EAL

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

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

“To determine whether short-term intervention with large doses of fish oil and/or melatonin combined with dietary advice in patients with advanced gastrointestinal cancer could influence a broad spectrum of variables presumed to reflect the development of cachexia, notably cytokines.”
To determine clinical benefits indicated by food intake, body weight, and quality of life.

Inclusion Criteria:

Have metastatic or locally advanced gastrointestinal cancer not amenable to curative or standard palliative treatment
Greater than 10% weight loss during the previous 6 months
Serum albumin level not greater than 35 g/l
Karnofsky’s performance status of at least 60
Two courses of chemotherapy complete before beginning the study, if patients was undergoing continuous chemotherapy

Exclusion Criteria:

Concomitant medication with anticoagulative agents
If non-steroidal anti-inflammatory drugs or corticosteroids taken, must have began at least 2 weeks before study inclusion.

Description of Study Protocol:

Recruitment

Patients who had advanced gastrointestinal cancer, visited the outpatient clinic (convenience sampling), and fulfilled inclusion criteria were asked to participate.

Design

Patients were randomized to receive fish oil OR melatonin for 4 weeks and followed by a new 4 week intervention with fish oil AND melatonin.

Intervention

1^st intervention period

Fish oil group
- 30 mL/d of fish oil mixture: 15 mL with morning meal & 15 mL with evening meal
  - ACO Omega 3 (Pharmacia, Stockholm, Sweden) for patients 1-20
  - Eskimo 3 (Cardinova, Uppsala, Sweden) for patients 21-24
  - Equivalent products, switched due to ceased production of ACO Omega 3
  - 18% EPA, 12% DHA
Melatonin group
- Received 6 capsules (3mg each)
- 18 mg/d melatonin in the evening

2^nd intervention period

All patients underwent combined interventions of fish oil & melatonin

Compliance assessment

All empty packages/bottles recorded
In fish oil group, changes in plasma fatty acids (doubling of EPA = good compliance)

Statistical Analysis

Mann-Whitey U test
Wilcoxen’s matched-pairs signed-rank test
Student’s t test
Correlations- Spearman’s rank correlation coefficient
Log-rank test for survival rate

Data Collection Summary:

Timing of Measurements

Biochemical

Morning after overnight fasting at baseline
After each 4 week intervention period
Blood hemoglobin, serum albumin, serum lactate dehydrogenase, CRP and plasma fibrinogen
Subsequent analysis (within 4 hours) of TNF-aIL-1ß, IL-6, IL-8, sIL-2R, EPA, DHA, linoleic acid, & arachidonic acid

Performance Status

Karnofsky’s performance status
Baseline
Last weeks of first & second intervention period

Quality of Life

European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC-QLQ-C30)
- Baseline
- Last weeks of first & second intervention period
- 30-item cancer-specific questionnaire that consists of:
  - five functional scales
    - physical, emotional, cognitive, social, and role
  - 3 symptom scales
    - fatigue, pain, nausea/vomiting
  - global health or quality of life scale
  - 6 items that assess symptoms & financial effects of disease
  - score range 0-100
    - functional & global scales: increased score = better function
    - symptom scale: increased score = increased symptoms

Food Intake

Baseline
End of first & second intervention period
4 day food diary
- booklet contain meal size photographs to estimate intake
- Reported intake converted to weight values
  - Compared to Nordic recommendations (kcals: 30% fat, 10-15% protein, 55-60% carbohydrate)
  - Recommended levels adjusted for age, sex, weight, & physical activity

Dependent Variables

Biochemical = Blood hemoglobin, serum albumin, serum lactate dehydrogenase, CRP and plasma fibrinogen, TNF-aIL-1ß, IL-6, IL-8, sIL-2R, EPA, DHA, linoleic acid, & arachidonic acid
Performance status
Quality of life
Food intake

Independent Variables

Fish oil supplement
Melatonin supplement
Fish oil + melatonin supplement

Description of Actual Data Sample:

Initial n = 24 (Fish oil: Male n=7, Female n=6; Melatonin: Male n=7, Female n=4)

Attrition

1^st intervention period

2 patients per intervention group did not accomplish
1 in each group died due to progressive disease
1 in each group dropped out of the study due to progressive disease

2^nd intervention period

1 in fish oil group & 3 in the melotonin group dropped out of the study due to progressive disease

Location

University of Uppsala, Uppsala, Sweden

Demographics, adapted from Table 1 of study

	Fish Oil (n = 13)	Melatonin (n = 11)
Men	7	7
Women	6	4
Diagnosis
Pancreatic	5	3
Biliary	1	3
Adenocarcinoma (unknown primary tumor)	2	0
Colorectal	4	4
Gastric	1	1
Age (y), mean±SD	66±9	69±10
Age range	52-78	53-83
Weight (kg) 6 mo previous, median (range)	70 (45-115)	69 (40-90)
Weight (kg) at baseline, median (range)	56.6 (35-101)	61.8 (33-80)
Weight loss in previous 6 mo (%)	-13.2 (8.4)	-10.8 (8)
BMI (kg/m²) 6 mo previously	24.9 (3.8)	21.6 (4.1)
BMI (kg/m²) at inclusion	23.8 (4.8)	21.1 (4.8)
Karnofsky’s performance status at inclusion median (range)	80 (60-90)	70 (40-90)
Chemotherapy
Previous	4	3
Ongoing	2	0

Summary of Results:

Compliance

1^st intervention period
- Fish oil group
  - 8 patients (62%) had good compliance
- Melatonin group
  - 5 patients (45%) took 100% of the supplement
  - 2 patients took 75% of the supplement
  - 4 took 50% or less of the supplement
- 2^nd intervention period
  - Those who added fish oil
    - 5 patients (62%) showed good compliance
  - Those who added melatonin
    - 4 patients (36%) showed 100% compliance

Side Effects

After 1st intervention period: side effects more likely related to study drugs
- Fish oil group: 1 patient- grade 3 anorexia
- Melatonin group: 1 patient- grade 3 fatigue
After 2nd intervention period
- Fish oil group
  - 1 patient- grade 3 anorexia
  - 1 patient- heartburn & grade 3 belching
- Melatonin group
  - 1 patient- grade 3 toxicity of central nervous system
  - 1 patient- grade 3 paraesthesia

Biochemistry

Beyond the normal range for most parameters in both groups.
sIL-2R is the only value statistically different to suggest poor state of health in melatonin group (P = 0.02).
All cytokines, except IL-1ß, had a statistically significant correlation with CRP and fibrogen (r = 0.53 – 0.70, P < 0.01 – 0.001).
Only B-hemoglobin was the only statistically different change from baseline in the fish oil group (P = 0.01) after the first 4 weeks intervention.
When analyzing all patients together, statistically significant changes were increased:
- IL-6 after 1^st intervention (P = 0.04).
- IL-8 after both intervention periods (P = 0.03)
Fatty acid distribution
- Baseline: no difference between groups
- After 1^st intervention period, in fish oil group- linoleic acid decreased and EPA and DHA increased.
- After 2^nd intervention period, the melatonin group had the same levels as the fish oil group.

Energy Intake & Weight

	Fish oil group	Melatonin group
Energy intake Baseline/before diet counsel	1750 ± 707 kcal	1495 ± 400
Change after 1^st period	-65 kcal	+ 187 kcal
Change after 2^nd period	-196 kcal	+19 kcal
Weight change
After 1^st period	- 0.6 kg	-1.8 kg
After 2^nd period	+ 0.2 kg	+ 0.8 kg

~50% of patients used commercial nutrition supplements, contributing 4-500 kcal/day.
Energy provided by fish oil not included (30 ml is approximately 280 kcal)
No clinical signs of fluid retention in any patient throughout the trial.

Performance Status & Quality of Life

Karnofsky’s Performance Status- no statistically significant differences between groups at randomization or during the study.

	Fish oil group	Melatonin group
Baseline	80 (range = 60-90)	70 (range = 40-90)
After 1^st period	70 (range = 60-90)	65 (range = 40-90)
After 2^nd period	80 (range = 60-90)	65 (range = 60-90)

EORTC-QLC-C-30

22 patients answered at baseline, 18 patients after 1^st period and 16 patients after 2^nd period.
Lower quality of life in melatonin group-
- physical functioning scales (P = 0.003)
- role functioning (P = 0.02)
Scores for global quality of life low at baseline with an insignificant increase during study.
Appetite scores decreased during 1^st period in both groups, but not statistically significant.
After 1^st period, physical functioning and financial difficulties had decreased statistically significant in fish oil group (P = 0.002; 0.04 respectively).
Statistically significant increase in pain for fish oil group after 1^st period (P = 0.004)

Survival Rate

No significant difference between groups
Fish oil group mean = 142 days (range = 8-645)
Melatonin group mean = 179 days (range = 55-313)

Pancreatic Cancer Subgroup

No significant differences compared to entire study group.
6 of 8 patients (75%) were weight responders after the 2^nd period.

Author Conclusion:

Conclusion: Fish oil, melatonin, and the combination did not produce substantial anti-inflammatory effects in cachetic patients with advanced gastrointestinal cancer. However, the appearance of a weight-stabilizing effect produced by the combination justifies additional clinical trials.

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

No true control (placebo) group
No blinding - open study
No power calculation
Most significant changes occurred during first 4 week intervention period (impact of disease progression of the patients rather than the supplements?)
Patients with significant malnutrition
Small sample size

Good compliance with fish oil intake was assessed by change in fatty acid profile of membrane phospholipids. Previous research (Wigmore et al) notes that the therapeutic dose of omega 3 fatty acids is 2 g/day. It is unknown from the data presented in this study if subjects actually took enough fish oil to meet the therapeutic dose."

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)	No
	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?	N/A
	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?		Yes
	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?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	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.)	No
	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?	Yes
	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?	Yes
	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?		Yes
	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?	No
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?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes