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 Evidencebased Practice Centers (EPCs) produced this

series of reports: the Southern California EPC

([SCEPC], based at RAND), the Tufts-New

England Medical Center EPC, and 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:

- 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?

Evidence Report/Technology Assessment

Number 113

Effects of Omega-3 Fatty Acids on Cancer

Summary

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

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

- 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 the trial design; the outcomes of interest;

the quality of the trial; the number and characteristics of the

patients; details on the intervention, such as the dose,

frequency, and duration; the types of outcome measures;

adverse events; and 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 omega3 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

3
4

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, postoperative 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 the 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. It is

expected to be available in February 2005. At that time, 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.

In addition, Internet users will be able to access the report and

this summary online through AHRQ’s Web site at

www.ahrq.gov.

Suggested Citation

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. Effects of Omega-3 Fatty Acids

on Cancer. Summary, Evidence Report/Technology Assessment

No 113. (Prepared by the Southern California Evidence-based

Practice Center under Contract No. 290-02-0003.) AHRQ

Publication No. 05-E010-1. Rockville, MD: Agency for

Healthcare Research and Quality. February 2005.

References

1. Jones P, Papamandjaris A. Lipids and cellular metabolism. Present

knowledge in nutrition. 8th edition. Vol. 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.

www.ahrq.gov

AHRQ Pub. No. 05-E010-1

February 2005

ISSN 1530-440X