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Evidence
Report/Technology Assessment: Number 113
Effects of Omega-3 Fatty Acids on Cancer
Summary
Under its Evidence-based Practice Program, the Agency for
Healthcare Research and Quality (AHRQ) is developing scientific
information for other agencies and organizations on which
to base clinical guidelines, performance measures, and other
quality improvement tools. Contractor institutions review
all relevant scientific literature on assigned clinical
care topics and produce evidence reports and technology
assessments, conduct research on methodologies and the effectiveness
of their implementation, and participate in technical assistance
activities.
Select for PDF version (165 KB). PDF Help.
Introduction / Methodology / Findings / Future Research
/ Availability of Full Report / References
MacLean CH, Newberry SJ, Mojica WA, Issa A, Khanna P, Lim
YW, Morton SC, Suttorp M, Tu W, Hilton LG, Garland RH, Traina
SB, Shekelle PG.
Introduction
This report was requested by the Agency for Healthcare Research
and Quality (AHRQ), the National Institutes of Health (NIH)
Office of Dietary Supplements, and several other NIH institutes.
It is one of several reports focusing on the role of omega-3
fatty acids in the prevention or treatment of various diseases.
Three Evidence-based Practice Centers (EPCs) produced this
series of reports:
• The Southern California EPC ([SCEPC], based at RAND)
• The Tufts-New England Medical Center EPC.
• The University of Ottawa EPC.
This particular report focuses on the effects of omega-3
fatty acids on cancer, specifically tumor incidence, clinical
outcomes after cancer treatment, and tumor behavior.
Over the past 40 years, an increasing number of physiological
functions have been attributed to omega-3 fatty acids, including
movement of calcium and other substances into and out of
cells, relaxation and contraction of muscles, and regulation
of clotting and secretion of substances that include digestive
enzymes and hormones.
Omega-3 fatty acids also play a role in the control of fertility,
cell division, and growth, suggesting they may protect against
certain types of cancer or may alter the response to cancer
treatment.1,2
The major dietary sources of omega-3 fatty acids in the
U.S. population are fish, fish oil, vegetable oils (principally
canola and soybean), walnuts, wheat germ, and some dietary
supplements.
Methodology
Study Questions
We convened a technical expert panel composed of distinguished
basic scientists and clinicians with established expertise
in omega-3 fatty acids, human nutrition, dietary assessment
methods, cancer biology, and oncology. The technical expert
panel advised us on refining the preliminary questions posed
to us by AHRQ, determining the proper inclusion/exclusion
criteria for the study and the populations of interest,
establishing the proper outcomes measures, and conducting
the appropriate analyses.
Based on the original questions received from AHRQ and input
from our technical expert panel, we addressed the following
questions in this study:
Tumor Incidence
• What is the evidence that omega-3 fatty
acids reduce the incidence of tumors?
• If omega-3 fatty acids influence the incidence of tumors:
o For what type of tumors?
o Is there an inverse relationship with intake?
o Is there a temporal relationship with intake?
o What is the evidence that genes involved in
omega-3 fatty acid transport or metabolism influence the
magnitude or direction of the influence on tumor incidence?
o What is the evidence that the response to omega-3 fatty
acids is independent of the intake of antioxidants such
as vitamin E or other bioactive food components?
o What is the evidence that the response is modified by
the state of the immune system?
Effects on Clinical Outcomes after Cancer Treatment
• What is the evidence that omega-3 fatty acids alter the
effects of cancer treatment on malignant tumors and clinical
outcomes after cancer treatments?
• What is the evidence that the response to omega-3 fatty
acids is independent of the intake of antioxidants such
as vitamin E or other bioactive food components?
• What is the evidence that the response is modified by
the state of the immune system?
Tumor Behavior
• What is the evidence that omega-3 fatty acids alter the
behavior of malignant tumors in terms of growth, differentiation,
and apoptosis?
• If omega-3 fatty acids influence the behavior of tumors:
o For what type of tumors?
o Is there an inverse relationship with intake?
o Is there a temporal relationship with intake?
o What is the evidence that genes involved in omega-3 fatty
acid transport or metabolism influence the magnitude or
direction of the influence on tumor behavior?
Search Strategy
Jessie McGowan, Senior Information Scientist, and Nancy
Santesso, Knowledge Translation Specialist, at the University
of Ottawa were responsible for developing a common search
strategy for omega-3 fatty acids for the three participating
EPCs. Nancy Santesso developed a core omega-3 search strategy
in collaboration with project librarians, biochemists, nutritionists,
and clinicians, who also provided biochemical names, abbreviations,
food sources, and commercial product names for omega-3 fatty
acids.
The literature search was not restricted by language of
publication or by study design, in order to increase sensitivity.
When possible, the searches were limited to studies involving
human subjects. For the SCEPC, this core search strategy
was incorporated into a specific search for cancer.
In consultation with our technical expert panel and the
task order officer, it was decided that, for the questions
pertaining to tumor behavior, i.e., apoptosis, tumor growth,
and differentiation, we would conduct a separate search
focusing on review articles and meta-analyses of animal
studies and cell culture studies pertaining to both humans
and animals.
