will be recorded.
A RAND-36 quality of life questionnaire and an exercise questionnaire will be completed at every time point [40] .
Data about preoperative blood transfusions, oral iron use or intravenous iron infusions will be collected. Operation data will also be collected: operation code, duration, blood loss, infused units of red cells, infused amounts of crystalloids and colloids, bowel preparation before the operation, peroral and intravenous antibiotic use, vasopressor use during the operation, operating surgeon, anastomosis technique, stoma use, operation type and intraoperative complications.
Complications after the primary operation will be collected. Data concerning the length of stay in intensive care and total length of stay in hospital and discharge to home or institution will be collected. The date of first flatus, first passage of stool, use of ONS during hospital stay and ambulatory capacity during hospital discharge will be collected.
Complication data after the primary operation and after possible reoperations will be collected at every follow-up time point. The comprehensive complication index (CCI) will be analyzed. Registered complications include wound, respiratory, cardiovascular, gastrointestinal, anastomosis leakage, urogenital and renal, thromboembolic complications and other infections. The Clavien-Dindo classification will be determined for every complication.
The side effects of chemotherapy will be monitored, as well as discontinuation of chemotherapy. Information about cancer recurrence will be collected at every follow-up point.
Follow-up
The follow-up protocol is presented in Table 2.
First meeting and the operation
All patients attending this study will visit the outpatient clinic two to three weeks prior to the surgery. In the first meeting, patients are randomized by NRS-2002 as described. Bioimpedance and handgrip strength are measured. Laboratory tests, colonoscopy and CT scan results are registered. Patients will fill out a QoL questionnaire and an exercise questionnaire. Salivary samples are taken. A food diary is given to patients, and patients will return it when they present for their operation. The food diary will be checked upon return by a clinical nutritionist. All patients are given cancer patient nutrition guidelines. On arrival at the operation, BMI and handgrip strength will be measured. Data on patients’ ONS intake will be collected.
Postoperative care
Postoperative care follows the ERAS protocol. Operative and postoperative data are registered as described in data collection.
One-month follow-up visit and three-month phone call
The first follow-up visit is at the outpatient clinic 30 days after the surgery. At that time, the patient is interviewed about recovery from surgery. Patients whose prolonged recovery from surgery requires a stay in a primary care unit will be asked about the length of stay and possible complications after leaving the hospital. Data on possible readmissions and reoperations will be collected. Weights of the patients will be measured, the NRS-2002 score will be calculated, the bioimpedance analysis will be performed and the handgrip strength will be measured. The patients will complete the four-day food diary, exercise questionnaire and QoL questionnaire. Use of postoperative ONS is inquired from the patients. Blood samples are also taken.
The second follow-up at three months after the surgery, will be performed by phone. Albumin, CRP, CEA, hemoglobin and leucocyte count will be measured in health-care centers on a routine basis and the patients will complete a four-day food diary and QoL and exercise questionnaires. The patients will be interviewed about possible readmissions, reoperations and complications. The food diary will be checked by phone by a clinical nutritionist.
One-, two- and five-year follow-up visits
Patients will have follow-up visits one, two and five years after surgery. As is routine, CEA, hemoglobin and leucocyte count will be measured every three months for two years and then every six months until five years post-operatively. During the one-, two- and five-year follow-up visits, creatinine, albumin and CRP will also be measured. Samples of plasma, serum and whole blood will be stored at -80°C for later analyses. Weight, BMI and bioimpedance analyses will be performed, the handgrip strength will be measured, and the NRS-2002 score will be calculated at each visit. The WHO classification, the Charlson comorbidity index and smoking habits will be recorded. The patients will also complete the QoL questionnaire and exercise questionnaire at each time point. All patients will receive a whole-body CT scan one year after the surgery. CT scans monitoring the response to adjuvant chemotherapy will be utilized for analysis of recovery from sarcopenia and its effect on the survival and toxicity of chemotherapy. A colonoscopy will be performed two and five years after the surgery. During colonoscopy biopsy samples of normal looking ascending and descending colon and possible adenomas and tumors will be taken. A suction sample of effluent will be taken from the ascending colon. Additionally, a stool sample will be taken before bowel preparation. During every follow-up visit the patient will be interviewed about recovery, and the complications will be recorded. Data on cancer recurrence and its treatment will be collected.
Table 2. Schedule of events
Schedule of events
|
1st meeting
|
operation
|
discharge
|
30 day
|
3 month phone call
|
1 year
|
2 year
|
5 year
|
Informed consent
|
x
|
|
|
|
|
|
|
|
NRS-2002
|
x
|
|
|
x
|
|
x
|
x
|
x
|
Laboratory tests
|
x
|
|
|
x
|
x
|
x
|
x
|
x
|
Stool sample
|
x
|
x
|
|
|
|
x
|
x
|
x
|
CT scan
|
x
|
|
|
|
|
x
|
|
|
BMI
|
x
|
x
|
|
x
|
|
x
|
x
|
x
|
Hand grip strength
|
x
|
x
|
|
x
|
|
x
|
x
|
x
|
Bioimpedance
|
x
|
|
|
x
|
|
x
|
x
|
x
|
Food diary
|
x
|
|
|
x
|
x
|
|
|
|
QoL
|
x
|
|
|
x
|
x
|
x
|
x
|
x
|
Colonoscopy
|
x
|
|
|
|
|
|
x
|
x
|
Exercise questionnaire
|
x
|
|
|
x
|
x
|
x
|
x
|
x
|
Protocol deviation*
|
x*
|
x*
|
x*
|
x*
|
x*
|
x*
|
x*
|
x*
|
Complications and cancer recurrence
|
|
x*
|
x*
|
x*
|
x*
|
x*
|
x*
|
x*
|
Study exit form
|
|
|
|
|
|
|
|
x**
|
* Complete if applicable
** Complete when lost to follow-up, consent withdrawal, or when the subject has completed all study-related visits
Abbreviations: NRS-2002, Nutritional risk screening 2002; CT, Computed Tomography; BMI, Body Mass Index; QoL, Quality Of Life
Study timeline
Randomization started on April 1, 2019 at the Oulu University Hospital and will last until 318 patients are recruited. Data will be collected until five years post-operatively.
Statistical analysis
This is a superiority trial. Participants will remain in the groups to which they were originally assigned (intention to treat principal). Additionally, per protocol analyses will be performed as sensitivity analyses. In the per protocol analyses, protocol violation is deemed if a patient consumed <50% of nutritional drinks in the intervention group or in control group if a patient drank more than 5 nutritional drinks.
All analyses will be adjusted by stratification variable (Nutritional status (NRS 2002) 2, 3-4 or 5). Additionally, the crude outcomes will be reported. The treatment effect will be assessed by odds ratios for categorical data, hazard ratios for survival data and mean differences for continuous data. Random effect models will be used in the case of repeatedly measured data (>2 repeated measurements). If the incidence of outcome of interest is common (>10%) then odds ratios will be converted to risk ratios [37].
The treatment effect will be calculated separately for each NRS 2002 stratification class (2, 3-4 and 5). However, as the sample size calculation was performed only for the total treatment effect, the results of the stratified analyses are hypothesis generating only.
ETHICAL CONSIDERATIONS
Patients participating in this study will be examined and treated with a standard protocol. Participation in this study is voluntary and will not affect the treatment. Patients were not involved in the design, or conduct, or reporting, or dissemination plans of the research. The results of this research will be published in compliance with the General Data Protection Regulations (GDPR).
There will not be any additional exposure to radiation due to this research. All imaging will be performed as a part of the routine treatment protocol. Tissue samples will be taken under general anesthesia during the cancer surgery and no additional pain will be induced. Harvesting of the samples may cause minor bleeding but not significant bleeding or surgical complications. Subcutaneous fat and muscle tissue will be taken from the operation field. All other samples will be taken from the resected bowel after the surgery.
There will be some additional laboratory examinations before and after the surgery. Additional blood sampling may cause minor pain but not significant complications. Bioimpedance analysis is a painless and noninvasive method to analyze body composition.
This research causes no extra costs to patients. The ONS is financed by research funding. There will be no support from the manufacturing industry.
This study follows the Declaration of Helsinki on medical protocols and ethics, and the study’s protocol has been approved by the Ethical Committee of Oulu University Hospital. Each participating hospital applied for study permission at their respective institutions. Important protocol modifications are communicated with the Oulu University Hospital Ethics Committee by amendments. All modifications are also registered at Clinical Trials.
Potential patients considered for participating in the research will give informed consent. Patients will be informed about this research in an outpatient clinic. They have the right to decline to participate without any impact on their treatment. Patients have the right to withdraw from the study without explanation at any time.
Patient confidentiality will be strictly maintained. Patients will be pseudonymised by study identification numbers, and all data will be handled without using names or personal social security numbers. Access to patient records will be limited to the study group and the investigator-delegated study coordinator.