EAL

Omega 3 Fatty Acid and Oncology

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to investigate whether nutritional status of cancer patients impacts immune response and survival. Dietary omega 3 fatty acid supplementation was used to evaluate immunomodulation and survival in four subgroups to include severely immunocompromised and severely malnourished cancer patients.

Inclusion Criteria:

Generalized solid tumors
Not currently under chemotherapeutic or immunomodulating treatment during the previous four months
No plans for patients to undergo subsequent treatment for cancer
Patients from Oncology Unit of Patras University Medical School
Written informed consent

Exclusion Criteria:

Any patient who has had chemotherapy or immunomodualating treatment during the previous four months

Description of Study Protocol:

Recruitment 64 cancer patients recruited from the Patras University Medical School Oncology Unit in Petras, Greece with solid tumors were randomized into the trial. Drop rate of 4 patients as they were not able to comply to treatment.

Design

Patients were randomized into two groups of 30 subjects each.
Group A received 18 grams of fish oil (6 capsules of MAXEPA 3 times daily containing 170mg of EPA and 115mg of DHA).
Group A also received 200mg of Vitamin E daily.
Group B received placebo (sugar tablet).
Group A and Group B were then subdivided into two groups: Group WN (patients were in good nutritional state) and Group MN (patients with malnutrition).
Those divided into the subgroup WN (well nourished) included patients who were:
- Weight loss less than 10% during last six months
- Serum albumin >30g/L
- Serum transferrin >2.0g/L
- Karnofsky performance status >60
Those divided into the subgroup MN (malnourished) included patients who were:
- Weight loss greater than 10% during last six months
- Serum albumin <30g/L
- Serum transferrin <2.0g/L
- Karnofsky performance status <60

Intervention

18 grams of fish oil (6 capsules of MAXEPA 3 times daily containing 170mg of EPA and 115mg of DHA per capsule and 200mg of Vitamin E provided to Group A and placebo provided to Group B.
Supplementation or placebo was provided to subjects daily until death.

Statistical Analysis

The kolmogorov-Smirnov goodness of fit test was used to check all data.
ANOVA was used to assess statistical significance of the difference amoung result values
Unpaired Student's t-test and Mann-Whitney U Test were used to determine groups which differed
Repeated measures analysis of variance for comparisons of data from the same group of patients but from different time intervals
Paired t-test or Wilcoxin signed rank for paired comparisons
Life table analysis used to estimate survival
Mantel-Haenszel chi-square test to measure differences in survival
Significance set at p>0.05

Data Collection Summary:

Timing of Measurements

Before and on day forty of fish oil supplementation - Total T-cells, T-helper cells, T-suppressor cells, natural killer cells, synthesis of interleukin-1, interleukin-6 and tumor necrosis factors by peripheral blood mononuclear cells.
One time measurement (unspecified time point) of T-cell subset and cytokines in control group
All other variables were not specified as to measurement timing

Dependent Variables

% and absolute number of CD3, CD4, CD8, CD4/8, NKcells
cytokines- serum IL-1, IL-6, TNF
Body weight
Lab values- albumin and transferrin
Karnofsky performance status
Survival
Days of hospitalization
Infections

Independent Variables

Fish oil
Placebo

Control Variables

15 healthy individuals

Description of Actual Data Sample:

Initial N: 64

Attrition (final N): 60(36 males, 24 females)

Age: 56-60 years old

Ethnicity: Not mentioned in patient characteristics

Other relevant demographics:

Tumor type: 13 breast cancer, 21 Gastrointestinal cancer, 11 Lung cancer, 7 Liver, 8 pancreas (appears to be equally distributed among the 4 groups, but information not analyzed)

Anthropometrics Weight loss as a percent was expressed to determine which subgroup (MN or WN) patients would be divided into but actual weight was not recorded in data

Location: Oncology Unit of the Department of Medicine, Patras University Medical School, Patras, Greece

Summary of Results:

1. T-Cell Subsets:

Absolute Numbers of T-Cell Subsets before and during Omega-3 PUFA Supplementation(+/- Standard Deviation)
	Group A/WN	Group A/MN	Group B/WN	Group B/MN	Control
CD3 Before Day 40	1431 +/- 346 1418 +/- 299	1005 +/- 248 1341+/- 286	1387 +/-285 1195 +/- 315	972 +/-186 895 +/-207	1575 +/-352
CD4 Before Day 40	881+/- 24 880+/-231	619 +/- 202 835 +/- 235	954 +/-216 859 +/- 308	664 +/- 162 590 +/- 199	1078 +/- 260
CD8 Before Day 40	508 +/- 162 437 +/- 145	598 +/- 155 382 +/- 151	533 +/- 181 529 +/-214	547 +/-125 504 +/- 172	484 +/- 209
NK Cells Before Day 40	247 +/- 53 296+/-70	237 +/-68 251+/-85	326 +/-61 351+/-68	411 +/-92 223 +/-112	318 +/-94

Significant decrease (P<0.05) in absolute numbers and percentages of total T-cells and Helper T-cells in the malnourished patients as compared to the controls and well nourished groups.
Omega 3 Supplementation recovered the low Th/T's ratio in the peripheral blood of the malnourished patients receiving Omega 3 supplementation but this did not happen in the placebo group.

2. Cytokine Production:

Cytokine Production by Endotoxin-Stimulated Peripheral Blood Mononuclear Cells (+/- Standard Deviation)
	GroupA/WN	GroupA/MN	GroupB/WN	GroupB/MN	Control Group
IL-1 Before Day 40	1810+/-180 1720+/-50	2160+/-510 3540+/-730	1685+/-236 2150 +/-144	1894+/-332 2730 +/198	2087+/-164
IL-6 Before Day 40	2089+/-178 1818 +/- 197	2056 +/-264 1998 +/-87	2340+/-328 1976+/-181	1943+/-165 2117+/-133	2376+/-163
TNF-a Before Day 40	778+/-88 1139+/-186	369+/- 32 784 +/-207	813 +/-135 756 +/-206	578+/-54 492+/-154	823 +/-71

Low levels of IL-6 detected in almost all patients
TNF synthesis was signficantly lower (p<0.001) in malnourished patients as compared to well nourished patients
Omega-3 supplementation resulted in a significant (p<0.05) increase in TNF production of malnourished patients

3. Nutritional response

No effect of omega 3 supplementation on body weight, serum albumin, or serum transferrin in either group.
Significant increase in Karnofsky performance status in the malnourished patients 40 days during omega-3 supplementation

4. Survival

Significantly (p<0.001) prolonged survival observed in well nourished vs malnourished cancer patients (481+/- 35 days versus 213+/- 19 days).
Omega 3 PUFA and Vitamin E supplementation resulted in a significant (p<0.025) increase in survival for all patients compared with placebo group

5. Some cases of mild abdominal distress and transient diarrhea with Omega 3 supplementation.

Author Conclusion:

Well nourished cancer patients have a longer mean survival as compared to malnourished patients
An inverse relationship between nutritional status and the T-helper/T suppressor cell ratio and the capacity of peripheral blood mononuclear cells to synthesize TNF-a in vitro.
Patients who supplemented with Omega-3 PUFA restored both the Th/Ts cell ratio and TNF production.
Omega-3 PUFA increased survival of all patients
Omega-3 PUFA and nutritional state seem to be independent prognostic factors for survival.

Funding Source:

University/Hospital:

Patras University Medical School

Reviewer Comments:

Limitations:

No mention of dietary intake prior to enrollment into study or during study.
Weight loss within past month or within past two weeks might have been more significant in determining criteria for the malnourished subgroup
Small sample size with mixed cancer sites
Did not perform intent to treat analysis
Did not indicate how intervention compliance was measured or if measured
Did not indicate timing of intervention (i.e., every 8 hours or with meals)
Did not record stages of disease
Did not analyze if patient characteristics (age, cancer sites, extent of disease, etc.) were similar among the groups
Did not explain blinding procedure
Appears that all 60 participants were available for 40 day analysis, but not clear

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?	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?	???
	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.)	???
	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?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.6.	Were extra or unplanned treatments described?	No
	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?	No
	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?	No
	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)?	???
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	???
	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?		No
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		No
	10.1.	Were sources of funding and investigators' affiliations described?	No
	10.2.	Was the study free from apparent conflict of interest?	???