Download Systematic review The effects of supplementation of n

Systematic review
The effects of supplementation of n-3 polyunsaturated fatty
acids on clinical outcome parameters in patients with cancer:
a systematic review
Abstract
BS van der Meij1*, JD Bauer2, EA Isenring2, T Brown3, WL Davidson4,
MAE van Bokhorst1, JAE Langius1, PAM van Leeuwen5
Introduction
Existing guidelines on nutrition
support in patients with cancer cachexia state limited evidence for the
beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on clinical
outcome. In order to report on the
latest evidence for n-3 PUFAs in cancer cachexia, we conducted a systematic literature review of randomized
controlled trials (RCTs), comparing the effects on clinical outcome
parameters of oral or enteral supplementation of n-3 PUFAs in cancer
patients receiving chemotherapy, radiotherapy, surgery or palliative care.
Materials and methods
In PubMed, EMBASE and the
Cochrane Library, search terms on
cancer, n-3 PUFAs and clinical outcome parameters (nutritional status,
morbidity, mortality and quality of
life) were entered on 1 April 2013,
using limits for adults, humans and
English language. The quality and evidence of the retrieved publications
* Corresponding author
Email: [email protected]
epartment of Nutrition and Dietetics, InterD
nal Medicine, VU University Medical Center
Amsterdam, the Netherlands
2
Centre for Dietetics Research, School of
Human Movement Studies, University of
Queensland, Brisbane, Australia
3
Department of Nutrition and Dietetics, Royal
Brisbane & Women’s Hospital, Brisbane, Australia
4
Department of Nutrition and Dietetic Services, Princess Alexandra Hospital, Brisbane,
Australia
5
Department of Surgery, VU University Medical Center Amsterdam, the Netherlands
1
were appraised by an expert team of
Australian and Dutch dieticians and
nutritionists, using the ADA grading
system. Fifteen RCTs were retrieved.
Results
Nine RCTs were of positive quality,
five of neutral quality and one of negative quality and were performed in
patients with various types of cancer.
Fair evidence shows that supplementation of n-3 PUFAs appears to be
safe and may improve the quality of
life and physical activity in patients
with cancer. However, supplementation of n-3 PUFAs does not improve
energy or protein intake, appetite or
survival and does not reduce postoperative complications. The evidence
for the effect on body weight, fatfree mass and performance status
­remains inconclusive.
Conclusion
Supplementation of n-3 PUFAs may
have some positive effects in patients
with cancer.
Introduction
Cancer cachexia, a complex ­metabolic
syndrome associated with underlying
illness, characterized by an increased
inflammatory status and loss of muscle mass with or without loss of fat
mass, is highly prevalent among patients with cancer1–7. This syndrome
is a result of complex alterations
in carbohydrate, lipid and protein
metabolism8,9, caused by inflammatory mediators such as ­cytokines and
tumour-derived catabolic drivers10.
Proteolysis-inducing factor (PIF) is
produced by the tumour and induces
protein catabolism11. As a result of
the acute-phase response, the liver
shows an increased protein turnover
for the production of ­inflammatory
mediators, using muscle mass to release amino acids9,10.
Changes in lipid metabolism in
cancer include a reduction of lipogenesis, with unchanged whole-body
lipolysis and mobilization of fatty
acids from fat tissue. Alterations in
glucose metabolism are reflected
by glucose intolerance and insulin
­resistance8,9,11.
Thus far, conventional nutritional
support has been limited in its ability
to stabilize body weight and maintain fat-free mass in patients with cachexia. Pharmaceutical interventions
sometimes improved appetite, body
weight and quality of life, but weight
gain mostly consisted of fat mass12–15.
n-3 Polyunsaturated fatty acids
(PUFAs), especially eicosapentaenoic acid (EPA), seem to be promising
agents to treat cancer cachexia. A dose
of around 2 g of EPA per day (alone
or combined with docosahexaenoic
acid, DHA) appears to decrease the
production of proinflammatory cytokines16,17 and PIF and is associated
with stabilization of body weight
and probably fat-free mass13,18. This
has been shown in animal studies
and in nonrandomized human trials in pancreatic cancer patients19,20.
However, randomized controlled
trials (RCTs) show contradictory results21–26. This may be due to issues
related to study limitations, such as
the disease severity, confounding
factors and nonadherence with n-3
PUFA supplements. Also, study designs and outcome parameters differ
in terms of ­supplementation dosage,
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic Reviewers
Page 1 of 17
Page 2 of 17
c­omparison with control or other
agents and outcome parameters.
Body weight is the most frequently
used primary outcome measure, but
may be biased by fluid retention. Another important issue is the heterogeneity in the assessment of cachexia
and weight loss in clinical studies.
From clinical and research perspectives, there is a need for an
­updated literature overview on the
­effectiveness of n-3 PUFAs in patients with cancer27,28. In the past,
several reviews and nutrition guidelines have addressed the issue of
the prescription of n-3 PUFAs in
patients with cancer cachexia29–34.
Overall, these guidelines conclude
that there are some indications for
the beneficial effects of n-3 PUFAs on
body weight and physical function
in cancer patients, but no effects on
survival. The available reviews only
included studies that were published
before 200629,31,34. We ­previously
published a systematic review and
included studies published until
April 201135. Since then, there have
been several new studies23,36–38 and
reviews published in this field39–41.
Therefore, the aim of this systematic review is to report on the latest
evidence for the effects of n-3 PUFAs on clinical outcome parameters
in patients with cancer and provide
recommendations for use in clinical
practice.
Materials and methods
Patient characteristics
This systematic review of RCTs
­involved adult (≥ 18 years of age) patients with cancer.
Literature search
A literature search was performed on
1 April 2013, using three databases:
PubMed (start date 1948), EMBASE
(start date 1986) and the Cochrane
Library (start date 2005). Medical
subject headings (MeSH or Emtree)
and free text words for n-3 PUFAs,
EPA, cancer and clinical outcome
parameters (body weight, fat-free
mass, morbidity, ­mortality, length of
stay and quality of life) were used to
select relevant publications (supplementary Table 1). Any oral or enteral
administration of n-3 PUFAs was included: (fish oil) capsules, oral nutritional supplements (ONSs) or tube
feeding containing n-3 PUFAs. Studies investigating multiple immuneenhancing compounds (e.g. arginine,
glutamine, nucleotides and n-3 FAs)
or studies with concurrent use of
appetite stimulants were excluded.
The literature search was limited to
RCTs in adult human subjects, which
were available in ­
English. Nonplacebo-controlled studies and singlearm studies were excluded. In case
a study was reported in more than
one publication, the earliest publication reporting at least one relevant
outcome variable was included. Two
members of the expert committee
(BvdM and MvB) assessed the eligibility of ­publications on n-3 PUFAs
in cancer patients by reviewing the
title and abstract and included eligible studies. Moreover, reference lists
of included articles were reviewed to
identify eligible studies, which were
not retrieved by the literature search.
Study quality and strength of the
evidence
BvdM composed an expert team of
Australian and Dutch dieticians and
nutritionists during an International
Cancer Technology Transfer fellowship from the UICC in Brisbane, Australia. The aim of the expert team was
to appraise the included studies and
to compose evidence statements and
recommendations to be used for clinical practice.
Two independent members of the
expert team appraised the quality of
individual studies using the Quality
Criteria Checklist of the online accessible Evidence Analysis Library
of the American Dietetic Association
(ADA)42. The checklist includes four
relevance questions that address applicability to dietetic practice and
10 validity questions that address
s­ cientific soundness, most importantly on potential selection bias,
randomization and blinding procedures and the validity and reliability
of outcome parameters. Study quality
was rated as positive (+), neutral (∅)
or negative (–). No authors reviewed
their own papers.
BvdM extracted data of individual
studies, using a data extraction form,
which was composed by using templates from the Cochrane association
and the ADA. The data extraction
form contained all fields that were
considered relevant to address our
study aim, such as study eligibility, reason for exclusion, quality rating, details on study design, results
per outcome parameter, statistical
methods, author’s conclusions and
reviewer’s comments.
Following the quality appraisals,
all team members summarized and
assessed the strength of the evidence per outcome parameter. The
evidence summary was created by
adding up the numbers of studies
and number of patients reporting a
beneficial, negative or no effect on
an outcome parameter. The number
of good, neutral and negative quality
studies was also documented in this
summary. Consecutively, the ADA additional levels of evidence and grades
for recommendations for developers
of guidelines were used to grade the
evidence42. The ADA grading system
for recommendations has been developed to assist guideline developers in assessing the entire body of
evidence and indicating the strength
of each guideline recommendation.
According to the ADA system, RCTs
and meta-analyses obtain a class
‘A’ evidence. The ADA grades of recommendation—I Good, II Fair, III
Limited, IV Expert Opinion, V Not Assessable—were used to evaluate the
quality of studies and consistency of
findings across studies42.
Members of the expert team
reached consensus on the strength
of the evidence and the evidence
statements for effects on outcome
­
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic review
Page 3 of 17
Systematic review
PubMed®
search
Medical subject headings and keywords
Limits: humans and English language
Results
#1
n-3 PUFA
“Eicosapentaenoic Acid” [MeSH] OR “Fish Oils” [MeSH] OR “Fatty Acids, Omega-3” [MeSH] OR
“Docosahexaenoic Acids” [MeSH] OR “Fatty Acids, Unsaturated” [MeSH] OR eicosapentaen* OR
eicosapentaenoic OR docosahexaeno* OR (fatty acid*) OR EPA [tiab] OR MaxEPA [tiab] OR DHA
[tiab] OR (fish* AND oil*) OR omega3* OR omega-3* OR (omega 3*) OR (cod oil*) OR (marine
oil*)
41215
#2
Cancer
“Neoplasms” [MeSH terms] OR neoplasm* OR malignan* OR cancer OR carcino* OR tumor OR
tumour
844623
#3
Oral or enteral nutrition
enteral* OR supplement* OR sip OR feed OR formula* OR liquid OR tube OR nasogastric OR
nasojejunal OR nasoduodenal OR gastrostomy OR jejunostomy OR Enteral Nutrition” [MeSH]
132837
#4
Nutritional status
“cachexia” [MeSH] OR cachexi* OR cachectic OR wasting OR “weight loss” [MeSH] OR (weight
loss) OR (weight gain) OR “body weight” [MeSH] OR “body composition” [MeSH] OR appetite OR
“Energy Metabolism” [Mesh] OR energy OR REE OR TEE OR hypermetabolism
168621
#5
Morbidity
“Postoperative Complications” [MeSH] OR complications OR complication* OR “morbidity”
[MeSH] OR morbidit*
1119366
#6
Mortality
“mortality” [MeSH terms] OR “hospital mortality” [MeSH terms] OR mortalit* OR death* OR
survival OR “survival” [MeSH terms]
487681
#7
Length of stay
length of stay OR LOS OR “length of stay” [MeSH terms]
66749
#8
Quality of life
“quality of life” [MeSH terms] OR quality of life OR qol OR QoL OR “Karnofsky Performance Status” [MeSH] OR “Activities of Daily Living” [MeSH]
104200
#9
#4 OR #5 OR #6 OR #7 OR #8
1583988
#10
#1 AND #2 AND #3 AND #9
246
parameters. The team resolved conflicting appraisals by discussion and
consensus.
Results
Included studies
Fifteen RCTs in relation to n-3 PUFA
administration in patients with
­cancer were retrieved (Table 2).
The quality of studies differed: nine
studies were rated as positive quality21–24,26,37,43–45, five as neutral quality36,46–49 and one as negative quality38.
Five studies included patients with
unintentional, self-reported, weight
loss of more than 5%21,38,44,48 or more
than 10%43. Two studies excluded
either patients who reported ≥10%
of unintentional weight loss over the
previous 3 months37 or patients with
severe malnutrition, as assessed by
the Subjective Global Assessment
(SGA) tool for malnutrition49. One
study did not report details on nutritional status47, and the remaining
studies only reported on the percentage of patients who had malnutrition
at baseline (8–50%) without selecting patients with severe weight loss.
However, these studies used various
methods to identify malnutrition
(see Table 2)22,23,26,45,46.
n-3 PUFAs were supplemented via
(fish oil) capsules (0.3–4 g EPA)22,24,36–
38,47,48
, ONSs (2–2.3 g EPA)24,43–45,49 or
tube feeding (2.3–6 g EPA)23,46. One
study prescribed ONS preoperatively
and tube feeding postoperatively (2.3
g EPA)26.
Fish oil capsules
This paragraph describes the design of the seven RCTs supplementing n-3 PUFAs by fish oil capsules,
of which the quality was graded to
be positive21,22,37, neutral36,47,48 and
negative38 (Table 2). A number of
studies have been conducted in
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Supplementary Table 1 Example of search strategy in PubMed®; effects of enteral supplementation of n-3 PUFA on clinical outcome in cancer
Page 4 of 17
Search result:
575
PubMed
310
EMBASE
265
Duplicates: 94
Potential studies (title or abstract):
PubMed 69
EMBASE 34
Excluded: Pubmed 58
Excluded: EMBASE 29
Reasons for exclusion:
- non-RCTs: 25
- no enteral supplementation of n-3 FA: 10
- no clinical outcome parameters: 6
- multiple immune enhancing compounds
and/or use of appetite stimulants: 12
- no cancer: 5
- in vivo/in vitro: 0
- no adult: 0
Reasons for exclusion:
- non-RCTs: 4
- no enteral supplementation of n-3 FA: 13
- no clinical outcome parameters: 0
- multiple immune enhancing compounds
and/or use of appetite stimulants: 9
- no cancer: 3
- in vivo/in vitro: 0
- no adult: 0
PubMed 10 RCTs
EMBASE 5 RCTs
Reference lists: 0
Studies included: 15 RCTs
Figure 1: Flow chart of systematic literature search
­ atients who did not receive antip
cancer treatment. Gogos and colleagues randomized 64 patients
with generalized solid tumour types
to receive 18 fish oil or placebo
capsules daily until death22. Bruera
and colleagues randomized 91 advanced cancer patients who showed
weight loss and anorexia, to receive
18 fish oil or placebo capsules per
day. The duration of this study was
2 weeks, which is too short to reach
effects on nutritional parameters
and quality of life48. In a large double-blinded study, 429 patients with
gastrointestinal (GI) or lung cancer
without anticancer treatment were
randomized to receive 2 g or 4 g EPA
by a diester or a placebo during 8
weeks21.
Four small studies during chemotherapy have been described, of
which three studies were nonblinded36,38,47 and one was double ­blinded37. In a Japanese study,
16 ­patients ­undergoing chemotherapy and allogeneic bone marrow
transplantation were randomized to
receive oral EPA three times daily,
or no capsules47. Another study randomized 23 patients with colorectal
cancer. Intervention patients were
offered four fish oil capsules per
day (total 600 mg EPA + DHA) and
the control group did not receive
any supplements36. Bonatto and colleagues performed an 8-week intervention of 2 g fish oil per day in 38
patients receiving chemotherapy after cancer surgery; control patients
did not receive any supplements38.
Finocchiaro and colleagues studied
33 patients with advanced non-small
cell lung cancer undergoing chemotherapy, randomized to receive four
capsules (510 mg EPA and 340 mg
DHA) or placebo capsules37.
In these seven RCTs, loss to followup of patients varied from 7% to
50% [21, 22, 36, 37, 48] or was not
reported38,47. Adherence with the fish
oil capsules was established by plasma fatty acids or diaries21,37,48 or not
reported22,36,38,47.
Oral nutritional supplements
containing n-3 PUFAs
We identified five RCTs investigating the effects of ONS containing n-3
PUFAs in patients with cancer, most
of positive quality24,43–45 and one of
negative quality49.
In a large double-blinded study,
200 weight-losing pancreatic cancer patients were randomized to
receive n-3 PUFA-containing ONS or
an isonitrogenous control ONS24. In a
small subgroup (n = 24) of this study,
Moses and colleagues investigated
resting energy expenditure (REE) by
indirect calorimetry as well as total
energy expenditure (TEE) by ­doubly
labelled water22. Two studies investigated n-3 PUFA-containing ONS
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic review
Page 5 of 17
Systematic review
Table 2 Summary of randomized controlled trials on the role of EPA in patients with cancer
Gogos et al.
199822
Non-blinded
RCT
Positive
Aim
Study
population
Conclusions
limitations
Intervention
Outcomes
40 days
E: n = 30 18 g/
day fish oil capsules (max-EPA,
3.06 g EPA + 2.07
g DHA)
C: n = 30 18 g/
day placebo
capsules
Four patients (6.7%) dropped
out of the study because of poor
adherence
Energy intake—NA
Protein intake—NA
Weight—ns improvement
FFM—NA
Functional capacity—KPS after
40 days in malnourished patients receiving fish oil only
Quality of life—NA
Survival—increased in E group
only (P < 0.025 compared with C)
Other—no effect of fish oil
on albumin or transferrin. No
toxicity of fish oil except for
mild abdominal discomfort and
transient diarrhoea
n-3 PUFA
seemed
to prolong
survival and
improve KPS in
malnourished
patients with
generalized
malignancy
To investigate
the effect of
n-3 PUFA plus
vitamin E on the
immune status
and survival of
well-nourished
and malnourished patients
with generalized
malignancy
64 patients with
mixed solid
tumour types
(prevalence of
malnutrition at
baseline: 50%)
Takatsuka et al.
200147
Non-blinded
RCT
Neutral
To assess the
effectiveness
of prophylactic
oral EPA therapy
in preventing
complications
in patients who
received bone
marrow transplantation
n = 16 patients
undergoing
chemotherapy
and allogeneic
bone marrow
transplantation
from unrelated
donors (details
on nutritional
status not provided)
21 days before
to 180 days after
bone marrow
transplantation
E: n = 7 capsules
(1.8 g EPA)
C: n = 9 no capsules
Zero dropouts reported
Energy intake—NA
Protein intake—NA
Weight—NA
FFM—NA
Functional capacity—NA
Quality of life—NA
Survival—higher survival rate in
E group (E: n = 0 died vs. C: n = 5
died) (P < 0.01)
Other—reduced complications
in E group (E: n = 3 graft-vs.-host
disease, n = 4 no complications
vs. C: n = 6 graft-vs.-host disease,
n = 4 thrombotic microangiopathy, n = 4 CMV disease)
Survival rate
was significantly higher
in the group
given EPA, and
EPA significantly reduced
the complications of BMT
Bruera et al.
200348
Double-blinded
RCT
Neutral
To determine
whether high
doses of fish oil,
administered
over 2 weeks,
improve symptoms in patients
with advanced
cancer
87 advanced
cancer patients
(> 5% weight
loss)
2 weeks
E: n = 30 fish oil
capsules (mean
EPA 1.8 g)
C: n = 30 placebo
capsules
Sixty patients completed the
study (dropout 31%)
Twenty-seven patients (31%) did
not complete the study
Energy intake—↑51 kcal E vs.
↓57 C kcal (ns)
Protein intake—NA
Weight—↑0.03 kg E vs. ¯0.89
kg C (ns)
FFM—NA
Functional capacity—KPS ↑
10.0 E vs. ↓ 6.9 C (ns)
Quality of life—NA
Survival—NA
No effects on
outcome parameters after
2 weeks of n-3
PUFA supplementation
Nonadherence
with protocol
in both groups
10%
Definition of
malnutrition:
weight loss
>10%, low serum
albumin and
transferrin, KPS
<60
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Author, year
study design
quality
Page 6 of 17
Systematic review
To compare EPA
diethyl ester
with placebo in
cachectic cancer
patients for effects on weight
and fat-free
mass in patients
with advanced
cancer
n = 518 upper/
lower gastrointestinal and lung
cancer patients
Finocchiaro et
al. 201137
Double-blinded
RCT
Positive
To investigate
the effect of
EPA and DHA
vs. placebo
on inflammatory condition
and oxidative
and nutritional
statuses
n = 33 patients
with lung cancer
(patients with
≥10% weight loss
over the previous 3 months
were excluded)
66 days
E: n = 19 4 fish
oil capsules (510
mg EPA + 310
mg DHA)
C: n = 14 4 olive
oil capsules (850
mg)
Bonatto et al.
201138
Non-blinded
RCT
Negative
To investigate
the effect of fish
oil in patients
receiving
n = 38 patients
tumours at
various sites
(predominantly
gastrointestinal)
8 weeks
Fearon et al.
200621
Double-blinded
RCT
Positive
(≥5% weight
loss)
8 weeks
E1: n = 175: 95%
diester (2 g EPA)
E2: n = 172: 95%
diester (4 g EPA)
C: n = 171: placebo
Other—appetite, tiredness,
nausea, well-being (ns). Same
number of patients with gastrointestinal complaints in both
groups (E: n = 5, C: n = 5)
High dropout
rate due to
intolerance of
fish oil
At week 8, 270 patients remained (dropout 48%)
Energy intake—NA
Protein intake—NA
Weight— ↑1.2 kg (2 g EPA) vs.
C; ↑0.3 kg vs. placebo (4 g EPA),
P = 0.066
FFM—2 g EPA: 0.9 kg vs. C; 4 g
EPA: –0.1 vs. C (ns)
Functional capacity—KPS, weakness (ns)
Physical function and KPS—ns
Quality of life—2 g EPA: ↑ 4.3
physical functioning; 4 g EPA:
–3.4 (P = 0.04)
Survival—2 g EPA: 155 days; 4 g
EPA: 142 days; C: 140 days (ns)
Other—appetite, albumin, CRP,
nausea, vomiting, diarrhoea
(ns), supplements were well
tolerated, adverse events (ns),
serious adverse events not
related to supplements
The results
indicate no
significant
benefit from
single-agent
EPA in the
treatment
of cancer
cachexia
Twenty-seven patients completed
the study (E: n = 13, C: n = 14),
adherence was good
Energy intake—ns between groups
Protein intake—ns between
groups
Weight—E increase of 3.4 kg (P
< 0.05 vs. baseline), C stable, ns
between groups
FFM—NA
Functional capacity—NA
Quality of life—NA
Survival—NA
Other—albumin, thyroxin-binding
prealbumin and transferrin: ns between groups, CRP and IL-6 after
66 days lower in E than C group (P
< 0.05)
Increase in
body weight in
the n-3 group;
reduction in
inflammatory indexes
and oxidative
status
Small sample
size, no data
on FFM or
quality of life
Zero dropouts reported
EPA and DHA in polymorphonuE: n = 19 fish oil clear cells increased significantly
capsules 2 g/
and AA decreased significantly
days (0.3 g EPA + after 8 weeks
Fish oil
prevented
the decline
in neutrophil
number and
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Table 2 (Continued)
Page 7 of 17
Table 2 (Continued)
chemotherapy
following
­surgery for
removal of a
tumour
Silva et al.
201236
Non-blinded
RCT
Neutral
Fearon et al.
200324
Double-blinded
RCT
Positive
To check
whether there
is a change in
the markers of
inflammation
and/or nutritional status of
patients with
colorectal cancer undergoing
chemotherapy
who were supplemented with
2 g of fish oil,
compared with
the non-supplemented ones
To compare
a protein and
energy-dense
supplement enriched with n-3
PUFA and antioxidants with
an isocaloric
isonitrogenous
control supplement for effects
on weight, FFM,
dietary intake
and quality of
life in cachectic
patients with
advanced pancreatic cancer
(prevalence of
malnutrition
at baseline not
reported)
0.4 g DHA)
C: n = 19 no
capsules
Energy intake—NA
Protein intake—NA
Weight—E + 1.7 kg, C—2.5 kg (P
< 0.002 for difference between
groups)
FFM—NA
Functional capacity—NA
Quality of life—NA
Survival—NA
Other
n = 23 patients
9 weeks, during Five individuals did not
with colorecchemotherapy
­complete the study (1 E, 4 C)
tal cancer in
(starting at
Energy intake—NA
chemotherapy
the first day of
Protein intake—NA
treatment
chemotherapy)
Weight—difference between
(prevalence of
baseline and week 9 E: no differmalnutrition at
E: n = 11 2 g fish ence (P > 0.05), C: reduction (P
baseline: 0 %, ac- oil capsules (four = 0.01)
cording to BMI,
capsule, 200 mg FFM—NA
52.2% lost > 5% EPA + DHA per
Functional capacity—NA
and 26.1% lost > capsule)
Quality of life—NA
10%)
C: n = 12 capSurvival—NA
sules
Other—E: decrease in CRP/albumin ratio (P = 0.005)
function and
decreases of
body weight
during chemotherapy
Two hundred
untreated pancreatic cancer
patients (>5%
weight loss over
the previous 6
months)
Both E and C
supplements
attenuated
weight loss.
FFM in E only,
post-hoc analyses showed a
dose response
effect on
weight, FFM
and quality of
life in compliant E patients
Nonadherence
with protocol
in both groups
High dropout
rate due to
death
8 weeks
E: n = 95 high
protein and energy ONS + 2.2 g
EPA + 0.9 g DHA
C: n = 105
isonitrogenous
control ONS
Around 110 patients completed
the study (dropout 45%)
Energy intake—↑224 kcal E vs.
68 kcal C (ns); significant ↑ E
baseline to 8 weeks only
Protein intake—↑15 g E vs. 6 g
C (ns); significant ↑ E baseline
to 8 weeks only
Weight—↓0.37 kg E vs. ↓0.25 kg
C (ns); significant change in baseline to 8 weeks E and C; weight ↑
correlated with intake cans E only
FFM— ↑0.27 E vs. 0.12 C (ns); ↑
FFM correlated intake cans E only
Functional capacity
Physical function and KPS—ns
Quality of life—Global E vs. C
(ns); post-hoc analysis ↑ QoL
and ↑ weight E only
Survival—142 days E vs. 128
days C (ns)
Other—ONSs were well tolerated, adverse events (ns), serious
adverse events not related to
study supplements
Beneficial
effects on nutritional status
of the fish oil
supplement
No control
intervention;
adherence
with capsules
and plasma
fatty acids not
reported
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic review
Page 8 of 17
Systematic review
Table 2 (Continued)
Guarcello et al.
200743
Non-blinded
RCT
Positive
van der Meij
et al. 201135,
201250
Double-blinded
RCT
Positive
To investigate
the effects of an
ONS containing
n-3 PUFA on
TEE, REE and
PAL in homeliving cachectic
patients with
advanced pancreatic cancer
n = 24 patients
with advanced
pancreatic
cancer (>5%
weight loss over
the previous 6
months)
8 weeks
E: n = 9 high protein and energy
ONS + 2.2 g EPA
+ 0.9 g DHA
C: n = 15
isonitrogenous
control ONS
Five patients did not complete
the study (E: n = 3, C: n = 2).
Adherence: mean intake E: 1.9
cans/day, C: 1.5 cans/day (ns)
Energy intake—increased significantly in E patients compared
with baseline intake, trend when
compared with C patients
Protein intake—increased significantly in E patients compared
with baseline intake, trend when
compared with C patients
Weight—ns
FFM—ns
Functional capacity—NA
Quality of life—NA
Survival—NA
Other—REE, TEE and PAL of C
patients did not change significantly; TEE and PAL of E patients
increased significantly, REE did
not change; no significant differences between groups
To evaluate the n = 46 lung
60 days
Twenty-five patients completed
influence of an ­cancer patients
E: n = 26 high
the study (dropout rate 45.7%)
EPA-enriched,
undergoing
protein and en- Energy intake—E: ↑700 kcal (P
energy-dense
chemotherapy
ergy ONS + 2.2 g < 0.05 vs. baseline) vs. C: ↑ 170
oral supplement (>10% weight
EPA + 1.0 g DHA kcal
on inflammaloss over the
C: n = 20 isocaProtein intake—E: ↑20 g (P <
tory and nutriprevious 6
loric ONS
0.05 vs. baseline) vs. C: ↑4.4 g
tional status, as months)
Weight—increase in E (E: ↑ 0.9 kg
well as on the
(P < 0.05 vs. baseline), C: ↑ 0.0 kg
quality of life
FFM—NA
of lung cancer
Functional capacity—NA
patients
Quality of life—functional status
E: ↑ 13.3 vs. C: ↑ 10, symptom
scale EPA: ↓ 12.8 vs. C: ↓ 6.5 (P
< 0.05 vs. baseline)
Survival—ns
Other—E: appetite after 30 days:
↑ 2 (P < 0.05 vs. baseline), C ↑
1 (ns), ONSs were well tolerated
To investigate
n = 40 patients
5 weeks
Seven patients did not complete
the effects of an with lung cancer
the study (dropout rate 17.5%).
ONS containing undergoing
E: n = 20 high
Adherence: mean dose ~1 pack/
n-3 PUFA on nu- chemoradiother- protein and
day (1.1 g EPA)
tritional status
apy (prevalence energy ONS +
Energy intake—E ↑ 2,456 kJ vs.
and inflammaof malnutrition
2.02 g EPA + 0.92 C after 4 weeks (P = 0.03)
tory markers in at baseline: 20%) g DHA
Protein intake—E ↑ 12.4 g (P =
patients with
C: n = 20 isoca0.08), ↑ 25.0 g (P = 0.01) vs.
stage III NSCLC
Definition of
loric control ONS C after 1 week and 4 weeks
malnutrition:
Weight—E better weight
Administration
in EPA-containing ONS
was associated with an
increase in PAL
ONS containing n-3
PUFA seems
effective in
improving the
nutritional
status and
quality of life
of lung cancer
patients
undergoing
chemotherapy
Increase in
time in n-3
group reported, no
differences between groups
reported
A protein- and
energy-dense
ONS containing n-3
PUFA beneficially affects
nutritional
status during
multimodality
treatment in
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Moses et al.
200444
Double-blinded
RCT
Positive
Page 9 of 17
Systematic review
Trabal et al.
201049
Non-blinded
RCT
Neutral
undergoing
multimodality
therapy. Secondary effect
parameters
included quality
of life and functional status
>5% weight loss
over the previous month,
>10% weight loss
over the previous 6 months or
BMI < 18.5
To assess the
effect of an intervention with
an EPA-ONS on
chemotherapy
tolerability in
patients with
advanced colorectal cancer
n = 13 patients
with stage IV
colorectal cancer
that were going to receive
first-line chemotherapy treatment (severely
malnourished
patients according to SGA were
excluded)
maintenance than C after 1, 2
and 4 weeks
↑ 1.1 kg (P = 0.07), ↑ 1.3 kg (P
= 0.02), ↑ 1.7 kg (P = 0.04)
FFM—E less decrease vs. C, difference: 1.5 kg (P = 0.05), 1.9 kg
(P = 0.02) after 3 and 5 weeks
Functional capacity—KPS E ↑
5.3 vs. C after 3 weeks (P = 0.04)
Quality of life—physical and
cognitive function E ↑ 11.6 and
↑ 20.7 (P < 0.01) vs. C; global
health status E ↑ 12.2 and social
function ↑ 22.1 vs. C (P = 0.04)
Survival—NA
Other—physical activity: E ↑ 6.6
(P = 0.04), ↑ 2.5 (P = 0.05) vs. C
after 3 and 5 weeks
REE: E ↓ 16.7% of predicted (P =
0.01), ↓ 4 kJ/kg (P = 0.07) vs. C
after 3 weeks
patients with
NSCLC
Average
consumption
of study ONS
during chemoradiotherapy
was approximately 1 can/d
(1 g EPA)
Two patients (15.4%) did not complete the study. Adherence: mean
E: n = 5 high pro- dose 1.6 packs/day (1.6 g EPA)
tein and energy Energy intake—E group conONS + 2 g EPA
sumed on average 312 kcal more
+ 0.9 g DHA +
than C group (ns between groups)
dietary counsel- Protein intake—E group conling
sumed on average 18 g protein
C: n = 6 dietary
more than C group (ns between
counselling
groups)
Weight—E group weight gain
+4.94 kg vs. –1.17 kg (C), P =
0.045
FFM—NA
Functional capacity—NA
Quality of life—
GHS/QoL scale—E: 3.33 vs. C:
–6.94 (ns)
Physical function: –4 vs. –15.56
(ns)
Role function—E: 13.33 vs. 2.78
(ns)
Social function—E: 16.67 vs. C:
–13.89; P = 0.038
Fatigue—E: –4.44 vs. C: 11.11
(ns)
Pain–E: –10 vs. 2.78 (ns)
Loss of appetite—E: 6.67 vs. C:
–16.67 (ns)
Survival—NA
Improvement
in weight gain
and some
important domains of QoL
in advanced
colorectal
cancer patients taking
EPA-containing
ONS plus dietary counselling
Small sample
size, no EPA
vs. control
ONS
12 weeks
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Table 2 (Continued)
Page 10 of 17
Systematic review
Table 2 (Continued)
Kenler et al.
199646
Double-blinded
RCT
Neutral
Ryan et al.
200926
Double-blinded
RCT
Positive
To compare the
safety, gastrointestinal tolerance and clinical
efficacy of feeding an enteral
diet containing
n-3 PUFA/MCT
vs. an isonitrogenous, isocaloric formula
in patients undergoing major
abdominal surgery for upper
gastrointestinal
cancer
n = 50 patients
with upper gastrointestinal cancer (prevalence
of malnutrition
at baseline: 48%)
To examine the
effects of perioperative EPAenriched enteral
nutrition on the
metabolic, nutritional and immunoinflammatory response
to oesophagectomy, and on
postoperative
complications
n = 70 oesophageal
cancer patients
(prevalence of
mild, moderate or severe
malnutrition at
baseline: 63%, >
10% weight loss:
19%)
Definition of
malnutrition:
MUAMC <10th
percentile
Definition of
malnutrition:
NRI (combining
serum albumin
and weight loss)
7 days postoperative
Fifteen patients did not complete the study (dropout rate
30%)
n = 17 n-3 PUFA/ Energy intake—ns
MCT tube feed- Protein intake—ns, nitrogen baling (4.0 g EPA;
ance—ns
1.9 g DHA)
Weight—NA
n = 18 isocaloric, FFM—NA
isonitrogenous
Functional capacity—NA
control tube
Quality of life—NA
feeding
Survival—mortality (ns)
Other—number of infections,
length of stay, nitrogen balance
(ns)
Fewer gastrointestinal complications in n-3 PUFA group (P =
0.053); 50% reduction in the
total number of infections in n-3
PUFA group (P = 0.037); lower
number of infected patients
with more than one infection in
n-3 PUFA group (P = 0.09)
Safety parameters (serum biochemistry, electrolytes, haematology, blood coagulation) (ns)
Tube feeding
containing n-3
PUFA after surgery appears
to be safe, and
to reduce gastrointestinal
complications
and infections
5 days preoperative (ONS) to
21 days postoperative (tube
feeding)
n-3 PUFA supplemented by
early enteral
nutrition is associated with
preservation
of FFM postoesophagectomy compared
with a standard enteral
nutrition
Preoperative
vs. postoperative day
21 (P value of
comparison
between time
points)
Fifty-three patients completed
the study (dropout rate 24%)
Energy intake—postoperative
day 10 to 21: E: 645 kcal vs. C
710 kcal (ns)
Protein intake—ns
E: n = 28 high
Weight—E stable, C ↓ 1.8 kg. E
protein and
n = 2 (8%) >5% weight loss, C n
energy ONS or
= 10 (39%) comparison between
tube feeding +
groups: P = 0.03
2.3 g EPA + 1.0 g FFM—E +0.3 kg (P = 0.8 vs.
DHA
baseline) vs. C –1.9 kg (P = 0.03
C: n = 25 isocavs. baseline)
loric control ONS Functional capacity—NA
or tube feeding
Quality of life—NA
Survival—NA
Other—major complications and
gastrointestinal complaints (ns)
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Other chemotherapy adherence:
none of five E patients had to
delay or stop their chemotherapy; four of six control patients
experienced toxicity and interruption (ns); routine laboratory
parameters (ns)
Page 11 of 17
Systematic review
Table 2 (Continued)
To assess the
effect of perioperative n-3
PUFA on clinical
outcome and
immune function after oesophagogastric
cancer surgery
n = 195 patients
with oesophageal or gastric
cancer, undergoing subtotal
oesophagectomy and total
gastrectomy
(prevalence of
malnutrition at
baseline: 8.2%)
7 days preopera- About 53.3% did not reach the
tive and 7 days
maximum feeding rate. Volume
postoperative
of enteral nutrition received was
not different between E and C1
E: n = 63 n-3
groups
PUFA containing Energy intake—NA
tube feeding (±
Protein intake—NA
600 ml preopWeight—ns
erative and ±600 FFM—mid-upper arm muscle
to 1,200 ml
circumference (ns)
postoperative,
Functional capacity—NA
3.1–6.1 g EPA +
Quality of life—NA
Definition of
1.3–2.6 g DHA)
Survival—postoperative mortalmalnutrition:
C1: n = 66 stand- ity (ns)
>10% weight loss ard tube feeding Other—total number of infecC2: n = 66 stand- tions, proportion of patients
ard postoperawho developed an infection,
tive tube feeding those requiring therapeutic
antibiotics, other complications,
critical carestay, hospital stay
(ns)
Immune function (HLA-DR
expression on monocytes and
activated T lymphocytes) (ns)
n-3 PUFAsupplemented
enteral nutrition did not
affect immune
function or
clinical outcome following oesphagogastric cancer
surgery
C, control; DEXA, dual-energy x-ray absorptiometry; DHA, docosahexaenoic acid; E, experimental; EPA, eicosapentaenoic acid; KPS, Karnofsky performance
status; FFM, fat-free mass, NA, not assessed; ns, not significant; ONS, oral nutritional supplement; PAL, physical activity level; RCT, randomized controlled
trial; REE, resting energy expenditure; TEE, total energy expenditure.
interventions in patients with lung
cancer: Guarcello and colleagues
compared the effects of n-3 PUFAcontaining ONS with an isocaloric,
isonitrogenous control ONS43. van
der Meij and colleagues compared
the effects of an n-3 PUFA-containing
ONS with an isocaloric control ONS in
a double-blinded RCT45. In addition, a
very small (n = 13) non-blinded RCT
of negative quality compared the effect of n-3 PUFA-containing ONS with
dietary counselling in patients with
stage IV colorectal cancer, who were
not severely malnourished49.
Again, variable losses to follow-up
were reported: 18%45, 40.5%24 and
50%43. The adherence with study
supplements was >75% of the recommended dose in most studies24,43,44,49
and about 50% in one study45. In
some studies, plasma phospholipids
EPA were assessed as an objective
indicator of compliance with n-3
PUFA supplementation24,44,45. Limitations to the quality of two studies
included not reporting the betweengroup comparisons43,49 and not describing blinding and randomization
­methods43.
Enteral nutrition
Three studies investigated enteral nutrition containing n-3 PUFA
around cancer surgery (Table 2).
These included two large, high-quality double-blinded RCTs in patients
undergoing oesophagogastric cancer
surgery. The first trial administered
n-3 PUFA-containing ONS 5 days preoperatively and n-3 PUFA-containing
tube feeding during 21 days postoperatively26. In the second large trial,
n-3 PUFA-containing enteral nutrition, or an isonitrogenous control enteral nutrition, was administered 7
days before and after surgery. A third
group only received standard enteral
nutrition during 7 days postoperatively23. A smaller study performed
a relatively short (7 days) postoperative intervention with n-3 PUFAcontaining enteral nutrition in 50
patients with upper GI cancer46.
Dropout rates of 12%23, 24%26
and 30%46 were reported, and due
to tolerance issues, enteral nutrition goals were not always reached
in two studies23,46. One study did not
specify blinding and randomization
methods46. One study, although of
high quality, did not report betweengroup differences for body weight
and fat-free mass, but only withingroup differences over time26.
Strength of the evidence
Appetite
It is suggested that n-3 PUFAs reduce
the inflammatory response, thereby
improving appetite. In five studies,
n-3 PUFAs did not affect appetite
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Sultan et al.
201223
Double-blinded
RCT
Positive
Page 12 of 17
Systematic review
Recommendation
n-3 PUFA supplementation does not
improve appetite (grade II).
Energy and protein intake
Energy intake was reported in seven
studies (n = 443, Fearon 2003 +, van
der Meij 2010 +, Finocchiaro +, Guarcello +, Moses +, Bruera ∅, Trabal
∅)24,37,43–45,48,49 and protein intake in
six studies (n = 356; Fearon 2003 +,
van der Meij 2010 +, Finocchiaro +,
Guarcello +, Moses +, Bruera ∅)24,37,43–
45,48
. There was no significant increase
in energy48 or both energy and protein intake with n-3 PUFAs (capsules
or ONS) compared with a control
supplement (n = 373, Fearon 2003
+, van der Meij 2010 +, Finocchiaro
+, Bruera ∅, Trabal ∅)24,37,45,48,49. One
study reported within-group clinically meaningful improvements in energy and protein intake with an n-3
PUFA ONS, but not in the group receiving the control ONS (+700 kcal/
day and +20 g protein/day vs. +170
kcal/day and+4.5 g protein/day) (n
= 46, Guarcello +)43, and one study
reported improved protein intake in
patients receiving the n-3 PUFA-containing ONS (+27 g/day vs. control +
4 g/day) (n = 24, Moses +)44.
Recommendation
There is no evidence that n-3 PUFA
supplementation influences energy
and protein intake (grade II).
Body weight
Results from 12 studies show
equivocal effects on stabilization
or improvement of body weight
after ­supplementation of n-3 PU-
FAs in cancer patients: five studies
did not find significant differences
between n-3 and control groups
(n = 570, Fearon 2003 + Moses +,
Gogos +, Sultan +, Bruera ∅); one
study observed a tendency for body
weight maintenance in the n-3 PUFA
group ­receiving 2 g EPA by diester
­emulsion, as compared with groups
receiving 4 g EPA or a placebo emulsion (n = 518, Fearon 2006 +)21; three
studies observed a significant body
weight maintenance in the n-3 PUFA
group versus a control intervention
(n = 91, van der Meij 2010 +, Trabal
∅, Bonatto –)38,45,49; and three studies
demonstrated a within-group weight
maintenance over time in the
n-3 PUFA group (n = 102, Silva ∅,
­Guarcello +, Finochiaro ∅)36,37,43.
Recommendation
The effects of n-3 PUFA supplementation on body weight maintenance
are inconclusive (grade II).
Fat-free mass
Five studies measured the effect of
an n-3 PUFA ONS on fat-free mass.
Three studies did not observe difference for fat-free mass as compared
with a control intervention (n = 742,
Fearon 2006 +, Fearon 2003 +, Moses
+)21,24,44. One study observed a better
maintenance of fat-free mass in patients with lung cancer receiving n-3
ONS, as compared with a control ONS
(n = 40, van der Meij 2010 +)45, and
one study observed a maintenance
of fat-free mass over time in patients
receiving n-3 PUFA-containing ONS
and enteral nutrition around oesophageal cancer surgery (n = 70, Ryan
+)26.
Recommendation
The effects of n-3 PUFA supplementation on fat-free mass are inconclusive (grade II).
Karnofsky performance status
Two large studies reported no
improvements in Karnofsky performance status with n-3 PUFAs
(n = 605, Fearon 2006 +, Bruera
∅)21,48. However two smaller positive quality studies (n = 104, van der
Meij 2012 +, Gogos +)22,50 reported
improvements in Karnofsky performance status.
Recommendation
The effects of n-3 PUFA supplementation on Karnofsky performance
status are inconclusive (grade II).
Quality of life
ONS containing n-3 PUFAs improved
global health status, physical, cognitive, and social function compared
with a control intervention in a small
study (n = 40, van der Meij 2012 +)50;
another small study only observed
a significant improvement in social
function in the n-3 PUFA group, not
in other quality-of-life parameters
(n = 13, Trabal ∅)49; one large study
found a trend for improved physical function in patients receiving 2
g EPA by a diester emulsion, compared with 4 g EPA or a placebo (n =
518, Fearon 2006 +)21; and one small
study found reduced tiredness to be
correlated with the n-3 PUFA dose
(n = 87, Bruera ∅)48. A small study
observed a within-group improvement of functional status and symptom scores over time in the n-3 PUFA
group (n = 46, Guarcello +)43. A large
positive trial did not find significant
differences for quality-of-life parameters (n = 200, Fearon 2003 +)24.
Recommendation
n-3 PUFA supplementation has modest beneficial effects on some aspects
of quality of life (grade II).
Physical activity level
Two small studies investigated the
effects of n-3 PUFA-containing ONS
on parameters of physical activity
(n = 64, Moses +, van der Meij 2012
+)44,50.
In one study in pancreatic cancer
patients, TEE (measured by doubly
labelled water) increased after 8
weeks in the group receiving the n-3
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
when compared with controls (van
der Meij 2012 +, Fearon 2003 +, Trabal ∅, Fearon 2006 +, Bruera ∅) (total
n = 858)21,24,45,48,49. One positive quality study found an improvement in
appetite over time (30 days, though
not after 60 days) in patients with
lung cancer receiving n-3 PUFA ONS,
but not in control patients (n = 46,
­Guarcello +)43.
Page 13 of 17
Systematic review
Recommendation
n-3 PUFA supplementation appears
to have beneficial effects on ­physical
activity in patients with cancer
(grade III).
Complications
In one small neutral quality study,
n-3 PUFA capsules reduced complication rate in bone marrow transplant
(BMT) patients (n = 16, Takatsuka
∅)47. Three studies investigated the
effects of a single n-3 PUFA intervention in the absence of multiple immune-enhancing compounds around
cancer surgery. One study observed a
significant reduction in infections in
the n-3 PUFA group (n = 50, Kenler
∅)46, contrary to a large study that did
not observe differences for infectious
complications (n = 195, Sultan +)23.
Furthermore, there were no effects
of n-3 PUFAs (by ONSs and/or tube
feeding) on major complications (n =
248, Ryan +, Sultan +)23,26.
Recommendations
n-3 PUFAs (by ONSs or tube feeding)
do not reduce complication rate in
cancer patients undergoing surgery
(grade II).
n-3 PUFA capsules may reduce
complication rate in BMT patients
­
(grade III).
Survival
There are seven studies that have
reported on the effects of n-3 PUFA
supplementation on survival. Three
large RCTs of positive quality (n =
913, Fearon 2003 +, Fearon 2006 +,
Sultan +)21,23,24 and two small RCTs
did not find improvement of survival
after supplementation of n-3 PUFAs,
via capsules, ONS or enteral nutrition
(n = 120, Kenler ∅, Ryan +)21,24. One
study found significantly longer survival in the group receiving n-3 PUFA
capsules (n = 64, Gogos +)22. Another
study demonstrated improved survival in patients who received n-3
PUFA capsules around BMT, but this
study had very small numbers (n =
16, Takatsuka ∅)47.
Recommendation
n-3 PUFA supplementation does not
improve survival (grade II).
Safety and GI tolerance
Other important issues include the
safety and tolerance of n-3 PUFA supplementation. Of the 15 retrieved
studies, 10 reported on tolerance or
adverse events during supplementation of n-3 PUFA.
Among the seven studies supplementing n-3 PUFA by capsules (n =
661), two studies observed GI side
effects in the n-3 PUFA group slightly
more frequently than in the control
group (P value not reported) (n =
120, Bruera ∅, Finocchiaro +)37,48. Another study reported adverse events
in n-3 PUFA and control groups; no
serious adverse events were related
to the study capsules (n = 518, Fearon
2006 +)21. Furthermore, in one small
study, no side effects related to fish
oil capsules were reported (n = 23,
Silva ∅)36.
In studies applying n-3 PUFAcontaining ONS (five studies, n =
299), two studies reported adverse
events in both groups and no serious
­adverse events related to n-3 PUFA
(n = 240, Fearon 2003 +, van der Meij
2010 +)24,45. Another study reported
excellent tolerance of the n-3 PUFAcontaining ONS (n = 46, Guarcello
+)43. Others reported chemotherapy
delays in both n-3 PUFA and control groups, but numbers were too
small to test for statistical significance (n = 53, Trabal ∅, van der Meij
2012 +)49,50.
In studies using enteral nutrition
in upper GI surgery patients, GI complaints and intolerance to the enteral
nutrition were similar in n-3 PUFA
and control groups (n = 315, Ryan +,
Sultan +, Kenler ∅)23,26,46. One study
reported minor GI complaints (no
serious adverse events) in both n-3
and control groups (n = 70, Ryan
+)26 and another study observed
slightly more GI complaints in the
control group (P value not reported,
n = 50, Kenler ∅)46. In one study, only
50% of the overall study population
reached the aimed feeding rate owing to problems with tolerance and/
or complications, such as diarrhoea,
ileus, nausea, vomiting or bloating (n
= 195, Sultan +)23.
Recommendations
n-3 PUFA supplementation by capsules or ONS appears to be safe to administer in cancer patients receiving
chemo(radio)therapy or palliative
care (grade II).
Intolerance to enteral nutrition
around upper GI cancer surgery does
not appear to be related to n-3 PUFAs
(grade II).
Discussion
The authors have referenced some of
their own studies in this ­systematic
review. These referenced studies
have been conducted in accordance
with the Declaration of Helsinki
(1964), and the protocols of these
studies have been approved by the
relevant ethics committees related
to the institution in which they were
performed. All human subjects, in
these referenced studies, gave informed consent to participate in
these studies.
This literature review gives an upto-date overview on the available
evidence for the effects of n-3 PUFAs
on clinical outcome parameters in
patients with cancer. We conclude
that fair evidence shows that supplementation of n-3 PUFA appears to
be safe and may improve the quality
of life and physical activity. However,
supplementation of n-3 PUFA does
not influence energy or protein intake, appetite, or survival in cancer
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
PUFA-containing ONS, not in the control group44. The second study was
performed in lung cancer patients.
Physical activity assessed by an accelerometer was higher in patients
with lung cancer receiving n-3 PUFA
ONS during 5 weeks of chemoradiotherapy50.
Page 14 of 17
patients. Effects on body weight, fatfree mass and performance status
are equivocal: around half of studies
find beneficial effects while others do
not show differences compared with
control interventions. Moreover, fair
evidence shows that supplementation does not reduce postoperative
complications.
These conclusions were drawn
after a systematic qualitative evidence analysis of studies published
until April 2013, carried out by an
international expert team. In order
to objectively evaluate the effects of
n-3 PUFAs in cancer, a meta-analysis
on this subject is required, but the
variability in study designs makes
it yet impossible to carry out metaanalyses. Also, some authors report
between-group differences, whereas
others only report within-group differences.
Thus far, conclusions from metaanalyses and systematic reviews on
this topic were equivocal and did
not strongly recommend supplementing n-3 PUFAs in patients with
cancer34,40,51. These reviews included
studies published until 2005/2006.
The current systematic review includes publications until April 2013,
in this way providing a new update.
Supplementation of n-3 PUFAs
appeared to be safe, but the way in
which they interact with anticancer
treatment needs to be further unravelled. EPA and DHA can inhibit
tumour growth through apoptosis,
inhibition of angiogenesis, and alterations to cell signalling52,53. An
improved response to chemotherapy
by n-3 PUFAs has also been observed
in clinical studies in patients with
lung54 and breast55 cancer. In most
included RCTs, chemotherapy outcomes in patients who received n-3
PUFAs appeared to be comparable
with ­
control patients. On the contrary, findings from a study in mice
found that platinum-induced PUFAs, metabolites of n-3 PUFAs from
algae and fish oil, were involved in
the resistance to platinum-based
c­ hemotherapy. ­Supplements containing pure EPA did not cause chemotherapy resistance56. It is yet unclear
if these metabolites are abundant in
all n-3 PUFA supplements, and if the
same resistance occurs in humans.
As such, it might be oversimplified
to discourage dietary n-3 PUFAs in
patients with cancer57. When supplementation of n-3 PUFAs during
chemotherapy is considered, it is recommended to use purified n-3 PUFA
supplements instead of less refined
whole fish oil or algae supplements,
and to carefully assess patients
chemotherapy outcomes in future
trials investigating n-3 PUFA supplements27.
A limitation of this review is the
heterogeneity of the 15 available
studies. The trials differed in terms
of patient populations, inclusion and
exclusion criteria, intervention strategies and study durations. The administered dose ranged from 300 mg
to 6 g of EPA, and in some studies, especially the studies with fish oil capsules, patient adherence with study
supplements was not documented.
In addition, the study populations are
heterogeneous in terms of nutritional status and cachexia. Some studies selected patients on the degree
of weight loss; others did not apply
an inclusion criterion on nutritional
status or cachexia. Some studies did
not have adequate statistical power:
around half of the studies were small
(10 studies included 60 or fewer participants). The large studies had a
high dropout rate (around 50%): this
may also have biased the results.
Apart from immune-modulating
effects of n-3 PUFAs in patients with
cancer cachexia, additional energy
and protein are required for body
weight maintenance and synthesis
of lean tissue. The effect of n-3 PUFAs combined with additive energy
and protein on nutritional status is
expected to be larger than the effect of a single n-3 PUFA intervention. Apart from the study of Trabal
and colleagues, all included studies
­rovided comparable amounts of
p
energy and protein and nutritional
counselling in both intervention and
control groups. As a result, these
studies ­investigated the pure effect of
n-3 PUFAs, provided that both groups
consumed a comparable amount of
n-3 PUFAs by normal foods. None of
the studies described the consumption of fish or other foods containing
n-3 PUFAs, such as walnuts containing alpha-linolenic acid. Alternatively, only a few studies checked the
plasma phospholipid EPA concentration as a measure of n-3 PUFA intake.
Study design is a limiting factor
when addressing the evidence of
n-3 PUFAs in cancer patients. The
­adherence to the study intervention
was not always monitored; suboptimal adherence to n-3 PUFA supplements could have resulted in a lack of
effect. Future trials should consider
a choice of supplementation format
(capsules or liquid), or the use of n-3
PUFA-containing enteral or parenteral nutrition, in order to improve
patients’ adherence.
The nutritional parameters also
differ between studies. Body weight
is widely used but is unreliable in case
of ascites or oedema and gives no information on body composition. Even
so, bioelectrical impedance analysis
to measure fat-free mass might be
unreliable in patients with cancer. CT
image analysis or dual-energy x-ray
absorptiometry is preferred as the
method to precisely quantify skeletal
muscle41,58. Ultimately, positive effects on body composition should be
translated to improvements of quality of life. A few RCTs observed positive effects of n-3 PUFAs on both body
weight and quality of life; the latter is
more relevant to patients with cancer43,45,49,50. Still, we need more large
RCTs confirming this relationship.
Conventional nutritional interventions for cancer patients have
limited effects on clinical endpoints
or the quality of life during chemotherapy59,60 or palliative care59. If
­supplementation of n-3 PUFAs does
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic review
Page 15 of 17
improve cancer cachexia parameters,
such as body weight and quality of life,
the effect is relatively small. Therefore, more benefits are expected from
combination treatments including
anticatabolic and orexigenic agents
and n-3 PUFAs61. In a five-arm RCT
in patients with cachexia, the combination regimen that included the administration of an appetite stimulant,
ONS with EPA and DHA, L-carnitine,
and thalidomide was shown to be the
most effective treatment in terms of
lean body mass, REE and fatigue62.
Another promising intervention to
improve fat-free mass and physical
function is physical exercise training
with resistance training. Accumulating
evidence suggests beneficial effects
of physical exercise training during
chemotherapy, but a combination intervention of training and nutritional
counselling or nutritional supplementation has yet to be studied. Rogers
and colleagues are currently conducting an open-label, prospective RCT on
EPA, the COX-2 inhibitor celecoxib,
combined with leucine supplementation and resistance training63.
Nutritional interventions are often
offered in patients with nutritional issues and weight loss; prophylactic nutritional intervention is not standard.
New insights suggest that early nutritional intervention in patients with
early-stage cachexia could be more effective than interventions in patients
with advanced cancer cachexia, but to
our knowledge, few studies on this topic have been published64–66. Recently, a
proposal for the definition of cancer
cachexia has been published, and attention has been paid to the identification of ­patients with ‘pre-cachexia’ as a
probable indication to start nutritional
intervention12,67. However, ­definitions
of cachexia and pre-cachexia need to
be validated and further refined.
Conclusion
This review helps clinicians to decide
on the prescription of n-3 PUFAs in
patients with cancer cachexia. There
is increasing evidence that n-3 PUFAs
are safe to administer to cancer patients and can improve quality of life
and physical activity. However the evidence for beneficial effects on body
weight and fat-free mass remains inconsistent. Research should focus on
early intervention and on multimodal
treatment strategies, with attention
to the adherence and feasibility of
n-3 PUFA supplementation methods.
Acknowledgements
This work was supported by an International Cancer Technology Transfer
fellowship from the I­nternational
­Union Against Cancer (UICC), ­Geneva,
Switzerland.
Abbreviations list
ADA, American Dietetic Association;
BMT, bone marrow transplant; EPA,
eicosapentaenoic acid; GI, gastrointestinal; ONS, oral nutritional supplement; PIF, proteolysis-inducing
factor; PUFA, polyunsaturated fatty
acid; RCT, randomized controlled trial; REE, resting energy expenditure;
SGA, Subjective Global Assessment;
TEE, total energy expenditure
References
1. Bennani-Baiti N, Davis MP. Cytokines
and cancer anorexia cachexia syndrome.
Am J Hosp Palliat Care. 2008 Oct–
Nov;25(5):407–11.
2. Khalid U, Spiro A, Baldwin C, Sharma
B, McGough C, Norman AR, et al. Symptoms and weight loss in patients with
­gastrointestinal and lung cancer at presentation. Support.Care Cancer. 2007
Jan;15(1):39–46.
3. Gioulbasanis I, Georgoulias P, Vlachostergios PJ, Baracos V, Ghosh S, Giannousi Z, et al. Mini Nutritional ­Assessment
(MNA) and biochemical markers of
cachexia in metastatic lung cancer patients: Interrelations and associations
with prognosis. Lung Cancer. 2011 Dec;
74(3):516–20.
4. Barber M.D. The pathophysiology and
treatment of cancer cachexia. Nutr Clin
Pract. 2002 Aug;17(4):203–9.
5. Evans WJ, Morley JE, Argilés J, Bales C,
Baracos V, Guttridge D, et al. Cachexia:
A new definition. Clin.Nutr. 2008 Dec;
27(6):793–9.
6. Laviano A, Meguid MM. Nutritional issues in cancer management. Nutrition.
1996 May;12(5):358–71.
7. Tchekmedyian NS. Costs and benefits
of nutrition support in cancer. Oncology
(Williston Park). 1995 Nov;9(11 Suppl.):
79–84.
8. Argilés JM, Olivan M, Busquets S,
López-Soriano FJ. Optimal management
of cancer anorexia-cachexia syndrome.
Cancer Manag Res. 2010 Jan;2:27–38.
9. Tisdale MJ. Cancer cachexia. Curr Opin
Gastroenterol. 2010 Mar;26(2):146–51.
10. Stephens NA, Skipworth RJ, Fearon
KC. Cachexia, survival and the acute phase
response. Curr Opin Support ­Palliat Care.
2008 Dec;2(4):267–74.
11. Tisdale MJ. Metabolic abnormalities
in cachexia and anorexia. Nutrition. 2000
Oct;16(10):1013–4.
12. Muscaritoli M, Anker SD, Argilés J,
Aversa Z, Bauer JM, Biolo G, et al. Consensus definition of sarcopenia, cachexia and
pre-cachexia: Joint document elaborated
by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases”
and “nutrition in geriatrics”. Clin Nutr.
2010 Apr;29(2):154–9.
13. Jho DH, Cole SM, Lee EM, Espat NJ.
Role of omega-3 fatty acid supplementation in inflammation and malignancy. Integr Cancer Ther. 2004 Jun;3(2):
98–111.
14. Kumar NB, Kazi A, Smith T, Crocker
T, Yu D, Reich RR, et al. Cancer cachexia:
traditional therapies and novel molecular
mechanism-based approaches to treatment. Curr Treat Options Oncol. 2010
Dec;11(3–4):107–17.
15. Baldwin C. Nutritional support for
malnourished patients with cancer.
Curr Opin Support Palliat Care. 2011
Mar;5(1):29–36.
16. Mayer K, Meyer S, Reinholz-Muhly
M, Maus U, Merfels M, Lohmeyer J, et al.
Short-time infusion of fish oil-based lipid emulsions, approved for parenteral
nutrition, reduces monocyte proinflammatory cytokine generation and adhesive
interaction with endothelium in humans.
J Immunol. 2003 Nov;71(9):4837–43.
17. Barber MD, Ross JA, Preston T, Shenkin
A, Fearon KC. Fish oil-enriched nutritional supplement attenuates progression
of the acute-phase response in weightlosing patients with advanced pancreatic
cancer. J Nutr. 1999 Jun;129(6):1120–5.
18. Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KC. The effect of an oral
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic review
Page 16 of 17
­ utritional supplement enriched with fish
n
oil on weight-loss in patients with pancreatic cancer. Br J Cancer. 1999 Sep;81(1):
80–6.
19. Jho DH, Babcock TA, Tevar R, Helton
WS, Espat NJ. Eicosapentaenoic acid supplementation reduces tumor volume and
attenuates cachexia in a rat model of progressive non-metastasizing malignancy.
JPEN J Parenter Enteral Nutr. 2002 Sep–
Oct;26(5):291–7.
20. Wigmore SJ, Ross JA, Falconer JS,
Plester CE, Tisdale MJ, Carter DC, et al.
The effect of polyunsaturated fatty acids
on the progress of cachexia in patients
with pancreatic cancer. Nutrition. 1996
Jan;12(1 Suppl.):S27–30.
21. Fearon KC, Barber MD, Moses AG,
Ahmedzai SH, Taylor GS, Tisdale MJ, et al.
Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid
diester in patients with cancer cachexia. J
Clin Oncol. 2006 Jul;24(21):3401–7.
22. Gogos CA, Ginopoulos P, Salsa B, Apostolidou E, Zoumbos NC, Kalfarentzos
F. Dietary omega-3 polyunsaturated
fatty acids plus vitamin E restore immunodeficiency and prolong survival
for severely ill patients with generalized
malignancy: a randomized control trial
Cachexia in cancer patients. Cancer. 1998
Jan;82(2):395–402.
23. Sultan J, Griffin SM, Di Franco F, Kirby
JA, Shenton BK, Seal CJ, et al. Randomized
clinical trial of omega-3 fatty acid-supplemented enteral nutrition versus standard
enteral nutrition in patients undergoing
oesophagogastric cancer surgery. Br J
Surg. 2012 Mar;99(3):346–55.
24. Fearon KC, Von Meyenfeldt MF, Moses AG, Van Geenen R, Roy A, Gouma DJ,
et al. Effect of a protein and energy dense
N-3 fatty acid enriched oral supplement
on loss of weight and lean tissue in cancer cachexia: a randomised double blind
trial. Gut. 2003 Oct;52(10):1479–86.
25. Jatoi A, Rowland K, Loprinzi CL, Sloan
JA, Dakhil SR, MacDonald N, et al. An eicosapentaenoic acid supplement versus
megestrol acetate versus both for patients with cancer-associated wasting: a
North Central Cancer Treatment Group
and National Cancer Institute of Canada
collaborative effort. J Clin Oncol. 2004
Jun;22(12):2469–76.
26. Ryan A, Reynolds JV, Healy L, Byrne M,
Moore J, Brannelly N, et al. Enteral nutrition enriched with eicosapentaenoic acid
(EPA) preserves lean body mass ­following
esophageal cancer surgery: results of a
double-blinded randomized controlled
trial. Ann Surg. 2009 Mar;249(3):1–9.
27. Vaughan VC, Hassing MR, Lewandowski PA. Marine polyunsaturated fatty
acids and cancer therapy. Br J Cancer.
2013 Feb;108(3):486–92.
28. Arshad A, Al-Leswas D, Stephenson
J, Metcalfe M, Dennison A. Potential applications of fish oils rich in n-3 fatty
acids in the palliative treatment of advanced pancreatic cancer. Br J Nutr. 2011
Sep;106(6):795–800.
29. Mazzotta P, Jeney CM. Anorexia-cachexia syndrome: A systematic review of
the role of dietary polyunsaturated fatty
acids in the management of symptoms,
survival, and quality of life. J Pain Symptom Manage. 2009 Jun;37(6):1069–77.
30. Arends J, Bodoky G, Bozzetti F, Fearon
K, Muscaritoli M, Selga G, et al. ESPEN
Guidelines on enteral nutrition: Nonsurgical oncology. Clin Nutr. 2006 Apr;
25(2):245–59.
31. Elia M, Van Bokhorst-de van der
Schueren MA, Garvey J, Goedhart A, Lundholm K, Nitenberg G, et al. Enteral (oral
or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: a systematic review.
Int J Oncol. 2006 Jan;28(1):5–23.
32. August DA, Huhmann MB; American
Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors.
A.S.P.E.N. clinical guidelines: nutrition
support therapy during adult anticancer treatment and in hematopoietic cell
transplantation. JPEN J Parenter Enteral
Nutr. 2009 Sep–Oct;33(5):472–500.
33. Bauer JD, Ash S, Davidson WL, Hill
JM, Brown T, Isenring EA, et al. Evidence based practice guidelines for the
nutritional management of cancer ca­
chexia. Nutr Diet. 2006 Sep;63(Suppl. 2):
S3–32.
34. Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic acid
(EPA, an omega-3 fatty acid from fish
oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev. 2007
Jan;(1):CD004597.
35. van der Meij BS, Langius JA, Smit EF,
Spreeuwenberg MD, von Blomberg BM,
Heijboer AC, et al. Oral nutritional supplements containing (n-3) polyunsaturated
fatty acids affect the nutritional status of
patients with stage III non-small cell lung
cancer during multimodality treatment. J
Nutr. 2010 Oct;140(10):1774–80.
36. Silva Jde A, Trindade EB, Fabre ME,
Menegotto VM, Gevaerd S, Buss Zda S, et
al. Fish oil supplement alters markers of
inflammatory and nutritional status in
colorectal cancer patients. Nutr Cancer.
2012;64(2):267–73.
37. Finocchiaro C, Segre O, Fadda M,
Monge T, Scigliano M, Schena M, et al.
Effect of n-3 fatty acids on patients with
advanced lung cancer: a double-blind,
placebo-controlled study. Br J Nutr. 2012
Jul;108(2):327–33.
38. Bonatto SJ, Oliveira HH, Nunes EA,
Pequito D, Iagher F, Coelho I, et al. Fish
oil supplementation improves neutrophil
function during cancer chemotherapy.
­Lipids. 2012 Apr;47(4):383–9.
39. Paccagnella A, Morassutti I, Rosti
G. Nutritional intervention for improving treatment tolerance in cancer patients. Curr Opin Oncol. 2011 Jul;23(4):
322–30.
40. Ries A, Trottenberg P, Elsner F, Stiel
S, Haugen D, Kaasa S, et al. A systematic
review on the role of fish oil for the treatment of cachexia in advanced cancer: An
EPCRC cachexia guidelines project. Palliat Med. 2012 Jun;26(4):294–304.
41. Murphy RA, Yeung E, Mazurak VC,
Mourtzakis M. Influence of eicosapentaenoic acid supplementation on lean body
mass in cancer cachexia. Br J Cancer.
2011 Nov;105(10):1469–73.
42. American Dietetic A. ADA Evidence
Library, 2010.
43. Guarcello M, Riso S, Buosi R, D’Andrea
F. EPA-enriched oral nutritional suport
in patients with lung cancer: effects on
nutritional status and quality of life. Nutr
Ther Metab. 2007;25(1):25–30.
44. Moses AW, Slater C, Preston T, Barber MD, Fearon KC. Reduced total energy
expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and
protein dense oral supplement enriched
with n-3 fatty acids. Br J Cancer. 2004
Mar;90(5):996–1002.
45. van der Meij BS, van Bokhorst-de van
der Schueren MA, Langius JA, Brouwer
IA, van Leeuwen PA. n-3 PUFAs in cancer,
surgery, and critical care: a systematic
review on clinical effects, incorporation,
and washout of oral or enteral compared
with parenteral supplementation. Am J
Clin Nutr. 2011 Nov;94(5):1248–65.
46. Kenler AS, Swails WS, Driscoll DF,
DeMichele SJ, Daley B, Babineau TJ, et
al. Early enteral feeding in postsurgical
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic review
Page 17 of 17
cancer patients. Fish oil structured lipidbased polymeric formula versus a standard polymeric formula. Ann Surg. 1996
Mar;223(3):316–33.
47. Takatsuka H, Takemoto Y, Iwata N,
Suehiro A, Hamano T, Okamoto T, et al.
Oral eicosapentaenoic acid for complications of bone marrow transplantation. Bone Marrow Transplant. 2001
Oct;28(8):769–74.
48. Bruera E, Strasser F, Palmer JL, Willey J, Calder K, Amyotte G, et al. Effect
of fish oil on appetite and other symptoms in patients with advanced cancer
and anorexia/cachexia: a double-blind,
­placebo-controlled study. J Clin Oncol.
2003 Jan;21(1):129–34.
49. Trabal J, Leyes P, Forga M, Maurel J.
Potential usefulness of an EPA-enriched
nutritional supplement on chemotherapy tolerability in cancer patients without
overt malnutrition. Nutr Hosp. 2010 Sep–
Oct;25(5):736–40.
50. van der Meij BS, Langius JA, Spreeuwenberg MD, Slootmaker SM, Paul MA,
Smit EF, et al. Oral nutritional supplements containing n-3 polyunsaturated
fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT. Eur
J Clin Nutr. 2012 Mar;66(3):399–404.
51. Colomer R, Moreno-Nogueira JM,
García-Luna PP, García-Peris P, Garcíade-Lorenzo A, Zarazaga A, et al. n-3 Fatty
acids, cancer and cachexia: a systematic
review of the literature. Br J Nutr. 2007
May;97(5):823–31.
52. Baracos VE, Mazurak VC, Ma DW., n-3
Polyunsaturated fatty acids throughout
the cancer trajectory: influence on disease incidence, progression, response to
therapy and cancer-associated cachexia.
Nutr Res Rev. 2004 Dec;17(2):177–92.
53. Das UN. Essential fatty acids and their
metabolites as modulators of stem cell
biology with reference to inflammation,
cancer, and metastasis. Cancer Metastasis
Rev. 2011 Dec;30(3–4):311–24.
54. Murphy RA, Mourtzakis M, Chu QS,
Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases firstline chemotherapy efficacy in patients
with advanced nonsmall cell lung cancer.
Cancer. 2011 Aug;117(16):3774–80.
55. Bougnoux P, Hajjaji N, Ferrasson MN,
Giraudeau B, Couet C, Le Floch O. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic
acid: a phase II trial. Br J Cancer. 2009
Dec;101(12):1978–85.
56. Roodhart JM, Daenen LG, Stigter EC,
Prins HJ, Gerrits J, Houthuijzen JM, et al.
Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.
Cancer Cell. 2011 Sep;20(3):370–83.
57. Murphy RA, Clandinin MT, Chu QS,
Arends J, Mazurak VC. A fishy conclusion
regarding n-3 fatty acid ­supplementation
in cancer patients. Clin Nutr. 2013
Jun;32(3):466–7.
58. Murphy RA, Mourtzakis M, Mazurak
VC. n-3 Polyunsaturated fatty acids: the
potential role for supplementation in
cancer. Curr Opin Clin Nutr Metab Care.
2012 May;15(3):246–51.
59. Brown JK. A systematic review of the
evidence on symptom management of
cancer-related anorexia and cachexia. Oncol Nurs Forum. 2002 Apr;29(3): 517–32.
60. Baldwin C, Spiro A, McGough C, Norman AR, Gillbanks A, Thomas K, et al.
Simple nutritional intervention in patients with advanced cancers of the gastrointestinal tract, non-small cell lung
cancers or mesothelioma and weight loss
receiving chemotherapy: a randomised
controlled trial. J Hum Nutr Diet. 2011
Oct;24(5):431–40.
61. Bosaeus I. Nutritional support in
multimodal therapy for cancer cachexia.
Support Care Cancer. 2008 May;16(5):
447–51.
62. Mantovani G, Macciò A, Madeddu
C, Serpe R, Massa E, Dessì M, et al. Randomized phase III clinical trial of five
different arms of treatment in 332 patients with cancer cachexia. Oncologist.
2010;15(2):200–11.
63. Rogers ES, MacLeod RD, Stewart J,
Bird SP, Keogh JW. A randomised feasibility study of EPA and Cox-2 inhibitor
(Celebrex) versus EPA, Cox-2 inhibitor
(Celebrex), resistance training followed
by ingestion of essential amino acids
high in leucine in NSCLC cachectic patients--ACCeRT study. BMC Cancer. 2011
Nov;11:493.
64. Gavazzi C, Colatruglio S, Sironi A,
Mazzaferro V, Miceli R. Importance of
early nutritional screening in patients
with gastric cancer. Br J Nutr. 2011
Dec;106(12):1773–8.
65. Isenring EA, Capra S, Bauer JD. Nutrition intervention is beneficial in oncology
outpatients receiving radiotherapy to the
gastrointestinal or head and neck area.
Br J Cancer. 2004 Aug;91(3):447–52.
66. Ravasco P, Monteiro-Grillo I, Vidal
PM, Camilo ME. Dietary counseling improves patient outcomes: a prospective,
randomized, controlled trial in colorectal
cancer patients undergoing radiotherapy.
J Clin Oncol. 2005 Mar;23(7):1431–8.
67. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al.
­Definition and classification of cancer
cachexia: an international consensus.
­Lancet Oncol. 2011 May;12(5):489–95.
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: van der Meij BS, Bauer JD, Isenring EA, Brown T, Davidson WL, van Bokhorst MAE, et al. The effects of
supplementation of n-3 polyunsaturated fatty acids on clinical outcome parameters in patients with cancer: a systematic
review. OA Epidemiology 2013 Apr 19;1(1):2.
Competing interests: none declared. Conflict of interests: none declared.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Systematic review