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ONC: Dietary Supplements and Medical Food Supplements Containing Fish Oil (2013)

Citation:

van der Meij BS, Langius JA, Smit EF, Spreeuwenberg MD, von Blomberg BM, Heijboer AC, Paul MA, van Leeuwen PA. Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment. J Nutr. 2010, Oct; 140(10): 1,774-1,780. 

PubMed ID: 20739445
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To investigate the effects of an oral nutritional supplement containing n-3 fatty acids on nutritional status and inflammatory markers in patients with non-small cell lung cancer (NSCLC) undergoing multi-modality treatment.

Inclusion Criteria:

Patients with histological or cytological proven stage IIIa-N2 or IIIb NSCLC were recruited. Patients 18 to 80 years of age were included if they were eligible for concurrent chemoradiotherapy and if their life expectancy was more than three months.

Exclusion Criteria:
  • Undergone surgery, chemotherapy or radiotherapy during the previous month
  • Edema, ascites, severe comorbidities (major gastrointestinal disease, chronic renal failure, uncontrolled diabetes mellitus or HIV)
  • Using medication that could modulate metabolism or body weight, in particular high-dose corticosteroids or fish oil supplements, during the previous month.
Description of Study Protocol:

Recruitment

Patients were recruited from the VU University Medical Center Amsterdam (The Netherlands).

Design 

  • Patients received oral nutritional supplements during the five weeks from the start of concurrent chemoradiotherapy and were monitored for clinical performance and nutritional and inflammatory markers
  • Random assignment to the intervention group  was performed by the pharmacist via sequential randomization in blocks of four participants with stratification for one of the three chemotherapy schedules. 

Blinding Used 

  • Patients, investigators and study personnel were unaware of the treatment group allocation
  • In the pharmacy, study supplements were packaged identically and not distinguishable from each other except for randomization number
  • The oral nutritional supplements were commercially available and provided in blank cans, identical in texture, both vanilla flavored and ready to use. 

Intervention

  • Patients were asked to consume two cans per day of either a protein- and energy-dense oral nutritional supplement containing n-3 PUFA providing 2.02g per day EPA + 0.92g per day DHA (480ml ProSure)
  • Intervention group (I) or an isocaloric control oral nutritional supplement without EPA and DHA (400ml Ensure), control group (C)
  • To evaluate compliance with study supplements, patients were instructed to record supplement intake in a compliance diary
  • Second, plasma phospholipid fatty acid concentrations at baseline and after five weeks were assessed as an objective indicator of study supplement intake. 

Statistical Analysis

  • A sample size of 17 patients was calculated to detect a difference in FFM of 0.5kg (± 0.5kg) between groups with a significance level of 0.05 and a power of 0.8. Based on an anticipated 15% attrition rate, 40 patients were required to be enrolled to obtain a minimum of 34 patients for data analyses.
  • Differences between groups for patient characteristics at baseline for nominal and ordinal variables were analyzed by chi-square tests. For continuous baseline variables, differences between groups were analyzed by independent samples T-tests and linear regression analyses with sex as covariate, as appropriate. Differences between malnourished and well-nourished patients at baseline were analyzed accordingly. Per protocol analyses were performed to evaluate the effect of n-3 fatty acids on primary effect parameters (body weight and FFM). For this purpose, compliant patients were selected according to their plasma phospholipid EPA after five weeks (I patients with plasma phospholipid EPA of 1.6% or more and C patients with plasma phospholipid EPA less than 1.6%. In addition, Pearson correlation analysis tests were performed to investigate the relationship of plasma phospholipid EPA and inflammatory markers in  patients who had a plasma phospholipid EPA increase of at least 1.5% after five weeks.
  • Generalized estimating equations (GEE), a longitudinal linear regression technique to account for the dependency of the observations in time was used to analyze effects of intervention over time. Adjustments were made by addition of baseline values and sex as covariates. Independent dummy variables for group (I or C group) and for separate time points (weeks one, two, three, four and five) were entered into the GEE model. Absolute differences between the I and C group were expressed as B. We used an exchangeable correlation structure to analyze the data. 

 

Data Collection Summary:

Timing of Measurements

  • Baseline
  • Three weeks
  • Five weeks. 

Dependent Variables

Compliance  with study supplements:

  • Patients recorded supplement intake into compliance diary
  • Plasma phospholipid fatty acid concentrations at baseline and five weeks
  • Nutritional intake and energy balance:
    • 24-hour dietary recall 
    • REE measured by via oxygen consumption and CO2 production
    • TEE calculated by REE x 1.3
    • Energy balance: Intake as a percentage of TEE.
  • Nutritional status:
    • Pre-illness weight, unintentional weight loss in the last month last six months and height recorded
    • Body weight measured via digital scale
    • BMI calculated as ratio of body weight (kg)/height (m)2
    • Mid-upper arm circumference (MUAC) measured
    • Fat-free mass (FFM) calculated by use of bioelectrical impedance analysis. 
  • Inflammatory markers:
    • C-reactive protein
    • Serum albumin
    • Whole blood leukocyte count
    • IL-6 and soluble tumor necrosis factor-p55 (sTNF-p55)
    • Human leukocytle antigen-DR (HDLA-DR).

Independent Variables

Consumption of 2.02g per day EPA and 0.92g per day of DHA via nutritional supplement.

Control Variables

  • Age
  • Form of cancer
  • Gender. 
Description of Actual Data Sample:
  • Initial N: 21 men and 19 women; 16 patients had stage IIIa NSCLC and 24 patients had stage IIIb NSCLC
  • Attrition (final N): 35 at three weeks and 33 at five weeks
  • Age: Median age of 57.8 years (range 39 to 80 years)
  • Anthropometrics: I group consisted of more men (N=16; 80%) than the C group (N=5; 25%) (P <0.01) but this was adjusted for in the statistical analysis
  • Location: Amsterdam, the Netherlands.
Summary of Results:

Key Findings

  • Consumption of study supplements during chemoradiotherapy was approximately one can per day (I: 1.1±1.0 vs. C: 1.0±0.9 can per day)
  • After five weeks, plasma phospholipid EPA concentrations in the I group were higher than in the C group (B=1.5%; P=0.06). Plasma phospholipid concentrations of DHA were also higher in the I group after five weeks (B=1.1%; P=0.04)
  • After one, two and four weeks, the I group had a better weight maintenance than the C group (B=1.1kg, P=0.07; B=1.3kg, P=0.02; and B=1.7kg, P=0.04, respectively)
  • Over time, FFM in both groups decreased but less in the I group than in the C group after three and five weeks (B=1.5kg, P=0.05 and B=1.9kg, P=0.02, respectively)
  • At week five, the I group tended to have lower IL-6 production in response to whole blood stimulation with lipopolysaccharide than the C group (B=−27.9; P=0.08). For I patients who had a plasma phospholipid EPA increase of at least 1.5% (N=6), serum IL-6 and CRP at week five were negatively correlated with plasma phospholipid EPA levels (Pearson R=−0.8, P=0.041 and −0.8, P=0.048, respectively).
  • Serum CRP, IL-6, sTNF-p55 and albumin concentrations and HLA-DR expression on monocytes were not different between groups at any time point
  • Five patients experienced an adverse event during the study period. In the I group, one patient experienced a cerebrovascular accident during chemoradiotherapy. Two patients in the I group and two patients in the C group experienced gastrointestinal complaints, which included nausea, vomiting, diarrhea, cramps and belching, after consumption of the study supplement.
Author Conclusion:

This randomized, double-blind, placebo-controlled study indicates beneficial effects of a protein- and energy-dense oral nutritional supplement containing n-3 fatty acids on nutritional status in stage III NSCLC patients.

Funding Source:
Industry:
Abbott Nutrition
Pharmaceutical/Dietary Supplement Company:
University/Hospital: VU University Medical Center, Amsterdam, the Netherlands
Reviewer Comments:
  • Patient compliance was approximately 50% of supplements in either group
  • Five patients in the I group dropped out before week three and zero dropped out in the C group. This resulted in the I group not having the required number of patients based on the power analysis. The authors discuss this point and state in the discussion that they could have observed more significant differences between the groups if the number of I group was increased.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? No
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? No
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? N/A
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? N/A
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes