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2017, Vol. 16(1) 32 –62
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Review Article
Introduction
Prostate cancer (PrCa) accounts for almost one quarter of can-
cers diagnosed among men. In Canada, there are approxi-
mately 24 000 new cancer cases (24% of all new male cancer
cases) expected in 2015.1 While 5-year survival rates have
dramatically improved, PrCa is still the third leading cause of
cancer death among men, with nearly 4000 deaths (10.1% of
all male cancer deaths) expected in 2015 in Canada.1 However,
PrCa incidence and mortality varies 60-fold globally, with a
dramatic increase observed in immigrants moving from low-
to high-risk countries, suggesting that dietary and lifestyle
factors play a role in its etiology and pathogenesis.2 With
Canadian men having approximately a 1 in 8 (12.8%) lifetime
probability of being diagnosed with prostate cancer, there is
strong interest in dietary and natural health product (NHP)
656052ICTXXX10.1177/1534735416656052Integrative Cancer TherapiesAucoin et al
research-article2016
1Canadian College of Naturopathic Medicine, Toronto, Ontario, Canada
2University of Toronto, Toronto, Ontario, Canada
3Ottawa Hospital General Campus, Ottawa, Ontario, Canada
4Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
5McMaster University, Hamilton, Ontario, Canada
6Ottawa Integrative Cancer Centre, Ottawa, Ontario, Canada
Corresponding Author:
Dugald Seely, Ottawa Integrative Cancer Centre, 29 Bayswater Avenue,
Ottawa, Ontario, K1Y 2E5 Canada.
Email: dseely@ccnm.edu
Fish-Derived Omega-3 Fatty Acids and
Prostate Cancer: A Systematic Review
Monique Aucoin, ND1, Kieran Cooley, ND1,
Christopher Knee, ND, MSc1, Heidi Fritz, ND, MA1,
Lynda G. Balneaves, RN, PhD2, Rodney Breau, MSc, MD, FRCSC3,
Dean Fergusson, MHA, PhD4, Becky Skidmore, MLS1,
Raimond Wong, MD, FRCSC5, and Dugald Seely, ND, MSc, FABNO1,4,6
Abstract
Background. The use of natural health products in prostate cancer (PrCa) is high despite a lack of evidence with respect
to safety and efficacy. Fish-derived omega-3 fatty acids possess anti-inflammatory effects and preclinical data suggest a
protective effect on PrCa incidence and progression; however, human studies have yielded conflicting results. Methods. A
search of OVID MEDLINE, Pre-MEDLINE, Embase, and the Allied and Complementary Medicine Database (AMED) was
completed for human interventional or observational data assessing the safety and efficacy of fish-derived omega-3 fatty
acids in the incidence and progression of PrCa. Results. Of 1776 citations screened, 54 publications reporting on 44 studies
were included for review and analysis: 4 reports of 3 randomized controlled trials, 1 nonrandomized clinical trial, 20
reports of 14 cohort studies, 26 reports of 23 case-control studies, and 3 case-cohort studies. The interventional studies
using fish oil supplements in patients with PrCa showed no impact on prostate-specific antigen levels; however, 2 studies
showed a decrease in inflammatory or other cancer markers. A small number of mild adverse events were reported
and interactions with other interventions were not assessed. Cohort and case-control studies assessing the relationship
between dietary fish intake and the risk of PrCa were equivocal. Cohort studies assessing the risk of PrCa mortality
suggested an association between higher intake of fish and decreased risk of prostate cancer–related death. Conclusions.
Current evidence is insufficient to suggest a relationship between fish-derived omega-3 fatty acid and risk of PrCa. An
association between higher omega-3 intake and decreased PrCa mortality may be present but more research is needed.
More intervention trials or observational studies with precisely measured exposure are needed to assess the impact of fish
oil supplements and dietary fish-derived omega-3 fatty acid intake on safety, PrCa incidence, treatment, and progression.
Keywords
fish oil, omega-3, fish, prostate cancer, prostate carcinoma, PSA
Submitted Date: 29 February 2016; Revised Date: 16 May 2016; Acceptance Date: 18 May 2016
Aucoin et al 33
interventions, which may be effective in either the prevention
or treatment of PrCa.
There is widespread evidence that many patients with
PrCa take NHPs, frequently without any clinical supervi-
sion. Surveys conducted in the United States, Britain,
Australia, and Canada suggest that complementary and
alternative medicine (CAM) is widely used among prostate
cancer patients; with estimates of CAM prevalence between
25 to 90%3-7 and rates of disclosure to the patient’s physi-
cian or oncologist as low as 25%.8
Fish-derived omega-3 fatty acids have emerged as a
topic of interest in the prevention and treatment of PrCa.
The omega-3 fatty acids found in fish include eicosapentae-
noic acid (EPA) and docosahexaenoic acid (DHA). These
fatty acids exhibit anti-inflammatory properties through
their impact on prostaglandin synthesis.9 Populations with a
high consumption of fish, such as those in Japan and
Alaskan Inuit, have lower rates of PrCa than populations
who consume the more typical Western diet, where intake
of fish and the anti-inflammatory fish-derived omega-3
fatty acids is generally lower,2 and intake of pro-inflamma-
tory omega-6 fatty acids is generally much higher.10
Additionally, a wide range of mechanisms by which
omega-3 fatty acids affect cancer development have been
elucidated11 and a large number of in vitro and animal stud-
ies show that EPA and DHA have inhibitory effects on PrCa
growth and progression.12-17 Briefly, some of the chief
mechanisms of action behind the cancer modulating effects
of fish oil include the following: suppression of raft-associ-
ated signal transduction, promotion of BAD-dependent
apoptosis via the PI3K/AKT survival pathway (phosphati-
dylinositol 3-kinase and serine/threonine protein kinase
AKT), reduction of oxidative stress-induced endothelial
Ca2+ influx via transient receptor potential channels (TSPs)
and nuclear factor erythroid-2-related factor 2 (Nrf2) acti-
vation, and resolution of inflammation through the action of
E-resolvins (RvE1 and RvE2), D-resolvins (RvD1 and
RvD2), and protectin (PD1) on cyclooxygenase (COX) and
lipoxygenase (LOX) pathways.18
The clinical potential of omega-3 fatty acids in the con-
text of PrCa prevention and treatment remains controver-
sial, and the results of numerous randomized controlled
trials (RCTs), case-control studies, epidemiological reports,
and systematic reviews assessing the role of fish-derived
omega-3 fatty acids in the incidence and progression of
PrCa have been largely inconsistent. The equivocal results
are complicated by high variability in study methodology in
terms of measurements of exposure (eg, food frequency
questionnaires [FFQ]; plasma, serum or prostate tissue fatty
acid levels); PrCa outcomes (eg, incidence, mortality, or
progression) and biomarkers (eg, prostate-specific antigen
[PSA] or inflammatory markers such as cyclooxygenase-2)
used to assess fish-derived omega-3 fatty acid status and
clinical outcomes.
To our knowledge, there are no evidence-based guide-
lines currently available for patients or clinicians indicating
whether fish-derived omega-3 fatty acids are safe or effec-
tive in the context of PrCa treatment, progression, and pre-
vention. In the absence of guidelines, men often
self-prescribe based on limited information found on the
Internet or obtained from family and friends.19
Patients and clinicians need to have access to reliable,
credible, and evidence-based information about potential
risks and benefits when making decisions about using NHPs
in the context of PrCa. Because previous studies have
reported mixed or conflicting result on the relationship
between fish-derived omega-3 fatty acid and PrCa, thor-
ough analysis of the entire body of literature is warranted.
Therefore, we performed a systematic, evidence-based
review of the available literature regarding fish-derived
omega-3 fatty acids for the treatment and prevention of
PrCa, with the purpose of developing comprehensive
knowledge translation tools for oncology health profession-
als and, ultimately, patients with PrCa.
Methods
Methods of the analysis and inclusion criteria were speci-
fied in advance and documented in a registered protocol
(PROSPERO 2014:CRD42014013014).20
Search Strategy
Electronic search strategies were developed by an experi-
enced medical information specialist in consultation with the
review team (Appendix A). Using the OVID platform, we
searched OVID MEDLINE, Pre-MEDLINE, Embase, and
the Allied and Complementary Medicine Database (AMED).
We also searched the Cochrane Library on Wiley and the
Cumulative Index to Nursing and Allied Health Literature
(CINAHL) on EBSCO and 2 Chinese-language databases
(Wanfang and China National Knowledge Infrastructure data-
bases). All database searches were performed on July 21,
2014 and updated June 21, 2015. Searches included controlled
vocabulary terms (eg, “Prostatic Neoplasms,” “Fatty Acids,
Omega-3,” “Docosahexaenoic Acids”) and key words (eg,
prostate cancer, Omega 3, PUFAs). There were no language or
date restrictions on any of the searches. ClinicalTrials.gov and
the International Clinical Trials Registry Platform (ICTRP)
were searched for current and completed clinical trials.
Inclusion Criteria
Eligible studies assessed male patients of any age for pri-
mary or secondary prevention or progression of PrCa. The
studies assessed, used, or measured dietary and/or supple-
mental intake of fish-derived omega-3 fatty acids with or
without other supplements or measured the omega-3 content
34 Integrative Cancer Therapies 16(1)
in biological samples obtained from participants. Studies
assessing non–fish-derived omega-3 fatty acids such as
alpha-linoleic acid or flaxseed oil were excluded. Studies
using placebos, comparator groups consisting of natural or
pharmacological agents, or no control were eligible. Eligible
study designs included RCTs, non–randomized controlled
trials (non-RCTs), and observational studies (case-control,
cohort) but not preclinical or cross-sectional studies.
Record Screening and Selection
All citations identified by the systematic search were down-
loaded into a reference database. Two investigators inde-
pendently reviewed all identified titles and abstracts for
eligibility. Disagreement regarding inclusion of records was
determined by consensus and third party arbitration by
another member of the research team, when appropriate.
Duplicate reports of studies were included.
Data Extraction
Data were extracted independently by 2 investigators using
data abstraction sheets that had been developed and piloted
among the investigative team. Outcome measures extracted
included relative risk (RR), hazard ratio (HR), and odds
ratio (OR). Outcome measures that were adjusted for known
PrCa risk factors such as age, ethnicity, family history,
smoking status, and body mass index (BMI) were extracted
when available. When not reported, unadjusted outcomes
were extracted. Study authors were contacted to clarify
results reported in 2 publications21,22; however, no new
information was obtained.
Outcomes
The primary outcome of this review is primary prevention of
PrCa. Secondary outcomes include PSA level, PSA doubling
time, Gleason score, recurrence, tumor response rates, sur-
vival, immune function (clinical or surrogate parameters),
quality of life (QOL), other cancer symptoms or chemother-
apy-related side effects, adverse events/toxicities, the Eastern
Cooperative Oncology Group (ECOG) and/or Karnofsky
performance scores, Edmonton Symptom Assessment Scale
(ESAS), prognostic scores (Glasgow PS), or other cancer
markers or relevant surrogates. Additionally, we assessed for
interactions, defined as a pharmacological or clinical
responses to the administration or co-exposure of a treatment
and another substance that modifies either the effectiveness
or safety of the treatment.23,24
Exposure
Data on the dose of fish-derived omega-3 fatty acid intake
were extracted from the studies. When these data were not
reported as mg of EPA + DHA per day, a conversion was
performed to create a standardized dose by weight. To facil-
itate conversion when intake was reported in servings of
fish, a standard of 0.798 g EPA + DHA per servings of fish
was used. This was calculated by finding the average EPA +
DHA content among the different fish and seafood types
listed in the Dietitians of Canada online reference.25 When
intake of fatty acids was reported as a percentage of daily
caloric intake, a standard of 2350 calories per day was uti-
lized based on the Health Canada Food Guide recommen-
dations for adult men with low activity level. The percentage
was multiplied by 2350 calories and divided by 9 cal/g to
approximate the grams of fish oil taken in per day.
Risk of Bias Assessment
The quality of clinical trials was assessed using the Cochrane
Risk of Bias tool.26 The quality of cohort and case-control
studies was assessed using the Newcastle-Ottawa Scale.27
All studies were assessed for their source of funding (indus-
try vs nonindustry). Assessment was completed indepen-
dently by 2 investigators and disagreement was resolved by
consensus or third party arbitration, when appropriate. For
nonrandomized trials, we assessed quality according to
reporting of blinding of patients and assessors, a priori sam-
ple size estimation and low loss to follow-up (<20%).
Data Analysis
Analysis was completed separately for each type of study
design. A random-effects model was used to pool results
from the studies, including the following measures of effect
and 95% confidence intervals (CIs): RR, HR, and OR.
When available, adjusted measures of effect were used.
Forest plots were created to display the results for different
types of studies that were pooled. When available, the effect
of total fish-derived omega-3 fatty acids on total incidence
of cancer was utilized. When these statistics were not avail-
able, other statistics were reported, such as the effect of EPA
only and DHA only on PrCa risk or the effects of omega-3
fatty acids on advanced and nonadvanced PrCa. Additional
forest plots were created to display the effects of fish-
derived omega-3 fatty acid son PrCa mortality, to compare
analyses of EPA alone to DHA alone and to compare studies
utilizing different methods of assessing fish-derived
omega-3 fatty acid exposure.
Planned sensitivity analyses included an assessment of
the effect of methodological quality of included trials, with-
drawals/losses to follow-up, and funding source, when fea-
sible. Homogeneity was assessed using the I-squared
statistic and the Zalen test. If some degree of homogeneity
existed (I2 < 75%), a meta-regression analysis (using
STATA) was conducted to determine the extent to which
factors contributed to heterogeneity. Variable coefficients
Aucoin et al 35
are displayed in the beta-coefficient with 95% CIs and
appropriate ORs with P values. A funnel plot test, using
Eggers test for publication bias, was used to assess the like-
lihood of publication bias. Both quantitative (meta-analy-
sis) and qualitative narrative synthesis of studies (based on
study design) were planned.
Results
Of 1776 records screened, 54 publications, reporting on 44
studies, were included for review and analysis. Figure 1
shows a flowchart of the literature search and study selec-
tion. Search of the Chinese databases yielded 17 records,
none of which met criteria for inclusion. Data extraction by
2 reviewers was found to have a high degree of agreement
and consensus was reached on all articles. Meta-analysis
was not completed due to the significant heterogeneity in
the observational data and limited amount of interventional
data. The results reported in the studies found were predom-
inantly focused on cancer prevention. Eight publications
reported on disease management and progression.28-35 Many
of the secondary outcomes that were planned in this review
were not assessed by any of the included studies.
Interventional Studies
Five publications28-32 reported on the results of 4 clinical tri-
als, including 1 non-RCT (Table 1). Of the 4 trials, 1 was in
patients with localized PrCA preprostatectomy,29 1 in patients
undergoing active surveillance,31 1 in postprostatectomy
patients,28 and 1 in patients with untreated localized or regional
PrCA.32 Interventions included a low-fat diet plus fish oil
supplementation (2400-5500 mg per day of fish oil providing
1600 to 2400 mg of EPA + DHA). PSA levels remained
unchanged in all four trials (Table 1). Many reported a lack of
significant effect on inflammatory markers; however, there
were significant reductions in malignant epithelial cell prolif-
eration (Ki-67) in one of the trials (decrease of 32.2% P <
.05)29 and decreased cell-cycle progression score, pro-inflam-
matory fatty acids 15-S-hydroxyeicosatetraenoic acid and leu-
kotriene B4 in another study30 (Table 1). The intervention
studies analyzed were of short duration. Three of the 4 trials
were three months or shorter in duration29,31,32 and the remain-
ing study was 2 years.28
Observational Evidence
Prospective Cohort Studies of Primary Prevention. Seventeen
publications reported on 11 cohort studies investigating pri-
mary prevention of PrCA (Table 2). These studies assessed
dietary fish-derived omega-3 fatty acids and supplementary
fish oil intake (13 assessed diet alone, 1 assessed supplement
intake alone, and 3 assessed both diet and supplement intake)
and assessed incidence and mortality of PrCa over an aver-
age of 12.2 years (range 4-23.5 years). One additional study
discussed in the nested case-control section of this review
contained a prospective cohort component36 that assessed
the relationship between dietary intake and supplemental
fish oil and the relationship with prostate cancer. In the stud-
ies assessing dietary intake, the highest quartile or quintile of
intake was compared with the lowest, which included indi-
viduals who consumed very little or no dietary fish. Sixteen
publications reported on the association of fish-derived
omega-3 fatty acid intake with PrCa incidence. Of these, 3
studies10,21,36 reported on advanced and nonadvanced pros-
tate cancer separately resulting in a total of 19 analyses. The
publications reported RR or HR and 12 publications reported
outcomes that had been adjusted for other factors.
Of the 19 analyses assessing PrCa incidence, 12 did not
show a statistically significant association.10,21,37-44 Five
analyses showed a significant association between increased
intake of fish-derived omega-3 fatty acids and decreased
PrCa incidence.36,45-48 In 2 of these studies, the authors con-
cluded that statistical significance was achieved based on the
P value despite nonsignificant 95%Cis.45,46 Two analyses
reported a significant association between increased intake
and increased PrCa risk.36,49 In a subanalysis, another study
demonstrated a positive association (ie, increased PrCa)
Figure 1. Literature flowchart.
36
Table 1. Characteristics of Human Trials Investigating Supplemental Fish-Derived Omega-3 Fatty Acids in Patients With Prostate Cancer.
Ref n Random Control Blind
PrCa Status; Other
Treatments Intervention
Duration
(Months)
Effect of Intervention
on PSA
Effect on
Inflammatory Markers
Effect on Additional
Outcomes
Randomized clinical trials
Higashihara
etal (2010)28
62 Yes No Tx NR PrCa PSA < 0.2 ng/
mL 3 months
postprostatectomy;
None
2400 mg/d EPA ethyl
ester
48 Equal PSA failure rate
(4 in EPA group, 8 in
placebo; Kaplan-
Meier P = .16)
Aronson etal
(2011)29
48 Yes Western
diet (15:1
n-6:n-3
ratio), no
placebo
Single Localized PrCa
preprostatectomy;
scheduled for surgery
in ≥4 weeks
Low-fat diet + 5.5 g/d
FO (1835 mg DHA,
1000 mg EPA); 2:1
n-6:n-3 ratio
1-1.5 ↔ PSA (change of 0.08
± 0.4 mg/mL vs −0.09
± 0.3 P = .53)
↔ serum IGF-1 (P = .25)
↔ serum IGFBP-1 (P = .84)
↔ serum IGFBP-3 (P = .14)
↔ urine PGEM (P = .36)
↔ Pr tissue PGE2
↔ COX-2
↓ malignant epithelial cell
proliferation (Ki67) by
32.2% (P < .05)
↓22RV1 cell proliferation
(−5.0% ± 1.8% vs 0.6% ±
1.9% P = .039)
↔ angiogenesis, apoptosis
immunostaining
Galet etal
(2014)30; post
hoc analysis
of Aronson
etal (2011)29
As Aronson 2011 ↓ 15(S)-HETE (−7.2 ± 6.6 vs 24.7
± 11.4 in placebo P = .02)
↓ LTB4 post-LFFO vs pre-LFFO,
but ↔ relative to control (14.9
± 5.6 vs −9.7 ± 7.4 in placebo)
↓ cell-cycle progression
score (P = .03)
Chan etal
(2011)31
69 Yes Placebo Double Low-grade PrCa; active
surveillance
3 g/d FO (1098 mg
EPA, 549 mg DHA)
3↔ PSA (change of 0.20
ng/mL vs −0.46 P
= .39)
↔ in COX-2 expression (change
of 0.39 ± 1.98 vs 0.40 ± 2.19 in
placebo)
Nonrandomized clinical trial
Aronson etal
(2001)32
9 No N/A N/A Untreated localized or
regional PrCa; none
Low-fat diet + 3 g/d
FO (1800 mg EPA,
1200 mg DHA) +
800 IU vit E
3↔ PSA (baseline: 11.15
± 2.9 ng/mL), final:
13.12 ± 4.0
↓ COX-2 in 4 of 7 patients
compared with baseline (not
statistically powered to detect)
Abbreviations: PrCa, prostate cancer; n-3, omega-3 fatty acid; n-6, omega-6 fatty acid; N/A, not applicable; NR, not reported; FO, fish oil; LFFO, low-fat diet + fish oil; Tx, treatment; EPA, eicosapentaenoic acid; DHA,
docosahexaenoic acid; PSA, prostate-specific antigen; IGF-1, insulin-like growth factor 1; IGFBP-1, insulin-like growth factor binding protein 1; IGFBP-3, insulin-like growth factor binding protein 3; PGEM, prostaglandin E2
metabolite; PGE2, prostaglandin E2; COX-2, cyclooxygenase-2; Pr, protein; CHO, carbohydrate; vit, vitamin; FA, fatty acid; ↔, no change; ↑, increase; ↓, decrease.
37
Table 2. Prospective Cohort Studies of Dietary and Supplemental Fish-Derived Omega-3 Fatty Acids and Risk of Primary Prostate Cancer.
Reference
Cohort/
Study Name Cohort n Cases n
Geographic
Area
PrCa Status
at Baseline;
Other Tx
Exposure
Assessment Years f/u
Highest group
(quartile, quintile, etc.); Dose
Effect of exposure on
outcome (highest vs. lowest exposure)
Allen etal
(2004)49
Life Span Study 18 115 196 Hiroshima or
Nagasaki,
Japan
No evidence
of disease
FFQ 16.9 Eating fish almost daily or
more often;
684 mg/d
↑ risk of PrCa RR 1.77 (1.01-3.11) P = .07
Augustsson
etal (2003)45
Health Professionals
Follow-Up Study
47 882 2482 USA Never FFQ 12 Eating fish more than 3×/wk;
342 mg/d
↓ risk total PrCa mvRR 0.93 (0.80-1.08),
advanced PrCa mvRR 0.83 (0.61-1.13),
metastatic PrCa mvRR 0.56 (0.37-0.86)
FO supp use ↔ risk of PrCa
Leitzmann etal
(2004)46
Health Professionals
Follow-Up Study
47 866 2965 USA Never FFQ and
supplement
inquiry
14 Dietary EPA + DHA
>0.214% energy;
558 mg/d
↓ risk of PrCa RR 0.89 (0.77-1.04) P = .002
↔ fatal PrCa 0.68 (0.40-1.17) P trend = .12
FO supp >2.5 g/d ↔ risk of PrCa mvRR 0.89 (0.62-1.30) P = .91
Giovannucci
etal (1993)37
Health Professionals
Follow-Up Study
47 885 300 USA Never FFQ 4 Median of 0.55 g/day n-3 fat
(from fish);
550 mg/d
↔ risk of PrCa
RR 0.90 (0.51-1.61) P = .30
Bonner etal
(2012)47
New York State Angler
Cohort
17 110 58 USA Never Self-administered
food
questionnaire
17 Ever eaten fish from Lake
Ontario (vs never)
↓ risk of PrCa
RR 0.5 (0.3-0.8)
Brasky etal
(2011)50
VITamins And Lifestyle
(VITAL) Cohort
35 239 1602 USA Never Questionnaire of
supplement use
6.1 User of fish oil supp (>1 d/
wk for >1 year)
↔ risk of PrCa mvHR
0.98 (0.82-1.17) P = .61
Daniel etal
(2011)39
NIH-AARP Diet and
Health Study
293 466 23 453 USA Never FFQ 9.1 21.4 g fish/1000 kcal;
535 mg/d
↔ risk of PrCa HR 1.02 (0.98-1.06) P = .67
Pelser etal
(2013)10
NIH-AARP Diet and
Health Study
288 268 23 281 USA Never FFQ 9 EPA 0.036% energy ↔ risk of advanced/nonadvanced PrCa
mvHR 0.93 (0.82-1.04) P = .15; mvHR
1.05 (1.00-1.10) P = .69
↓ risk of fatal PrCa mvHR 0.82 (0.64-1.04)
Ptrend = .02
EPA + DHA 0.103% energy;
269 mg/d
↔ risk of advanced (mvHR 0.97 (0.86-
1.09) P = .31); nonadvanced (mvHR 1.04
(1.00-1.10) P = .45); or fatal PrCa (mvHR
0.87 (0.68-1.10) P = .10)
Bosire etal
(2013)51
NIH-AARP Diet and
Health Study
293 464 23 453 USA Never FFQ 8.9 >0.66 ounce/d of fish;
199 mg/d
↓ risk of fatal PrCa mvHR 0.79 (0.65-0.96)
≥250 mg/d marine n-3;
250 mg/d
↓ risk of fatal PrCa mvHR 0.94 (0.90-0.98)
Terry etal
(2001)48
N/A 6274 466 Sweden Never Self-administered
food
questionnaire
21.4 Fish accounted for “large
part of diet”
↓ risk of PrCa
mvRR 0.43 (0.22-0.83) P < .05;
↓ risk of PrCa death
mvRR 0.30 (0.17-0.56) P < .01
(continued)
38
Reference
Cohort/
Study Name Cohort n Cases n
Geographic
Area
PrCa Status
at Baseline;
Other Tx
Exposure
Assessment Years f/u
Highest group
(quartile, quintile, etc.); Dose
Effect of exposure on
outcome (highest vs. lowest exposure)
Crowe etal
(2008)40
EPIC 142 520 2727 10 European
countries
Never FFQ 8.7 Not defined ↔ risk of PrCa
Total PrCa risk mvHR per 1% increase in
energy from fish fat: 1.00 (0.93-1.07)
P = .977
↔ risk of localized, advanced, high-grade,
or low-grade PrCa
Kristal etal
(2010)21
Prostate Cancer
Prevention Trial
9559 1703 USA and
Canada
Never;
Finasteride
or placebo
FFQ and
supplement
questionnaire
7 Total EPA + DHA >0.28
mg/d;
0.28 mg/d
↔ risk of PrCa
For GS 2-7 OR 1.11 (0.94-1.31) P = .230
For GS 9-10 OR 1.46 (0.86-2.50) P = .193
Pham etal
(2009)52
Miyako Study 5589 21
deaths
Japan Never Self-administered
questionnaire
13.4 Fish consumed at least 2-4×/
wk;
342 mg/d
↓ risk PrCa death mvHR 0.12 (0.05-0.32)
Chavarro etal
(2008)41
Physician’s Health
Study
20 167 2162
cases,
230
deaths
USA Never;
aspirin
and beta-
carotene
FFQ 19 Fifth quintile of seafood n-3
FA intake
↔ risk of PrCa mvRR 1.09 (0.95-1.25) P
= .55
↓ risk of PrCa death
mvRR 0.65 (0.42-0.99) P = .02
Sato etal
(2008)42
Osaki National Health
Insurance Subscribers
Cohort Study
24 895 95 Japan Never FFQ 7 Fish intake >100 g/d;
1064 mg/d
↔ risk of PrCa;
mvHR 0.72 (0.40-1.33) P = .23
Among >70-year-olds mvHR 0.44 (0.18-
1.11) P = 0.08
Wallstorm
etal (2007)43
Malmo Diet and
Cancer Cohort
10 564 817 Sweden Never Questionnaire
(including
Supplement)
and Menu
record
11 1.30 g/d of EPA + DHA
supplement;
1300 mg/d
↔ risk of PrCa
mvRR 1.26 (1.00-1.59) P = .056
0.47 g/d EPA ↑ risk of PrCa mvRR 1.30 (1.03-1.64) P =
.043
0.88 g/d DHA ↔ risk of PrCa
mvRR 1.26 (1.00-1.59) P = .062
Chavarro etal
(2010)44;
full text not
published
Physician’s Health
Study
488 94 Pr
CA
deaths
USA Never Blood FA levels
at baseline
23.5 Quartiles of serum FAs ↔ risk of PrCa death (data not provided
in abstract)
Torfadottir
etal (2013)36
AGES-Reykjavik
Cohort Study
133 1944 Iceland Never FFQ 7 Once a week or more intake
of salted or smoked fish
↑ risk advanced PrCa intake later life OR
2.28 (95% CI: 1.04, 5.00)
↓ risk of localized PrCa intake later life
AOR 0.63 (0.40-1.00)
Fish oil use daily ↓ risk of advance PrCa HR 0.43 (0.19-0.95)
with use in later life
Abbreviations: PrCa, prostate cancer; mvRR, multivariate relative risk; mvHR, multivariate hazard ratio; AOR, adjusted odds ratio; FFQ, Food Frequency Questionnaire; Tx, treatment; N/A, not applicable; ×/wk, times per week;
f/u, follow-up; Bl, baseline; ↓, decrease; ↑, increase; ↔ no effect; GS, Gleason score; FO fish oil; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; n-3, omega-3; NR, not reported; Supp, supplement.
Table 2. (continued)
Aucoin et al 39
with increased EPA intake but not with increased intake of
DHA or EPA + DHA.43 The results of the primary cohort
studies are presented in a forest plot (Figure 2); with the
exception of 1 study where the data were not available.44
Five prospective cohort analyses assessed the impact of
fish oil supplements (or the combination of diet and fish oil
supplements in 1 study); 4 demonstrated no statistically sig-
nificant association with the risk of PrCa incidence.43,45,46,50
One demonstrated a relationship between daily supplemen-
tal fish oil intake in later life and a decrease in advanced
PrCa incidence.36
Among the 7 cohort study reports assessing the risk of
death related to PrCa, 5 studies reported a significant asso-
ciation between higher intake of fish-derived fatty acids and
decreased risk of death.35,41,48,51,52 Of the 2 remaining stud-
ies, one showed a significant association between decreased
risk of death and higher EPA intake and a nonsignificant
association with higher total EPA + DHA.10 The remaining
study showed an association between decreased risk of
death and higher total EPA + DHA intake that approached
significance.46
Prospective Cohort Studies of Secondary Prevention. Three pub-
lications reported on cohort studies assessing progression or
risk of death among patients with PrCa (Table 3).31,34,35 In
these 3 studies, patients underwent conventional individual-
ized treatment for their PrCa. One study measured the time
to PrCa-related death35 while one defined progression as
either PrCa death, bone metastases from PrCa, biochemical
recurrence, or initiation of secondary treatment.34 The third
study asked the patient’s treating physician to whether or not
the patient’s prostate cancer had recurred or progressed since
the initial treatment33 and when not available defined pro-
gression as 2 or more successive rises in PSA, initiation of
second therapy or positive scans for metastasis. Two studies
utilized an FFQ to assess dietary fish intake after diagnosis
of PrCa and analyzed risk of disease progression; no impact
from high fish intake was found33,34. The third study assessed
risk of PrCa death and found an association between lower
risk and higher fish-derived omega-3 fatty acid intake in the
year prior to diagnosis.35
The results of the primary and secondary cohort studies
assessing risk of death are presented together in a forest plot
(Figure 3).
Dose of Fish-Derived Omega-3 Fatty Acids. Among the cohort
studies, the amount of fish-derived omega-3 fatty acid
intake in the highest quartile of dietary intake varied widely,
Figure 2. Risk of prostate cancer (PrCa) incidence with fish-derived omega-3 fatty acid intake: Prospective cohort studies. When the
effect of fish-derived omega-3 fatty acid intake on total PrCa risk was not available, subanalyses reporting on different stages of cancer
(eg, advanced cancer and nonadvanced cancer) are reported. *Study authors concluded that the results achieved statistical significance
based on P value and confidence interval.
40
Table 3. Prospective Cohort Studies of Dietary Fish-Derived Omega-3 Fatty Acids and Risk of Prostate Cancer Progression or Death.
Reference
Cohort/
Study Name Cohort n Cases n
Geographic
Area
PrCa Status at
Baseline
Study
Objective
Exposure
Assessment
Years
f/u
Highest Exposure
Group (Quartile,
Quintile, etc); Dose
Effect of Exposure on
Outcome (Highest vs
Lowest Exposure)
Chan etal
(2006)31
Health Professionals
Follow-up Study
1202 392 cases
progression
USA Present Prevent
progression
FFQ of intake
postdiagnosis
10 Not reported ↔ Risk of PrCa
progression HR 0.73
(0.52-1.02)
Richman
etal
(2010)34
Cancer of the Prostate
Strategic Urologic
Research Endeavour
(CaPSURE)
1294 127 cases
progression
USA Present
(excluding
advanced or
metastatic)
Prevent
progression
FFQ of intake
postdiagnosis
2 Median 4.3
servings/wk;
490 mg/d
↔ Risk of PrCa
progression mvHR
1.13 (0.70-1.84)
Epstein etal
(2012)35
N/A 525 222 cases of
PrCa death
Sweden Present Prevent death
due to PrCa
FFQ of intake
1 year
prediagnosis
20 0.8 g marine FAs/
day;
800 mg/d
↓ risk PrCa death
HR 0.59 (0.4-0.87)
P = .04
Abbreviations: PrCa, prostate cancer; mvRR, multivariate relative risk; mvHR, multivariate hazard ratio; AOR, adjusted odds ratio; FFQ, Food Frequency Questionnaire; ×/wk times per week; f/u
follow-up; Bl, baseline; ↓, decrease; ↑, increase; ↔ no change; RBC, red blood cells; FA, fatty acids.
Aucoin et al 41
ranging from approximately 200 to 1300 mg/d of EPA +
DHA (Table 2). No relationship between the dose of the
exposure and study outcome was apparent. Individual stud-
ies reporting findings of increased risk of PrCA incidence,
decreased risk of PrCA incidence, and no effect on risk of
PrCA incidence had the following average intake of fish-
derived omega-3 fatty acids in the highest quartile: 577,
373, and 666 mg, respectively.
Three case-cohort studies assessed the impact of fish
intake on PrCa incidence (Table 4). Two studies showed no
association between fish intake and PrCa.53,54 One study
showed no association between EPA intake and PrCa and a
relationship between higher dietary intake of DHA and
higher incidence of PrCa.55
Sixteen publications reported on 15 case-control studies
and 10 publications reported on 8 nested case-control stud-
ies. These results are presented in Tables 5 and 6 and dis-
played in Figures 4 and 5. There was considerable
heterogeneity in the results of the different studies as well as
the methodology, analyses and reporting in individual stud-
ies. The studies varied in their method of assessing expo-
sure, the time of exposure, the type of fish eaten and the
marine fatty acids measured (EPA, DHA, EPA + DHA). Of
the case-cohort, case-control, and nested case-control stud-
ies, 10 utilized whole blood, plasma, serum or RBC fatty
acid analysis to assess fish-derived omega-3 fatty acid
exposure, whereas 21 assessed intake through participant
recall using a FFQ.
Among those that assessed fish-derived omega-3 fatty
acid intake through recall with significant findings, 8 analy-
ses showed an association between higher intake and lower
risk of PrCa incidence56-61 while 4 analyses showed an asso-
ciation with higher risk of incidence.36,61-63 Among the stud-
ies that assessed blood levels, 3 analyses reported an
association between higher intake and lower risk22,41 and 5
reported an association with higher risk of incidence.40,50,55,64,65
Among the studies reporting an association between higher
fish intake on recall and higher risk, the type of fish intake
assessed was related to the outcome. One study showed an
association with increased risk with higher intake of cod,
saithe, shellfish, and “fish fingers” but an association with
decreased risk with higher intake of salmon-type fish while
adjusting for intake of the other fish types.61 It also showed
that when overall intake of EPA + DHA was assessed, the
effect was protective. Another study showed an association
with increased risk with higher white fish intake (unadjusted
OutcomeLower CIUpper CIN CohortNDeaths
Risk Raos
Chavarro 2008 0.65 0.42 0.99 20167 230
Leitzmann 20040.680.401.17 47866 448
Terry 20010.300.170.56 6274 340
Hazard Raos
Bosire 2013 0.94 0.90 0.98 293464 428
Epstein 2012 0.59 0.40 0.87 525 222
Pham 2008 0.12 0.05 0.32 5589 21
Pelser 2013 0.87 0.68 1.10 288268 725
Measure of Effect & 95% CIs
Favors higher Intake Favors lower intake
Figure 3. Risk of prostate cancer (PrCa) mortality with fish-derived omega-3 fatty acid intake: Prospective cohort studies case-
cohort, case-control and nested case-control studies.
42
Table 4. Case-Cohort Studies of Fish-derived omega-3 fatty acids and Prostate Cancer Incidence.
Reference
Cohort/Study
Name Cases n Controls n
Geographic
Area
Exposure
Assessment
Highest Group
(Quartile, Quintile, etc)
Effect of Exposure on Outcome
(Highest vs Lowest Exposure)
Assessing blood levels of fatty acids
Bassett etal
(2013)53
Melbourne
Collaborative
Cohort Study
464 1717 Australia PPL FAs and
FFQ at
baseline
Quintiles %PPL EPA
and DHA (not
defined)
↔ risk of PrCa EPA mvHR 1.05 (0.93-1.18) P = .42; DHA
mvHR 0.99 (0.88-1.11) P = .86
Dietary intake quintiles
(not defined)
↔ risk of PrCa EPA mvHR 0.79 (0.56-1.12) P = .53; DHA
mvHR 0.878 (0.61-1.25) P = .52
Brasky etal
(2013)55
SELECT Trial 834 1393 USA, Canada,
Puerto Rico
Serum PPL at
baseline
EPA >0.82% total FAs ↔ risk of total, low-grade or high-grade PrCa
DHA >3.62% total FAs ↑ Total PrCa and low-grade PrCa DHA mvHR 1.39 (1.06-1.82)
P = .009; mvHR 1.42 (1.06-1.89) P = .08
↔ risk of high-grade PrCa with DHA
Assessing dietary intake of fatty acids
Schuurman
etal
(1999)54
The Netherlands
Cohort Study
642 1525 Netherlands FFQ at baseline
of cohort
study
EPA intake 0.10 g/d
DHA intake 0.18 g/d
↔ PrCa risk for EPA RR 1.00 (0.73-1.35) P = .10 and DHA RR
1.03 (0.75-1.40) P = .19
Abbreviations: PPL, plasma phospholipid; FA, fatty acids; PrCA, prostate cancer; mvRR, multivariate relative risk; mvHR, multivariate hazard ratio; FFQ, Food Frequency Questionnaire; ↓ decrease, ↑
increase, ↔ no effect; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.
43
Table 5. Case Control Studies of Fish-derived omega-3 fatty acids and Prostate Cancer Incidence.
Reference
Cohort/
Study Name Cases n Controls n
Geographic
Area
Exposure
Assessment
Highest Group (Quartile,
Quintile, etc)
Effect of Exposure on Outcome
(Highest vs Lowest Exposure)
Assessing blood levels of fatty acids
Ukoli etal
(2010)64
N/A 48 African
American, 66
Nigerian
125 African
American, 274
Nigerian
Nigeria/USA FFQ and plasma FA Quartiles of plasma FA
(not defined)
In African Americans:
↑ PrCa risk, Q3 vs Q1 DHA OR 6.63
(2.02-21.77) Ptrend < .004
↔ PrCa risk Q4 vs Q1 DHA OR 1.35
(0.40-4.61)
Cheng
(2013)81
Carotene and Retinol
Efficacy Trial
(CARET)
458 1369 USA Serum PPL FA at baseline Quartiles of serum EPA +
DHA (not defined)
↔ risk of nonaggressive PrCa EPA +
DHA mvOR 1.14 (0.80-1.63) P = .45
↔ risk of aggressive PrCa mvOR 1.05
(0.71-1.55) P = .53
Assessing dietary intake of fatty acids
Vlajinac etal
(2010)62
N/A 101 202 Serbia 150-item FFQ Tertiles and terciles of
average daily intake (not
defined)
↑ PrCa risk OR 2.60 (1.45-4.65) p<0.01
(mostly canned/processed)
Williams
(2011)82
N/A 79 187 Virginia Harvard 12-month FFQ EPA 0.079-0.83% and
DHA 0.10% to 0.64% (of
total energy)
↔ PrCa risk EPA OR 1.13 (0.56-2.24)
P = .73 DHA 0.82 (0.40-1.68) P = .6
Mina etal
(2008)60
National Enhanced
Cancer Surveillance
System (NECSS)
1534 1607 Canada 60-item FFQ Fresh/canned fish ≥2
servings /wk
↔ PrCa risk AOR 1.10 (0.84-1.42)
Preserved (smoked/dried/
salted fish) ≥1 serving /
wk
↓ PrCa risk 1-3 servings/mo preserved
fish (vs 0/mo) AOR 0.78 (0.64-0.95)
Hu etal
(2008)69
National Enhanced
Cancer Surveillance
System (NECSS)
1799 5039 Canada Self-administered 69-item
FFQ for previous 2
years
≥5 ounce fish/wk ↔ PrCa risk OR 0.8 (0.7-1.0) P = .08
Hedelin etal
(2007)61
Cancer Prostate in
Sweden (CAPS)
Study
1499 (diet only),
1378 with
blood samples
1130 (diet only),
782 with blood
samples
Sweden Self-administered 261-
item 12-month FFQ
≥1 serving/wk Salmon-type: ↓ PrCa risk OR 0.57
(0.43-0.76)
Cod/saithe/fish fingers: ↑ PrCa risk OR
1.45 (1.12-1.88)
Shellfish:↑ PrCa risk OR 0.81 (1.28-2.56)
0.11 g EPA + DHA/day-MJ ↓ PrCa risk OR 0.70 (0.51-0.97)
Chen
(2005)83
N/A 237 481 Taiwan Interviewed FFQ for
previous 10 years
Intake of “more”
compared with others
↔ PrCa risk AOR 1.12 (0.80-1.56)
Sonoda etal
(2004)56
N/A 140 140 Japan Interviewed 102-item FFQ
for previous 5 years
≥130.7 g/d fish intake ↓ PrCa risk OR 0.45 (0.20-1.02) P = .04
Pawlega etal
(1996)57
N/A 76 152 Cracow, Poland Self-administered 44-item
FFQ for previous 20
years
Fish consumption ≥once/
wk vs <rarely
↓ PrCa risk smoked fish OR 0.5 (0.2-0.8)
P < .05
↓ PrCa risk fried fish 0.5 (0.2-0.9) P < .05
Talamini
etal
(1992)68
N/A 271 685 Northern Italy Interviewed 14-item FFQ
for preceding year
Fish intake ≥2 servings/wk ↔ PrCa risk OR 0.79 (0.53-1.17) P = .36
(continued)
44
Reference
Cohort/
Study Name Cases n Controls n
Geographic
Area
Exposure
Assessment
Highest Group (Quartile,
Quintile, etc)
Effect of Exposure on Outcome
(Highest vs Lowest Exposure)
Deneo-
Pellegrini
(2012)84
N/A 326 1488 Uruguay Interviewed 64-item FFQ
for previous 5 years
Tertiles of fish intake
(continuous servings per
year, not defined)
↔ PrCa risk OR 1.34 (0.95-1.89) P = .09
Kristal etal
(2002)66
Seattle-Puget Sound
Surveillance
Epidemiology and
End Results Registry
605 592 Seattle, WA Self-administered FFQ for
previous 3-5 years
>0.24 g/d EPA + DHA
intake (food and
supplements)
↔ local PrCa risk AOR 1.05 (0.68-1.63)
P = .51
↔ regional/distant PrCa risk AOR 0.84
(0.44-1.58) P = .81
Joshi etal
(2012)63
California
Collaborative
Prostate Cancer
Study
717 localized,
1140 advanced
1096 California Interviewed FFQ for
previous 12-month
intake
Tertiles fish intake
White fish: >12.41-167
g/1000 kcal/d
↔ PrCa risk T3 intake tuna, dark fish or
deep-fried fish
↑ risk advanced PrCa white fish AOR
1.3 (1.0-1.7) Ptrend = .014
Raimondi
etal
(2010)58
N/A 197 197 Canada FFQ for 1 year prior to
diagnosis
Finfish/shellfish intake
>30.4 g/d
↓ PrCa risk OR 0.54 (0.30-0.97) P = .05
Fradet etal
(2009)59
N/A 466 478 USA FFQ reflecting the period
before diagnosis
EPA intake 0.167 g/d
DHA intake 0.368 g/d
↓ PrCa risk EPA AOR 0.35 (0.24-0.52)
P < .0001; DHA AOR 0.36 (0.25-0.53)
P < .0001
>1 serving per week dark
fish
↓ PrCa risk AOR 0.43 (0.29-0.63) Ptrend
< .0001
>1 serving per week white
fish
↓ PrCa risk AOR 0.66 (0.45-0.96) Ptrend
= .32
>1 serving per week
shellfish
↓ PrCa risk AOR 0.51 (0.35-0.74) Ptrend
< .0001
>1 serving per week tuna ↓ PrCa risk AOR 0.75 (0.51-1.09)
P = .04
>1 serving per week fried
fish
↓ PrCa risk AOR 0.56 (0.37-0.86)
P = .03
Assessing blood levels and dietary intake of fatty acids
Norrish etal
(1999)22
Auckland Prostate
Study
317 480 Auckland, New
Zealand
Self-administered 107-
item FFQ and RBC EPA
and DHA
Quartiles EPA and DHA
intake (not defined)
↔ PrCa risk EPA mvRR 0.96 (0.63-1.48)
DHA mvRR 1.10 (0.71-1.70)
RBC EPA >0.83 mol% and
RBC DHA >1.70 mol%
↓ PrCa risk EPA RR 0.59 (0.37-0.95)
DHA RR 0.62 (0.39-0.98)
Abbreviations: PrCa, prostate cancer; mvRR, multivariate relative risk; mvHR, multivariate hazard ratio; AOR, adjusted odds ratio; FFQ, Food Frequency Questionnaire; ×/wk, times per week; f/u follow-up; Bl, baseline; ↓,
decrease; ↑, increase; ↔, no change; FA, fatty acids; PPL, plasma phospholipids; RBC, red blood cell; n-3, omega-3; PUFA, polyunsaturated fatty acids; sICAM-1, soluble intercellular adhesion molecule-1; EPA, eicosapentaenoic
acid; DHA, docosahexaenoic acid.
Table 5. (continued)
45
Table 6. Nested Case-Control Studies of Fish-Derived Omega-3 Fatty Acids and Prostate Cancer Incidence.
Reference Cohort/Study Name Cases n Controls n
Geographic
Area Exposure Assessment
Highest Group
(Quartile,
Quintile, etc)
Effect of Exposure on Outcome
(Highest vs Lowest Exposure)
Assessing blood levels of fatty acids
Dahm etal
(2012)65
European Prospective
Investigation into
Cancer and Nutrition
(EPIC) cohort
962 1061 10 European
countries
Plasma FAs at baseline Quintiles of
plasma marine
n-3 PUFA (not
defined)
↑ risk of PrCa based on treelet transform analysis
OR 1.36 (0.99, 1.86) Ptrend = .041
Crowe etal
(2008)40
European Prospective
Investigation into
Cancer and Nutrition
(EPIC)
926 926 10 European
countries
Plasma PPL FAs EPA 1.95-9.49
mol%
↔ risk of total PrCa mvRR 1.31 (0.96-1.81) P = .09
↑ risk of high-grade PrCa mvRR 2.00 (1.07-3.76) Ptrend = 0.031 ↔
risk of localized, advanced or low-grade PrCa
DHA 5.34-10.37
mol%
↔ risk of total PrCa DHA mvRR 1.39 (1.02-1.90) P = .158
↔ risk of localized, advanced, high-grade or low-grade PrCa
Brasky etal
(2011)38
Prostate Cancer
Prevention Trial
1658 1803 USA Serum PPL FA at baseline EPA >0.74% ↔ risk of low-grade or high-grade PrCa
DHA >3.30% ↑ risk high-grade PrCa OR 2.50 (1.34, 4.65) P = .04
↔ risk of low-grade PrCa
EPA + DHA
>4.02%
↔ risk of low-grade
↔ risk of high-grade PrCa AOR 1.99 (1.08-3.68) P = .08
Park (2009)85 The Multiethnic Cohort
Study
376 729 USA RBC FA at baseline EPA >0.77%
DHA >8.00%
↔ risk PrCa
Chavarro etal
(2008)41
Physician’s Health Study 476 476 USA Whole blood FAs EPA >2.36% ↓ risk of localized PrCa mvRR 0.57 (0.36-0.92) P = .02
↔ risk of advanced, aggressive or nonaggressive PrCa
DHA >3.37% ↓ risk of localized PrCa mvRR 0.60 (0.39-0.93) P = .07
↔ risk of advanced, aggressive or nonaggressive PrCa
Harvei etal
(1997)67
N/A 141 141 Norway Serum PPL FAs EPA 2.00%
DHA 5.67%
↔ risk of PrCa EPA OR 1.2 (0.6-1.2) P = .1; DHA OR 1.0 (0.5-1.8)
P = .08
Assessing dietary intake of fatty acids
Touvier
(2012)86
SUVIMAX
(Supplementation en
Vitamines et Mineraux
AntioXydants) Cohort
Study
129 760 France 24-hour dietary records
every 2 mo for first 2
years of study; baseline
plasma sICAM-1
1.2 g/d n-3 fatty
acid intake in
women, 1.6 g/d
in men
Relation between sICAM-1and PrCa modulated by n-3 PUFA intake;
sICAM-1 associated with ↑ risk PrCa in patients with n-3 intakes
below the median OR 6.1; (1.1-34.5) Ptrend = .03; no association
in patients with intakes above median OR 0.3 (0.1-1.6) Ptrend = .2
Torfadottir
etal
(2013)36
AGES-Reykjavik Cohort
Study
343 1914 Iceland FFQ assessing early, mid-
and late-life fish intake
>4 servings total
fish/wk
↔ PrCa risk with intake early- and midlife AOR 0.87 (95% CI: 0.66,
1.13), 1.05 (95% CI: 0.71, 1.57)
Once a week or
more intake
of salted or
smoked fish
↑ risk advanced PrCa intake early life OR 1.98 (95% CI: 1.08, 3.62);
↔ risk with intake in midlife
↔ risk of total and localized PrCa with intake in early life, midlife
Fish oil use daily ↔ risk of total, localized, or advanced PrCa with supplementation
in early life or midlife
Assessing blood levels and dietary intake of fatty acids
Gann (1994)87 Physician’s Health Study 120 120 USA Plasma FAs and FFQ at
baseline
Quartiles of
plasma FAs (not
defined)
↔ risk of PrCa EPA RR 0.87 (0.41-1.82) P = .81
Abbreviations: PrCa, prostate cancer; mvRR, multivariate relative risk; mvHR, multivariate hazard ratio; AOR, adjusted odds ratio; FFQ, Food Frequency Questionnaire; ×/wk, times per week; f/u follow-up; Bl, baseline; ↓,
decrease; ↑, increase; ↔, no change; FA, fatty acids; PPL, plasma phospholipids; RBC, red blood cell; n-3, omega-3; PUFA, polyunsaturated fatty acids; sICAM-1, soluble intercellular adhesion molecule-1; EPA, eicosapentaenoic
acid; DHA, docosahexaenoic acid.
46 Integrative Cancer Therapies 16(1)
for intake of other fish) and no effect from higher intake of
tuna, dark fish, or deep fried fish.63 Another study that found
an association with increased risk reported mixed results
including an increased risk of advanced PrCa with higher
intake of salted or smoked fish in early life, a lower risk of
localized PrCa with intake later in life and no effect on other
stages of PrCa and other intake time points.36
No case-cohort, case-control, or nested case-control
studies reported on the risk of death.
One case-control study assessed supplemental fish oil
intake in addition to dietary fish intake; however, the intake
amounts were combined in analysis to reflect overall fish-
derived omega-3 fatty acid intake.66 One nested case-
control study assessed supplemental fish oil intake and
found that daily use in early or midlife was not associated
with and PrCa risk.36
When the observational results were organized by the
type of fish-derived fatty acid analyzed (EPA and DHA), no
association was observed (Figures 6 and 7).
Adverse Events and Interactions. In the RCTs and non-RCT,
adverse events ranged from none to mild. In 1 study, 2 of 32
subjects experienced nausea and withdrew.28 One study
reported increased flatulence (5 subjects compared with 1
in the placebo group), self-limiting diarrhea (2 participants
compared with 1 in the placebo group), and eructation (1
participant).29 Two studies stated that no adverse events
were reported.31,32 No studies reported a statistically signifi-
cant difference in adverse reaction rates between fish oil
and control/placebo arm.
Among the studies that used fish oil supplement inter-
ventions in patients with PrCa, no interactions with conven-
tional care were reported; however, the studies excluded
many participants receiving conventional cancer therapies.
Of the 3 RCTs and 1 non-RCT, 3 excluded men receiving
antihormonal therapies, 2 excluded men receiving 5-alpha-
reductase inhibitors, and 3 excluded men taking anti-
inflammatory medication. None of the studies included
men receiving chemotherapy or radiation; 2 studies included
men who were untreated,31,32 1 included men postprostatec-
tomy,28 and 1 preprostatectomy.29 No clinical studies spe-
cifically reported an active assessment of interactions with
other therapies, surgical procedures, or medications.
Risk of Bias. Among the RCTs, all studies had a high risk of
bias when evaluated with the Cochrane Risk of Bias Assess-
ment; the results are displayed in Figure 8. Risk was identi-
fied in most studies due to incomplete outcome data and in
OutcomeLower CIUpper CINControls NCases Total N
Hazard Raos
Basse 2013 EPA1.050.931.18 1717 4642181
Basse 2013 DHA0.990.881.11 1717 4642181
Brasky 2013 DHA1.391.061.82 1393 8342227
Brasky 2013 EPA1.180.901.54 1393 8342227
Brasky 2011 high grade 1.991.083.68 1803 1658 3461
Brasky 2011 low grade 1.130.921.38 1803 1658 3461
Odds Raos
Cheng 2013 non-aggressive 1.14 0.80 1.63 1369 4581827
Cheng 2013 aggressive1.050.711.55 1369 4581827
Dahm 2012 1.36 0.99 1.86 1061 9622023
Gann 19940.870.411.82 120 120240
Harvei 1997 EPA1.200.602.10 141 141282
Harvei 1997 DHA1.000.501.80 141 141282
Park 2009 EPA1.110.731.67 729 3761105
Park 2009 DHA1.110.731.69 729 3761105
Ukoli 2010 African American EPA 0.82 0.21 3.24 125 48 173
Ukoli 2010 African American DHA 1.57 0.60 4.12 125 48 173
Ukoli 2010 Nigerian EPA 0.82 0.35 1.91 274 66 340
Ukoli 2010 Nigerian DHA 0.75 0.35 1.62 274 66 340
Risk Raos
Chavarro 2007 EPA localized 0.57 0.36 0.92 476 476952
Chavarro 2007 DHA localized 0.60 0.39 0.93 476 476952
Crowe 2008 EPA1.310.961.81 926 9261852
Crowe 2008 DHA1.391.021.90 926 9261852
Norrish 1999 EPA0.590.370.95 480 317797
Norrish 1999 DHA0.620.390.98 480 317797
Measure of Effect & 95% CIs
Favors higher Intake Favors lower intake
Figure 4. Risk of prostate cancer (PrCa) incidence with fish-derived omega-3 fatty acid intake: Case-cohort, case-control, and nested
case-control studies using blood assessment of fatty acids. When the effect of total fish-derived omega-3 fatty acid intake on PrCa risk
was not available, sub-analyses reporting on individual fatty acids or different stages of cancer are reported.
Aucoin et al 47
Figure 5. Risk of prostate cancer (PrCa) incidence with fish-derived omega-3 fatty acid intake: Case-cohort, case-control, and nested
case-control studies using Food Frequency Questionnaire (FFQ) assessment of fatty acid exposure. When the effect of total fish-
derived omega-3 fatty acid intake on PrCa risk was not available, subanalyses reporting on individual fatty acids, different stages of
cancer, and different time points of fish exposure are reported.
OutcomeLower CIUpperCIN Total N Cases NTotal
Hazard Raos
Basse 2013 FFQ 1.05 0.93 1.18 1717 464 2181
Basse 2013 serum FA1.050.931.181717 464 2181
Brasky 2011 low grade1.010.831.241803 1658 3461
Brasky 2011 high grade 1.09 0.63 1.86 1803 1658 3461
Brasky 20131.180.901.541393 834 2227
Pelser 2013 adv 0.93 0.82 1.04 285338 2930 288268
Pelser 2013 nonadv1.051.001.10269334 18934 288268
Odds Raos
Cheng 2013 1.07 0.75 1.52 1369 458 1827
Fradet 20090.350.240.52 478 466 944
Harvei 19971.200.602.10 141 141 282
Norrish 1999 FFQ0.960.631.48 480 317 797
Norrish 1999 RBC FA 0.59 0.37 0.95 480 317 797
Park 20091.110.731.67 729 376 1105
Ukoli 2010 African American 0.82 0.21 3.24 125 48 173
Ukoli 2010 Nigerian 0.820.351.91 274 66 340
Risk Raos
Williams 2011 1.13 0.56 2.24 187 79 266
Chavarro 2007 0.57 0.36 0.92 476 476 952
Crowe 2008 1.31 0.96 1.81 926 926 1852
Leitzmann 2004 0.880.761.01 44901 2965 47866
Schuurman 1999 1.00 0.73 1.35 1525 642 2167
Wallstorm 2007 1.30 1.03 1.64 10564 817 11381
Measure of Effect & 95% CIs
Favors lower intake Favors higher intake
Figure 6. Risk of prostate cancer (PrCa) incidence with eicosapentaenoic acid (EPA) intake: Observational data. When the effect of
total fish-derived omega-3 fatty acid intake on PrCa risk was not available, subanalyses reporting on individual fatty acids or different
stages of cancer are reported.
48 Integrative Cancer Therapies 16(1)
OutcomeLower CIUpper CIN Total NCasesNTotal
Hazard Raos
Basse 2013 FFQ 0.88 0.61 1.25 1717464 2181
Basse 2013 serum FA 0.99 0.88 1.11 1717464 2181
Brasky 2011 low grade 1.18 0.97 1.44 18031658 3461
Brasky 2011 high grade 2.50 1.34 4.65 18031658 3461
Brasky 20131.391.061.82 1393834 2227
Pelser 2013 nonadv 1.02 0.98 1.07 269334 18934 288268
Pelser 2013 adv1.030.911.16 285338 2930 288268
Odds Raos
Cheng 20131.000.701.41 1369458 1827
Fradet 20090.360.250.53 478 466 944
Harvei 19971.000.501.80 141 141 282
Norrish 1999 FFQ 1.10 0.71 1.70 480 317 797
Norrish 1999 RBC FA 0.62 0.39 0.98 480 317 797
Park 20091.110.731.69 729 376 1105
Ukoli 2010 African American 1.57 0.60 4.12 125 48 173
Ukoli 2010 Nigerian 0.750.351.62 274 66 340
Williams 2011 0.820.401.68 187 79 266
Risk Raos
Chavarro 2007 0.600.390.93 476 476 952
Crowe 2008 1.39 1.02 1.90 926 926 1852
Leitzmann 2004 0.89 0.78 1.04 44901 2965 47866
Schuurman 1999 1.03 0.75 1.40 1525642 2167
Wallstorm 20071.261.001.59 10564 81711381
Measure of Effect & 95% CIs
Favors lower intake Favors higher intake
Figure 7. Risk of prostate cancer (PrCa) incidence with docosahexaenoic acid (DHA) intake: Observational data. When the effect of
total fish-derived omega-3 fatty acid intake on PrCa risk was not available, sub-analyses reporting on individual fatty acids or different
stages of cancer are reported.
some studies due to lack of blinding for participants and in
outcome assessment. Allocation concealment was unclear
in all studies. Among the 3 RCTs, 1 was industry funded,28
1 was non–industry funded,29 and 1 was funded by a combi-
nation.31 The 1 nonrandomized clinical trial did not use
blinding, had no loss to follow-up; and a priori sample size
estimation and funding source were unclear.32
Among the observational studies, the cohort studies,
case-control studies and case-cohort studies had an aver-
age score of 7.06, 7.27, and 8.33 out of 9, respectively, on
the Newcastle-Ottawa Quality Assessment Scale. Two
cohort studies were not assessed because full text publica-
tion in English was not available.42,44 The results are dis-
played in Figures 9, 10, and 11. The most notable
deficiency in both the cohort and case-control studies was
for the ascertainment of fish-derived omega-3 fatty acid
exposure as most studies relied on written, self-report of
dietary information rather than a structured interview.
Additionally, many of the case-control studies failed to
report the difference in nonresponse rate between cases
and controls. Among the observational studies, 40 were
funded by nonindustry sources, 2 by a combination of
industry and nonindustry sources,34,36 and 8 were unclear
in their reporting of funding.43,47,56-58,67-69
Discussion
Summary of Findings
The interventional studies of fish-derived omega-3 in
patients with PrCa showed no impact on PSA levels; how-
ever, some studies showed a decrease in inflammatory
markers. A small number of mild adverse events were
reported and interactions with other interventions were not
assessed. Cohort, case-cohort and case-control studies
assessing the risk of PrCa incidence were equivocal. Cohort
studies assessing the risk of PrCa mortality suggested an
association between higher intake and decreased risk. The
results of this review are consistent with other systematic
reviews conducted,70,71 which also assessed prevention and
secondary PrCa outcomes using diet and supplement expo-
sure and found no association.
Study Weaknesses: Method of Exposure
Ascertainment in Observational Studies
While all of the cohort studies assessed patient-reported
fish-derived omega-3 fatty acid intake to ascertain expo-
sure, case-control and nested case-control studies utilized
either patient questionnaires or blood levels to assess
Aucoin et al 49
Figure 8. Cochrane Risk of Bias Assessment of randomized
controlled trials (RCTs). (+), low risk of bias; (−), high risk of
bias; neither symbol, unclear risk of bias.
fish-derived omega-3 fatty acid exposure; however, both
have limitations. The method of assessing fish-derived
omega-3 fatty acid exposure may be of importance as more
of the studies utilizing blood levels reported an association
with increased risk of PrCa while more of the studies
assessing self-reported intake reported an association with
deceased risk of PrCa. A recent study compared the differ-
ent methods of fish intake assessment.72 They followed a
group of men with low-risk PrCa undergoing active sur-
veillance to first repeat biopsy and assessed relationships
between the risk of progression and the different methods
of fatty acid assessment—dietary recall, RBC fatty acids,
and prostate tissue fatty acids. While dietary intake and
RBC fatty acids were not correlated with risk of progres-
sion, men with the highest tertile of prostate EPA had a
significantly lower risk of progression (OR = 0.08, 95% CI
0.01-0.72, P = .02).
Blood assessment is limited by the challenge of differen-
tiating endogenously produced fats from those consumed
and the impact of individually varying rates of metabolism
and deposition in tissues as a result of genetic, dietary and
lifestyle differences.73 Additionally an individual fatty acid
is reported as a percentage of total fatty acids, not as an
absolute amount; as a result, larger intake of one fatty acid
could affect the relative proportion of others. Lastly, disease
can affect fatty acid levels; for example, tumors selectively
take up high amounts of polyunsaturated fatty acids.73
Among the studies included in this review that used blood
samples, 9 of 12 assessed plasma or serum fatty acids, 2
assessed RBC fatty acids and 1 assessed whole blood.
Plasma fatty acids are known to reflect short-term or recent
fat intake while RBCs reflect the previous 3 weeks’ to 3
months’ intake due to their longer life span.74 Considering
the length of time required for the pathogenesis of cancer-
ous lesions, these fatty acid evaluations that reflect rela-
tively recent intake may be of limited utility in assessing a
role in causation, particularly if the participant has made
changes to their diet over time.
Diet recall also presents challenges, including intention-
ally or unintentionally inaccurate recall and low reproduc-
ibility. Studies assessing the reproducibility of FFQs for
polyunsaturated fatty acids have found a Spearman correla-
tion coefficient from 0.38 to 0.59.75 With cancer known to
develop over a long period of time, some of the shorter
times between observation of exposure and outcome of
interest may neither be sufficient to allow for detection, pro-
gression, or substantive change, nor represent the time
when carcinogenesis or early cancer development occurred.
Conversely, when studies asked participants to recall dietary
patterns from 10 years ago, there could be concern about the
patients’ ability to do so accurately.
Possible Mechanisms of Protective Effect
There have been a number of proposed mechanisms by
which fish-derived omega-3 fatty acids may influence PrCa
risk or progression, largely related to their effect on decreas-
ing inflammation through inhibition of the cyclooxygenase
enzymes76 and affecting the immune system. Inflammation
is suspected to trigger PrCa progression77 and the use of
nonsteroidal anti-inflammatory drugs (NSAIDS) results in
a decreased risk of PrCa.61 In vitro studies assessing the
impact of fish oil on PrCa cells demonstrate increased can-
cer cell death,12 enhanced cytotoxic effects of docetaxel,13
prolongation of the androgen-dependent state,14 and inhibi-
tion of cell adhesion, invasion and migration, which effect
metastasis.15,16 A mouse study comparing diets based on
fish, olive, corn, or animal fat showed slowed tumor growth
and increased survival in the fish oil group.17
Alternatively, another factor in the fish may be exerting
an anticancer effect. Dietary fish is a source of vitamin D78
and while results are varied, vitamin D is suspected to have
a possible protective effect in prostate cancer.79 None of the
studies reviewed assessed vitamin D levels; however, one
study acknowledged that the protective effect of fish oil
supplementation may have been related to the vitamin D
50 Integrative Cancer Therapies 16(1)
02468101214161820
Representaveness of exposed cohort
Selecon of non exposed cohort
Ascertainment of exposure
Outcome of interesnt not present at study start
Study controls for most important factor
Study controls for secondary factors
Assessment of outcome
Follow up long enough for outcome to appear
Adequacy of follow up
Number of studies (n=19)
Yes
No
Figure 9. Newcastle-Ottawa Quality Assessment Scale: Cohort studies.
0510 15 20 25 30
Adequate case definion
Representaveness of cases
Selecon of Controls
Defino n of Controls
Study cont rols for most import ant factor
Study cont rols for secondary fact or
Ascertainment of exposure
Ascertainment method for cases and contro l
Non-Response Rate
Number of studies (n=26)
Yes
No
Figure 10. Newcastle-Ottawa Quality Assessment Scale: Case-control studies.
content found in fish liver oil, the most common form of
fish oil supplementation used in the study population.36
Possible Mechanisms of Harmful Effect
Some of the studies reviewed found associations between
higher fish-derived omega-3 fatty acid exposure and PrCa
incidence risk. No biological mechanism has been proposed
to explain these results. The studies suggesting harm were
more likely to be retrospective studies than prospective
studies and many showed a combination of harmful, protec-
tive or null effect, resulting in unclear conclusions. Although
they were of short duration, the intervention trials did not
produce results suggesting a risk in the form of side effects,
or negative effects on clinical outcomes such as laboratory
markers or mortality.
One study suggested that the omega-3:omega-6 ratio
might be of more importance than the absolute amount of
marine omega-3 intake because of their competitive metab-
olism and antagonistic effects on inflammation.61 The study
conducted by Joshi et al63 explored the relationship between
different types of fish, different methods of preparation, dif-
ferent levels of “done-ness” (ie, preconsumption cooking
and/or preparation) and the risk of PrCa. Fish that was pan-
fried or cooked to “well done” was associated with increased
risk while fish cooked “just until done,” “well done at low
Aucoin et al 51
0123
Adequate case definion
Representaveness of cases
Selecon of Controls
Definon of Controls
Study controls for most important factor
Study controls for secondary factor
Ascertainment of exposure
Ascertainment method for cases and control
Non-Response Rate
Number of studies (n = 3)
Yes
No
Figure 11. Newcastle-Ottawa Quality Assessment Scale: Case-cohort studies.
temperatures,” and “just done at high temperatures” was
not. The authors concluded that mutagenic heterocyclic
amines produced in cooking might be responsible for the
association.
Other studies hypothesized that environmental toxins, such
as polychlorinated biphenyls found in the fish that was
ingested,43 or involved in processing and packaging,62 could
be the biologically active constituent responsible for the asso-
ciation with cancer rather than the fatty acids EPA + DHA.
While not part of this systematic review, a brief search of
preclinical data yielded only 1 study showing procancer
effects of EPA at low concentrations in cancer cell lines.
The remaining 50 in vitro/in vivo studies reported antican-
cer effects or mechanisms of omega-3 fatty acids (Appendix
B). Unlike the observational studies that posed very large
challenges in assessing exposure, the cell culture and ani-
mal studies involved doses of fish oil exposure that were
was precisely known.
Alternatively, the relationship may be related to a behav-
ioral factor rather than a biological one. PrCa risk is
increased with increasing education, which may be associ-
ated with more health conscious behaviors such as consum-
ing dietary fish or fish oil supplements.80
Systematic Review Strengths and Limitations
Strengths of our review include a comprehensive search
including all interventional and observational studies con-
ducted in humans. Our methodology, including duplication
of screening and data extraction demonstrates reliability of
the synthesis.
One significant limitation of this review relates to pri-
mary research available and specifically the lack of well
designed, long duration studies examining the effects of
fish oil interventions in patients with or without PrCa. Of
the 4 interventional studies reported on, 3 studies were 3
months or shorter in duration, which may not be an ade-
quate length of time to observe a response to treatment, pro-
gression, recurrence of PrCa or to monitor long-term
adverse events. Because of the relatively small number of
studies assessing the role of fish oil in patients with PrCa,
the majority of the evidence included in this review assessed
primary prevention of PrCa. While this information may be
useful in understanding a potential anticancer or procancer
effect of these constituents, it is a significant limitation in
answering the original question of whether or not fish oil
supplementation is indicated in patients with PrCa. Because
the majority of the studies were observational, the results
provide limited information on causality and may reflect
correlations or other associations. Additionally, the methods
used to assess exposure possessed limitations. Although we
included a large number of studies, it was not possible to
pool the data due to heterogeneity.
Conclusions
Taken together, there are inadequate data to determine if
fish-derived omega-3 fatty acids are associated with PrCa
incidence and progression and how to advise PrCa patients
who are considering fish oil supplementation. Preliminary
research suggests that an association between higher
omega-3 intake and decrease PrCa mortality may be present
but more research is needed. Because of the challenges
related to assessing exposure, more intervention trials or
observational studies with precisely measured exposure and
longer duration are needed to assess the impact of supple-
mental or dietary fish-derived omega-3 fatty acid intake on
PrCa incidence, treatment and progression.
52 Integrative Cancer Therapies 16(1)
Appendix A
Prostate Cancer—Omega 3
Final Search Strategy
2014 Jul 21
OVID Searches
Database: AMED (Allied and Complementary Medicine) <1985 to July 2014>, Embase Classic+Embase <1947 to 2014
July 18>, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present>
Search Strategy:
——————————————————————————–
1 exp Prostatic Neoplasms/ (253131)
2 ((prostate or prostatic) adj3 (cancer* or carcinoid* or carcinoma* or carcinogen* or adenocarcinoma* or adeno-carci-
noma* or malignan* or neoplasia* or neoplasm* or sarcoma* or tumour* or tumor*)).tw. (230129)
3 ((prostate or prostatic) adj3 (anticancer* or anti-cancer* or anticarcinogen* or anti-carcinogen* or antineoplas* or anti-
neoplas* or chemoprevent* or chemo-prevent* or (tumo?r adj2 suppress*))).tw. (2285)
4 Prostate/de (3838)
5 Prostatic Hyperplasia/ (47434)
6 ((prostate or prostatic) adj3 (hyperplasia* or adenoma* or hypertroph* or enlarg*)).tw. (40106)
7 BPH.tw. (19805)
8 Prostate-Specific Antigen/ (55668)
9 (PSA or prostate-specific antigen* or prostatic-specific antigen* or gamma-seminoprotein* or (hK3 adj1 Kallikrein) or
semenogelase or seminin).tw. (76299)
10 or/1-9 (349314)
11 Fatty Acids, Omega-3/ (25712)
12 Eicosapentaenoic Acid/ (15147)
13 (eicosapentanoic acid* or icosapentaenoic acid* or icosapentaenoate or omega-3-eicosapentaenoic acid* or timn-
odonic acid* or eicosapen).tw. (600)
14 (“5,8,11,14,17-Eicosapentaenoic Acid” or “5,8,11,14,17-Icosapentaenoic Acid”).tw. (143)
15 EPA.tw. (24393)
16 Eicosapentaenoic Acid.rn. (4358)
17 exp Docosahexaenoic Acids/ (18855)
18 (docosahexaenoic acid* or docosahexaenoate or dhasco).tw. (18092)
19 dha.tw. (20493)
20 25167-62-8.rn. (17617)
21 (“omega 3” or omega3 or n-3 fatty acid* or n3 fatty acid* or n-3 polyunsaturated fatty acid* or n-3 poly-unsaturated
fatty acid* or n3 polyunsaturated fatty acid* or n3 poly-unsaturated fatty acid* or n-3 PUFA or n3 PUFA or PUFAs).tw.
(35392)
22 (Maxepa or Omacor).tw. (998)
23 or/11-22 (80037)
24 10 and 23 (816)
25 exp Fishes/ (309824)
26 exp Food/ (1803802)
27 exp Diet/ (439211)
28 25 and (26 or 27) (34591)
29 (fish$2 or fishoil* or shellfish$2 or shell fish$2 or seafood* or sea food* or marine*).tw. (403998)
30 28 or 29 (415408)
31 10 and 30 (2226)
32 24 or 31 (2842)
33 exp Animals/ not (exp Animals/ and Humans/) (8758181)
34 32 not 33 (2574)
35 (comment or editorial or interview or letter or news).pt. (2839640)
Aucoin et al 53
36 34 not 35 (2521)
37 36 use prmz (860)
38 exp prostate cancer/ (228398)
39 ((prostate or prostatic) adj3 (cancer* or carcinoid* or carcinoma* or carcinogen* or adenocarcinoma* or adeno-carci-
noma* or malignan* or neoplasia* or neoplasm* or sarcoma* or tumour* or tumor*)).tw. (230129)
40 ((prostate or prostatic) adj3 (anticancer* or anti-cancer* or anticarcinogen* or anti-carcinogen* or antineoplas* or
anti-neoplas* or chemoprevent* or chemo-prevent* or (tumo?r adj2 suppress*))).tw. (2285)
41 prostate hypertrophy/ (29272)
42 ((prostate or prostatic) adj3 (hyperplasia* or adenoma* or hypertroph* or enlarg*)).tw. (40106)
43 BPH.tw. (19805)
44 prostate specific antigen/ (55668)
45 (PSA or prostate-specific antigen* or prostatic-specific antigen* or gamma-seminoprotein* or (hK3 adj1 Kallikrein)
or semenogelase or seminin).tw. (76299)
46 or/38-45 (337349)
47 omega 3 fatty acid/ (28576)
48 icosapentaenoic acid/ (10789)
49 (eicosapentanoic acid* or icosapentaenoic acid* or icosapentaenoate or omega-3-eicosapentaenoic acid* or timn-
odonic acid* or eicosapen).tw. (600)
50 (“5,8,11,14,17-Eicosapentaenoic Acid” or “5,8,11,14,17-Icosapentaenoic Acid”).tw. (143)
51 EPA.tw. (24393)
52 1553-41-9.rn. (164)
53 icosapentaenoic acid.rn. (9979)
54 docosahexaenoic acid/ (13096)
55 (docosahexaenoic acid* or docosahexaenoate or dhasco).tw. (18092)
56 dha.tw. (20493)
57 25167-62-8.rn. (17617)
58 docosahexaenoic acid.rn. (11891)
59 (“omega 3” or omega3 or n-3 fatty acid* or n3 fatty acid* or n-3 polyunsaturated fatty acid* or n-3 poly-unsaturated
fatty acid* or n3 polyunsaturated fatty acid* or n3 poly-unsaturated fatty acid* or n-3 PUFA or n3 PUFA or PUFAs).tw.
(35392)
60 (Maxepa or Omacor).tw. (998)
61 or/47-60 (80408)
62 46 and 61 (839)
63 exp fish/ (173462)
64 exp food/ (1803802)
65 exp diet/ (439211)
66 63 and (64 or 65) (19916)
67 (fish$2 or fishoil* or shellfish$2 or shell fish$2 or seafood* or sea food* or marine*).tw. (403998)
68 66 or 67 (410094)
69 46 and 68 (2203)
70 62 or 69 (2836)
71 exp animal experimentation/ or exp models animal/ or exp animal experiment/ or nonhuman/ or exp vertebrate/
(37835447)
72 exp humans/ or exp human experimentation/ or exp human experiment/ (28781117)
73 71 not 72 (9055973)
74 70 not 73 (2577)
75 (editorial or letter).pt. (2524137)
76 74 not 75 (2527)
77 76 use emczd (1648)
78 prostatic neoplasms/ (119512)
79 ((prostate or prostatic) adj3 (cancer* or carcinoid* or carcinoma* or carcinogen* or adenocarcinoma* or adeno-
carcinoma* or malignan* or neoplasia* or neoplasm* or sarcoma* or tumour* or tumor*)).tw. (230129)
80 ((prostate or prostatic) adj3 (anticancer* or anti-cancer* or anticarcinogen* or anti-carcinogen* or antineoplas* or
anti-neoplas* or chemoprevent* or chemo-prevent* or (tumo?r adj2 suppress*))).tw. (2285)
54 Integrative Cancer Therapies 16(1)
81 exp prostatic hypertrophy/ (47487)
82 ((prostate or prostatic) adj3 (hyperplasia* or adenoma* or hypertroph* or enlarg*)).tw. (40106)
83 BPH.tw. (19805)
84 (PSA or prostate-specific antigen* or prostatic-specific antigen* or gamma-seminoprotein* or (hK3 adj1 Kallikrein)
or semenogelase or seminin).tw. (76299)
85 or/78-84 (315938)
86 fatty acids/ (172045)
87 (eicosapentanoic acid* or icosapentaenoic acid* or icosapentaenoate or omega-3-eicosapentaenoic acid* or timn-
odonic acid* or eicosapen).tw. (600)
88 (“5,8,11,14,17-Eicosapentaenoic Acid” or “5,8,11,14,17-Icosapentaenoic Acid”).tw. (143)
89 EPA.tw. (24393)
90 (docosahexaenoic acid* or docosahexaenoate or dhasco).tw. (18092)
91 dha.tw. (20493)
92 (“omega 3” or omega3 or n-3 fatty acid* or n3 fatty acid* or n-3 polyunsaturated fatty acid* or n-3 poly-unsaturated
fatty acid* or n3 polyunsaturated fatty acid* or n3 poly-unsaturated fatty acid* or n-3 PUFA or n3 PUFA or PUFAs).tw.
(35392)
93 (Maxepa or Omacor).tw. (998)
94 or/86-93 (230884)
95 85 and 94 (851)
96 fishes/ (141926)
97 exp food/ (1803802)
98 exp diet/ (439211)
99 96 and (97 or 98) (21782)
100 (fish$2 or fishoil* or shellfish$2 or shell fish$2 or seafood* or sea food* or marine*).tw. (403998)
101 99 or 100 (409563)
102 85 and 101 (2072)
103 95 or 102 (2769)
104 exp Animals/ not (exp Animals/ and Humans/) (8758181)
105 103 not 104 (2474)
106 (comment or editorial or interview or letter or news).pt. (2839640)
107 105 not 106 (2450)
108 107 use amed (7)
109 37 or 77 or 108 (2515)
110 remove duplicates from 109 (1778) [UNIQUE RECORDS]
111 110 use prmz (821) [MEDLINE RECORDS]
112 110 use emczd (956) [EMBASE RECORDS]
113 110 use amed (1) [AMED RECORD]
***************************
Cochrane Library
Search Name: Prostate Cancer - Omega 3
Date Run: 21/07/14 13:43:26.496
Description: Final 2014 Jul 21
ID Search Hits
#1 [mh “Prostatic Neoplasms”] 3374
#2 ((prostate or prostatic) near/3 (cancer* or carcinoid* or carcinoma* or carcinogen* or adenocarcinoma* or adeno-carci-
noma* or malignan* or neoplasia* or neoplasm* or sarcoma* or tumour* or tumor*)):ti,ab,kw 5130
#3 ((prostate or prostatic) near/3 (anticancer* or anti-cancer* or anticarcinogen* or anti-carcinogen* or antineoplas* or anti-
neoplas* or chemoprevent* or chemo-prevent* or (tumo*r* near/2 suppress*))):ti,ab,kw 48
#4 [mh Prostate/de] 103
#5 [mh “Prostatic Hyperplasia”] 1361
#6 ((prostate or prostatic) near/3 (hyperplasia* or adenoma* or hypertroph* or enlarg*)):ti,ab,kw 1980
Aucoin et al 55
#7 BPH:ti,ab,kw 856
#8 [mh “Prostate-Specific Antigen”] 998
#9 (PSA or prostate-specific antigen* or prostatic-specific antigen* or gamma-seminoprotein* or (hK3 near/1 Kallikrein) or
semenogelase or seminin):ti,ab,kw 2239
#10 {or #1-#9} 7311
#11 [mh ^”Fatty Acids, Omega-3”] 1258
#12 [mh “Eicosapentaenoic Acid”] 647
#13 (eicosapentanoic next acid*) or (icosapentaenoic next acid*) or icosapentaenoate or (“omega-3-eicosapentaenoic” next
acid*) or (timnodonic next acid*) or eicosapen:ti,ab,kw 260
#14 (“5,8,11,14,17-Eicosapentaenoic Acid” or “5,8,11,14,17-Icosapentaenoic Acid”):ti,ab,kw 1
#15 EPA:ti,ab,kw 830
#16 [mh “Docosahexaenoic Acids”] 694
#17 (docosahexaenoic next acid*) or docosahexaenoate or dhasco:ti,ab,kw 1399
#18 dha:ti,ab,kw 995
#19 “omega 3” or omega3 or ((“n-3 fatty” or “n3 fatty” or “n-3 polyunsaturated fatty” or “n-3 poly-unsaturated fatty” or “n3
polyunsaturated fatty” or “n3 poly-unsaturated fatty”) next acid*) or “n-3 PUFA” or “n3 PUFA” or PUFAs:ti,ab,kw 2804
#20 Maxepa or Omacor:ti,ab,kw 106
#21 {or #11-#20} 3714
#22 #10 and #21 21
#23 [mh Fishes] 218
#24 [mh Food] or [mh Diet] 29205
#25 #23 and #24 155
#26 fish or fishes or fishoil* or shellfish* or (shell next fish*) or seafood* or (sea next food*) or marine*:ti,ab,kw 3060
#27 #25 or #26 3064
#28 #10 and #27 17
#29 #22 or #28 33
DSR - 3
DARE - 2
CENTRAL - 27
Cochrane Groups - 1 (did not download)
CINAHL
2014 Jul 21
# Query Limiters/Expanders Results
S38 S35 NOT S36 Limiters: Exclude MEDLINE
records
Expanders: Apply related words
Search modes: Boolean/Phrase
57
S37 S35 NOT S36 Expanders: Apply related words
Search modes: Boolean/Phrase
113
S36 PT comment or editorial or interview or letter or news Expanders: Apply related words
Search modes: Boolean/Phrase
306 747
S35 S31 NOT S34 Expanders: Apply related words
Search modes: Boolean/Phrase
127
S34 S32 NOT (S32 AND S33) Expanders: Apply related words
Search modes: Boolean/Phrase
26 845
S33 (MH “Human”) Expanders: Apply related words
Search modes: Boolean/Phrase
848 532
S32 (MH “Animals+”) Expanders: Apply related words
Search modes: Boolean/Phrase
29 062
S31 S22 OR S30 Expanders: Apply related words
Search modes: Boolean/Phrase
130
(continued)
56 Integrative Cancer Therapies 16(1)
# Query Limiters/Expanders Results
S30 S10 AND S29 Expanders: Apply related words
Search modes: Boolean/Phrase
55
S29 S23 OR S27 OR S28 Expanders: Apply related words
Search modes: Boolean/Phrase
5992
S28 TI ( fish or fishes or fishoil* or shellfish* or (shell n1 fish*) or seafood* or
(sea n1 food*) or marine* ) OR AB ( fish or fishes or fishoil* or shellfish*
or (shell n1 fish*) or seafood* or (sea n1 food*) or marine* )
Expanders: Apply related words
Search modes: Boolean/Phrase
4355
S27 S24 AND (S25 OR S26) Expanders: Apply related words
Search modes: Boolean/Phrase
2413
S26 (MH “Diet+”) Expanders: Apply related words
Search modes: Boolean/Phrase
48 485
S25 (MH “Food+”) Expanders: Apply related words
Search modes: Boolean/Phrase
66 225
S24 (MH “Fish”) Expanders: Apply related words
Search modes: Boolean/Phrase
2413
S23 (MH “Seafood+”) Expanders: Apply related words
Search modes: Boolean/Phrase
2998
S22 S10 AND S21 Expanders: Apply related words
Search modes: Boolean/Phrase
96
S21 S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19
OR S20
Expanders: Apply related words
Search modes: Boolean/Phrase
5246
S20 TI ( Maxepa or Omacor ) OR AB ( Maxepa or Omacor ) Expanders: Apply related words
Search modes: Boolean/Phrase
22
S19 TI ( “omega 3” or omega3 or ((“n-3 fatty” or “n3 fatty” or “n-3
polyunsaturated fatty” or “n-3 poly-unsaturated fatty” or “n3
polyunsaturated fatty” or “n3 poly-unsaturated fatty”) n1 acid*) or “n-3
PUFA” or “n3 PUFA” or PUFAs ) OR AB ( “omega 3” or omega3 or
((“n-3 fatty” or “n3 fatty” or “n-3 polyunsaturated fatty” or “n-3 poly-
unsaturated fatty” or “n3 polyunsaturated fatty” or “n3 poly-unsaturated
fatty”) n1 acid*) or “n-3 PUFA” or “n3 PUFA” or PUFAs )
Expanders: Apply related words
Search modes: Boolean/Phrase
2309
S18 TI dha OR AB dha Expanders: Apply related words
Search modes: Boolean/Phrase
633
S17 TI ( (docosahexaenoic n1 acid*) or docosahexaenoate or dhasco ) OR AB
( (docosahexaenoic n1 acid*) or docosahexaenoate or dhasco )
Expanders: Apply related words
Search modes: Boolean/Phrase
684
S16 (MH “Docosahexaenoic Acids”) Expanders: Apply related words
Search modes: Boolean/Phrase
975
S15 TI EPA OR AB EPA Expanders: Apply related words
Search modes: Boolean/Phrase
801
S14 TI ( “5,8,11,14,17-Eicosapentaenoic Acid” or “5,8,11,14,17-Icosapentaenoic
Acid” ) OR AB ( “5,8,11,14,17-Eicosapentaenoic Acid” or
“5,8,11,14,17-Icosapentaenoic Acid” )
Expanders: Apply related words
Search modes: Boolean/Phrase
1
S13 TI ( (eicosapentanoic n1 acid*) or (icosapentaenoic n1 acid*) or
icosapentaenoate or (“omega-3-eicosapentaenoic” n1 acid*) or
(timnodonic n1 acid*) or eicosapen ) OR AB ( (eicosapentanoic n1
acid*) or (icosapentaenoic n1 acid*) or icosapentaenoate or (“omega-3-
eicosapentaenoic” n1 acid*) or (timnodonic n1 acid*) or eicosapen )
Expanders: Apply related words
Search modes: Boolean/Phrase
13
S12 (MH “Eicosapentaenoic Acid”) Expanders: Apply related words
Search modes: Boolean/Phrase
678
S11 (MH “Fatty Acids, Omega-3”) Expanders: Apply related words
Search modes: Boolean/Phrase
3404
S10 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 Expanders: Apply related words
Search modes: Boolean/Phrase
13 411
S9 TI ( (PSA or prostate-specific antigen* or prostatic-specific antigen* or
gamma-seminoprotein* or (hK3 N1 Kallikrein) or semenogelase or
seminin) ) OR AB ( (PSA or prostate-specific antigen* or prostatic-
specific antigen* or gamma-seminoprotein* or (hK3 N1 Kallikrein) or
semenogelase or seminin) )
Expanders: Apply related words
Search modes: Boolean/Phrase
2125
(continued)
Appendix A (continued)
Aucoin et al 57
# Query Limiters/Expanders Results
S8 (MH “Prostate-Specific Antigen”) Expanders: Apply related words
Search modes: Boolean/Phrase
2517
S7 TI BPH OR AB BPH Expanders: Apply related words
Search modes: Boolean/Phrase
401
S6 TI ( ((prostate or prostatic) N3 (hyperplasia* or adenoma* or hypertroph*
or enlarg*)) ) OR AB ( ((prostate or prostatic) N3 (hyperplasia* or
adenoma* or hypertroph* or enlarg*)) )
Expanders: Apply related words
Search modes: Boolean/Phrase
713
S5 (MH “Prostatic Hypertrophy”) Expanders: Apply related words
Search modes: Boolean/Phrase
1332
S4 (MH “Prostate/DE”) Expanders: Apply related words
Search modes: Boolean/Phrase
42
S3 TI ( ((prostate or prostatic) N3 (anticancer* or anti-cancer* or
anticarcinogen* or anti-carcinogen* or antineoplas* or anti-neoplas*
or chemoprevent* or chemo-prevent* or (tumo#r N2 suppress*))) )
OR AB ( ((prostate or prostatic) N3 (anticancer* or anti-cancer* or
anticarcinogen* or anti-carcinogen* or antineoplas* or anti-neoplas* or
chemoprevent* or chemo-prevent* or (tumo#r N2 suppress*))) )
Expanders: Apply related words
Search modes: Boolean/Phrase
59
S2 TI ( ((prostate or prostatic) N3 (cancer* or carcinoid* or carcinoma* or
carcinogen* or adenocarcinoma* or adeno-carcinoma* or malignan* or
neoplasia* or neoplasm* or sarcoma* or tumour* or tumor*)) ) OR AB
( ((prostate or prostatic) N3 (cancer* or carcinoid* or carcinoma* or
carcinogen* or adenocarcinoma* or adeno-carcinoma* or malignan* or
neoplasia* or neoplasm* or sarcoma* or tumour* or tumor*)) )
Expanders: Apply related words
Search modes: Boolean/Phrase
7,608
S1 (MH “Prostatic Neoplasms”) Expanders: Apply related words
Search modes: Boolean/Phrase
10,199
Appendix A (continued)
Appendix B
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Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
study was funded by a CIHR Knowledge Synthesis Grant (KRS
316843).
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