EAL

Omega 3 Fatty Acid and Oncology

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine whether high doses of fish oil, administered over 2 weeks, improve symptoms in patients with advanced cancer and decreased weight gain and appetite.

Inclusion Criteria:

Persons with advanced cancer (defined as locally recurrent or metastatic cancer) and

Presence of anorexia (defined as >3 on a visual analog scale [VAS] of 0 to 10),
Weight loss (defined as loss of >5% preillness body weight),
Ability to maintain oral food intake over the course of the study (2 weeks),
Normal cognition (defined as a normal Mini-Mental State Score for the patient's age and level of education), and
Written, informed consent

The Alberta Cancer Board Institutional Review Board approved this study.

Exclusion Criteria:

Not meeting inclusion criteria.

Description of Study Protocol:

Recruitment

Patients were recruited from the Acute Palliative Care Unit at Grey Nuns Hospital and the inpatient and outpatient areas at the Cross Cancer Institute in Edmonton, Alberta, Canada, from April 1999 until September 2000.

Design

A 14-day RCT. Patients were randomly assigned by using sealed envelopes produced by a computer-generated random sequence, to either a fish oil supplement or placebo group. Subjects were instructed to consume supplements orally for duration of the trial and effects on cancer symptoms were documented.

Blinding used

A pharmacist administered either fish oil or olive oil capsules to the patients. The pharmacist did not disclose to either the investigators or the patients, until the end of the study or unless clinically required to do so, the type of medication given to the patients.

Intervention

Patients received a daily dose of 18 gelatin capsules containing:

Fish oil (treatment): 1,000 mg fish oil, containing 180 mg eicosapentaenoic acid (EPA), 120 mg docosahexaenoic acid (DHA), and 1 mg of vitamin E.
Placebo/olive oil (control): 1,000 mg olive oil.

Special notes:

The fatty acid composition of the fish oil and olive oil/placebo capsules was verified by gas liquid chromatography.
The initial dose was calculated based on the approximation of 90 mg of n-3 fatty acid per day per kilogram for an individual weighing 60 kg.
After random assignment of 19 of the 90 patients, researchers determined that these first 19 patients could not tolerate 18 large capsules per day. Researchers amended the protocol to a minimum requirement of six capsules per day, with patients encouraged to take as many capsules as possible, up to 18 per day.
The patients were allowed to continue on their medication regimen during the study; however, no changes were made during the 14-day study except for administering analgesics or taking other major symptom control measures.

Statistical Analyses

N based on the detection of a 15-mm decrease in appetite with a power of 80% and p = 0.05.
Descriptive statistics - patient characteristics, results of baseline assessment and capsule regimen tolerability.
t test - average baseline scores for age, weight, appetite, tiredness in the two groups, and comparisons of the differences between days 1 and 14 between groups.
Chi-square test - baseline sex distribution.
Fisher's exact test - differences in the distribution of tumor types between groups.
Wilcoxon two-sample test used for findings similar to those of the corresponding t-test analyses.
Pearson's correlation coefficient - average number of capsules taken; variables such as appetite and tiredness in the fish oil group only.

Data Collection Summary:

Timing of Measurements:

Subjective and objective outcome measurements were performed at baseline and on day 14.

Dependent Variables

Appetite, nausea, tiredness, and patients' overall sensation of well-being were measured using a VAS of 0 to 100 mm (0 mm = best, 100 mm = worst)
Food intake: 3-day food diary at baseline.
Anthropometric measurements: height and preillness stable weight documented, current weight, body composition (total body fat, lean mass, and water) measured using multiple frequency bioimpedance analysis, arm muscular circumference, nondominant arm triceps skinfold, and subscapular skinfold.
Plasma phospholipids (PLs) were measured following standard procedures.
Tolerance: Measured on Day 14 using a scale of 1 to 4 (1=no difficulty, 4=extremely difficult).

Independent Variables

Daily consumption of fish oil or placebo capsules. Compliance with and tolerability of the capsule regimen were assessed during the first 14 days (subjects recorded number of capsules taken and adverse symptoms).

Description of Actual Data Sample:

Initial N: 91; (46 fish oil (20 females, 20 males), 45 olive oil/placebo (23 females, 7 males))

Final N: 60 (30 fish oil, 30 olive oil/placebo)

Mean Age, + SD: Fish oil: 63.0 + 9.1, Olive oil/placebo: 64.6 + 9.4

Ethnicity/Other relevant demographics: Not provided.

Anthropometrics: No significant differences in any of the subjective or objective measures between the two groups.

Weight loss (kg), + SD at Baseline: Fish oil: 16.0 + 11, Olive oil/placebo: 15.6 + 8

Weight loss (kg), + SD at Day 14: Fish oil: 0.03 + 2.8, Olive oil/placebo: -0.89 + 3.8

Location: Edmonton, Alberta, Canada

Summary of Results:

Patients in the fish oil group took a mean of 9.8 + 4 capsules per day. Patients in the placebo group took a mean of 9.2 + 3 capsules (P = NS).
Patients receiving fish oil had 14.0 + 4.5 mcg/mL EPA and those receiving the placebo had 0.9 + 0.2 mcg/mL EPA.

Table 1. Difference between fish oil and placebo groups at baseline and day 14

Variable*	Fish Oil (n=30)	Placebo (n= 30)	Statistical Significance in Group Differences P
Appetite VAS, 0-100 mm	-9.8 + 20	-9.0 + 27	NS
Tiredness VAS, 0-100 mm	-5.5 + 22	4.2 + 33	.19
Nausea VAS, 0-100 mm	-5.2 + 22	0.5 + 37	NS
Overall well-being VAS, 0-100 mm	-4.6 + 20	-9.8 + 32	NS
Weight, kg	0.03 + 2.8	-0.89 + 3.8	NS
Caloric intake, kcal	51 + 1177	-57 + 1299	NS
KPS, score, 0-100	0.0 + 8	-6.9 + 10	NS
EFAT, score, 0-30	0.3 + 3	0.2 + 2	NS

*Data are shown as the mean + SDand report the difference between day 14 and baseline (negative numbers denote improvement in VAS). NS (not significant); KPS (Karnofsky scale of performance status); and EFAT, (Edmonton Functional Assessment Tool).

A strong trend for improved appetite occurred in both groups.
Neither group significantly improved in lean body mass, triceps skinfold and arm circumference.

Tolerance/Side Effects

The tolerability of the capsule regimen was rated "not difficult at all" by 20 and 19 patients in the fish oil and placebo groups, respectively; "slightly difficult" in 8 and 8 patients, respectively; "moderately difficult" in 2 and 3 patients, respectively; and "extremely difficult" in no patients.
18 patients in the fish oil group and 8 patients in placebo group experienced new symptoms including fish belching, fish aftertaste, soft stools, bloating and gas, nausea/vomiting, and other (bitter taste, constipation, nonfish belching, loss of appetite).

Author Conclusion:

No significant improvement in appetite, other symptoms, nutritional status, or physical function after the administration of fish oil for 2 weeks using a mean daily dose of 1.8 g of EPA and 1.2 g of DHA as compared with that of the placebo in patients having advanced cancer.
Fish oil used as an alternative or complementary medicine at the study dose or even at much higher doses is not useful in improving subjective and objective manifestations of cancer anorexia/cachexia.

Limitations

High doses of fish oil and placebo capsules (> 10 capsules/day) not well tolerated by patients with cancer, possibly due to oil content.
Did not document whether placebo group may have purchased and used fish oil capsules.
A longer observation (> 2 weeks) more desirable for clinically useful results.
10 of 27 patients who withdrew from the study experienced gastrointestinal symptoms.

Funding Source:

Industry:

Banner Pharmacaps

Pharmaceutical/Dietary Supplement Company:

University/Hospital:

University of Texas M D Anderson Cancer Center, Palliative Care Program, Grey Nuns Community Hospital and Health Center, Cross Cancer Institute, and University of Alberta, Department of Agricultural, Food and Nutritional Sciences, and Department of Oncology (Canada), Swiss Cancer Research Inselspit

In-Kind support reported by Industry:

Yes

Reviewer Comments:

Previous studies demonstrate that an effective dose of EPA is 2g/day. Because the subjects did not consume that amount of EPA, this study does not provide insight as to whether omega-3 fatty acids can alter the catabolic process of cancer.

Strengths

Study with adequate power and sample size
Numerous subjective and outcome measures performed

Limitations

Need more information about blinding procedures and pharmacist involvement.
No information on patients' race
Assessment of EPA sources from food not recorded
No intent-to-treat analysis information presented.
Differences between the baseline characteristics of those who completed the study and drop outs is not presented.
The subject dropout rate was 34%; however, we have chosen to include this study because it offers additional information about the efficacy of fish oil supplements to improve symptoms associated with cancer.

Project support

Tobacco Settlement Foundation, Houston, TX.

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?	???
	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?	Yes
	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?		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.)	Yes
	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)?	No
	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?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes