Summary
Evidence Report/Technology Assessment: Number 113
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.
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Introduction / Methodology / Findings / Future Research / Availability of Full Report / References
Authors: 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.
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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:
- For what type of tumors?
- Is there an inverse relationship with intake?
- Is there a temporal relationship with intake?
- 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?
- 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?
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:
- For what type of tumors?
- Is there an inverse relationship with intake?
- Is there a temporal relationship with intake?
- 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.
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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.
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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.
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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 is also online on the National Library of Medicine Bookshelf, or can also be downloaded as a PDF File (4 MB) [PDF Help].
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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.
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AHRQ Publication Number 05-E010-1
Current as of February 2005
Internet Citation:
MacLean CH, Newberry SJ, Mojica WA, et al. Effects of Omega-3 Fatty Acids on Cancer. Summary, Evidence Report/Technology Assessment: Number 113. AHRQ Publication Number 05-E010-1, February 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/o3cansum.htm
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