The following databases were searched: MEDLINE® (1966-October
week 5, 2003), PreMEDLINE® (Nov 7, 2003), EMBASE (1980-Week
44, 2003), Cochrane Central Register of Controlled Trials
(3rd Quarter, 2003), CAB HEALTH® (1973-October 2003).
All of these databases were searched using the OVID interface,
except CAB HEALTH, which was searched through SilverPlatter.
Any duplicate records were identified and removed within
each search question using Reference Manager® software.
The citations obtained from these literature searches were
sent to the SCEPC via E-mail. In addition, we sent letters
to industry experts recommended by the Office of Dietary
Supplements to obtain any unpublished data.
Selection Criteria
Two reviewers independently reviewed each
article considered for inclusion in the study. Any disagreements
between the reviewers were resolved through consensus. For
the questions pertaining to tumor incidence and response
to treatment, we included any articles that pertained to
the effects of omega-3 fatty acids on cancer, presented
research on human subjects, and reported the results of
randomized clinical trials, controlled clinical trials,
or cohort/case control studies. We were unable to identify
human studies that assessed the effects of omega-3 fatty
acids on tumor behavior, i.e., cell growth, differentiation,
and apoptosis. Hence, to evaluate the effects of omega-3
fatty acids on tumor behavior, we turned to the animal and
cell culture literature. The initial intent was to summarize
only meta-analyses and systematic reviews; however, because
a total of only one meta-analysis and four systematic reviews
were identified, the decision was made to summarize all
relevant reviews. Language was not a barrier to inclusion.
Data Extraction and Analysis
For each article on tumor incidence and response to treatment
included in the study, two reviewers independently extracted
data about:
• Trial design.
• Outcomes of interest.
• The quality of the trial.
• Number and characteristics of the patients.
• Details on the intervention, such as the dose, frequency,
and duration.
• Types of outcome measures.
• Adverse events.
• The elapsed time between the intervention and outcome
measurements.
Any disagreements between the reviewers were resolved through
consensus. For each article, we then evaluated the quality
of the design and execution of trials using a system developed
by Jadad;3 determined a combined applicability grade based
on applicability to the U.S. population and health state;
performed a meta-analysis of those studies that sufficiently
assessed interventions, populations, and outcomes to justify
pooling; and performed a qualitative analysis of the remaining
studies. The reviews and meta-analyses on tumor behavior
were reviewed and summarized by the medical editor, a nutritional
biochemist.
Findings
Tumor Incidence and Outcomes after Cancer Treatment
We screened 4,834 article titles. From these article titles,
we chose to review 1,210 full-text articles. Of these full-text
articles, 356 met our selection criteria and were chosen
for data extraction. After data extraction, 52 articles
met our inclusion criteria: 33 reported on cancer incidence,
and 19 reported on cancer treatment (all 19 reported on
surgery). The 19 cohorts that participated in the studies
of tumor incidence varied widely with respect to demographics
and intake of omega-3 fatty acids.
Omega-3 Fatty Acids and Tumor Incidence
Among 43 risk ratios calculated across the 19 cohorts for
11 different types of cancer and 5 different ways to assess
omega-3 fatty acid consumption (fish consumption, total
omega-3 consumption, alpha-linolenic acid [ALA] consumption,
docosahexaenoic acid [DHA] consumption, and eicosapentaenoic
acid [EPA] consumption), only four are statistically significant.
Significant associations between omega-3 consumption and
cancer risk were reported for lung cancer in two studies;
for breast cancer in one; for prostate cancer in one; and
for skin cancer in one.
However, for lung cancer, one of the significant associations
was for increased cancer risk and the other was for decreased
risk (four other risk ratios were not significant for lung
cancer). For breast cancer, five other estimates did not
show a significant association. Only one study assessed
skin cancer risk. No effects were reported for cancers of
the aerodigestive tract, bladder cancer, colorectal cancer,
lymphoma, ovarian cancer, pancreatic cancer, or stomach
cancer. Thus, omega-3 fatty acids do not appear to decrease
overall cancer risk.
Temporal and/or Dose-Response Relationship Between Tumor
Incidence and Omega-3 Fatty Acid Intake
Data were insufficient to permit assessment of a temporal
or dose-response relationship.
Evidence for Involvement of Genes for Omega-3 Fatty Acid
Transport or Metabolism
No studies were identified that investigated the role of
omega-3 fatty acid transport or metabolism genes in any
putative effect of omega-3 fatty acids on tumor incidence.
Evidence for Dependence on Intake of Antioxidants or Other
Bioactive Food Components
No studies were identified that allowed this question to
be answered.
Evidence for Modification of Response to Omega-3 Fatty Acids
by Immune Status
No studies were identified that examined the possible modification
of the effect of omega-3 fatty acids by immune status.
Effect of Omega-3 Fatty Acids on Clinical Outcomes
We identified 19 studies from which the effect of omega-3
fatty acids on clinical outcomes after cancer therapy could
be ascertained, all of which pertained to patients who had
undergone cancer surgery for upper gastrointestinal malignancies.
We did not identify any studies that assessed the effects
of omega-3 fatty acids on clinical outcomes after chemotherapy
or radiation surgery. Among the identified studies, 14 described
the effect on post-operative complications, 13 on hospital
length of stay, 10 on mortality, 11 on nutrition and three
on weight. In pooled analyses, omega-3 fatty acids had no
effect compared to placebo on post-operative complications,
hospital length of stay, or mortality.
With the exception of one study that demonstrated higher
mean nitrogen intake for subjects treated with omega-3 fatty
acids relative to placebo, no significant effect on nutrition
or weight loss was observed.
Evidence for Dependence of Effects on Clinical Outcomes
on Intake of Antioxidants or Other Bioactive Food Components
No studies were identified that allowed this question to
be answered.
Evidence for Modification of Effects on Clinical Outcomes
by Immune Status
No studies were identified that examined the possible modification
of the effect of omega-3 fatty acids on clinical outcomes
by immune status.
Tumor Behavior
To assess the effects of omega-3 fatty acids on tumor growth,
differentiation, and apoptosis in animal and in vitro models,
we screened a total of 369 citations, of which 82 were considered
relevant. Of those 82, 60 could be retrieved. Of the 60,
27 were accepted for further review because they reviewed
the effects of omega-3 fatty acids (added to the diet or
to cell cultures) on cancer development, apoptosis, or cell
differentiation in laboratory animals or cell culture systems.
Although much of the evidence favored a role for dietary
omega-3 fatty acid enrichment in the inhibition or prevention
of colon, mammary, pancreatic, and prostate tumor growth,
at least in some animal models, the quality of the reviews
is not sufficient to permit strong conclusions to be drawn.
Evidence was presented in a small number
of reviews that omega-3 fatty acids can stimulate cellular
differentiation and apoptosis, two proposed mechanisms for
the inhibition of tumor development and proliferation; however,
the evidence is insufficient to assess the relevance of
these findings.
Evidence for an Inverse or Temporal Relationship with Intake
Insufficient evidence was presented to assess dose-response
effects or to ascertain the stage of tumor development that
might be affected by omega-3 fatty acids.
Evidence that Genes Involved in Omega-3 Fatty Acid Transport
or Metabolism Influence the Magnitude or Direction of the
Influence on Tumor Behavior
Several reviews provided evidence that omega-3 fatty acids
may affect tumor behavior by competing with omega-6 fatty
acids for the enzymes that metabolize them to their bioactive
products or by influencing the genes for these enzymes;
however, other evidence suggests an effect on intracellular
redox state and the integrity of membrane lipids.
Future Research
Following are our observations and recommendations regarding
future research on the effects of omega-3 fatty acids on
cancer. Given the large body of evidence that suggests no
association between omega-3 fatty acid consumption and cancer
incidence, future research in this general area is unlikely
to reveal significant associations. However, should new
evidence suggest a role for omega-3 fatty acids in the growth
or development of a particular type of cancer, studies to
assess the effect of omega-3 fatty acids on the incidence
of that particular type of cancer might be warranted.
Although existing studies do not demonstrate an effect of
omega-3 fatty acids on mortality, hospital length of stay,
post-operative complications, or nutrition after cancer
surgery, the body of literature is small and does not support
strong conclusions.
Given a plausible model for an omega-3 effect on outcomes
after cancer therapy, future directed trials might be warranted.
Although the body of literature that describes the effects
of omega-3 fatty acids on tumor behavior in animal and cell
culture models is large, it is heterogeneous in terms of
the models used, the carcinogens used and the dose, timing
and duration of exposure to omega-3 fatty acids. The development
and dissemination of a consensus statement about goals and
standards of research in this area might lead to more efficient
and fruitful research in this area.
Availability of Full Report
The full evidence report from which this summary was taken
was prepared for the Agency for Healthcare Research and
Quality (AHRQ) by the Southern California Evidence-based
Practice Center under Contract No. 290-02-0003. Printed
copies may be obtained free of charge from the AHRQ Publications
Clearinghouse by calling 800-358-9295. Requesters should
ask for Evidence Report/Technology Assessment No. 113, Effects
of Omega-3 Fatty Acids on Cancer.
The Evidence Report can also be downloaded as a PDF File.
References
1. Jones P, Papamandjaris A. Lipids and cellular metabolism.
In: Bowman BA, Russell R, editors. Present Knowledge in
Nutrition, 8th ed. Chapter 10. Washington, DC: International
Life Sciences Institute; 2003.
2. James M, Gibson R, Cleland L. Dietary polyunsaturated
fatty acids and inflammatory mediator production. Am J Clin
Nut 2000;71(1):343S-8S.
3. Jadad A, Moore A, Carrol D, et al. Assessing the quality
of reports of randomized clinical trials: Is blinding necessary?
Control Clin Trials 1996;17:1-12.
AHRQ Publication Number 05-E010-1
Current as of February 2005
http://www.ahrq.gov/clinic/
epcsums/o3cansum.htm
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