EAL

ONC: Dietary Supplements and Medical Food Supplements Containing Fish Oil (2013)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the acceptability and effects of oral supplementation with high-purity eicosapentaenoic acid (EPA) in weight-losing patients with advanced pancreatic cancer. To test the hypothesis that EPA is one of the biological active components of fish oil responsible for anticachetic activity.

Inclusion Criteria:

Men or nonpregnant, nonlactating women between 18 and 80 years of age with histological confirmation or unequivocal operative or radiological diagnosis of unresectable adenocarcinoma of the pancreas.
Life expectancy greater than 2 months.
World Health Organization (WHO) performance status of 2 at enrollment.
Written informed consent.

Exclusion Criteria:

Radiotherapy or chemotherapy within the previous six weeks.
Surgery or endoscopic stenting within the previous four weeks.
Other active medical conditions.
Another malignancy.

Description of Study Protocol:

Recruitment

A total of 26 patients were recruited into the study: 23 patients had unresectable pancreatic cancer and 3 patients had unresectable ampullary cancer (considered to behave similarly to pancreatic cancer). Confirmation occurred with histology (21 of 26) or unequivocal operative or radiological findings (5 of 26).

Design

Time series (12-week). The Lothian Ethical Committee approved the study protocol.

Blinding used

Not used in this study.

Intervention

The 26 patients recruited received EPA at the following dosing schedule:

Week 1 - 1 g/day
Week 2 - 2 g/day
Week 3 - 4 g/day
Weeks 4-12 - 6 g/day

This dose, 12 capsules per day, was believed to be the highest that was reasonable to expect this group of patients to tolerate via oral route.

High-purity (95%) EPA, as the free acid, in the form of gelatin capsules, each containing 500 mg of EPA. A hospital pharmacy dispensed the EPA capsules and patients were instructed to store them in a refrigerator.

Statistical Analysis

Comparisons performed using Wilcoxon's signed rank test. Survival is plotted as the cumulative probability of survival (Kaplan-Meier analysis). Data are presented as the median and interquartile range.

Data Collection Summary:

Timing of Measurements

The following measurements were assessed in all patients before entry into the study, and 4, 8, and 12 weeks thereafter:

Anthropometry (Ht, Wt, MAMC, TSF)
Body composition (BIA)
Level of acute-phase protein response (APPR)
Performance Status (WHO)
Plasma phospholipid fatty acid

Dependent Variables

Anthropometry

At the initial assessment, height, pre-illness stable weight, and duration of weight loss
Weight
Midarm muscle circumference (MAMC) was calculated using Jelliffe's equation
Triceps skinfold thickness (TSF) was measured using Harpenden calipers

Body composition

Total body resistance and total body water were measured using a multiple-frequency bioelectrical impedance analyzer

APPR

-APPR was documented by assaying serum C-reactive protein

Fatty acid analysis

-Plasma phospholipid fatty acid analyis was performed by gas chromatography. Percentage of EPA and arachidonic acid (AA) in plasma phospholipids was determined.

Toxicity assessment

-Blood was drawn for full blood count, electrolytes, urea, glucose, and liver function tests.

Performance status

WHO performance status of 2 at enrollment

Survival

Survival was recorded from the time of diagnosis to the time of death. Diagnosis was defined as the date of confirmation of adenocarcinoma of the pancreas by histological examination or of unequivocal operative or radiological findings.

Independent Variable

High-purity (95%) EPA, as the free acid, in the form of gelatin capsules, each containing 500 mg of EPA.

No control variables were used in this study.

Description of Actual Data Sample:

Initial N: 26 (14 females, 12 males)

Attrition (final N): 14 (number of females and males not stated)

Age: Median age 56 (range 39 to 75 years)

Ethnicity: Not provided.

Tumor stages:

26 Pancreatic Cancer Patients:

Stage 2: n= 5
Stage 3: n= 8
Stage 4: n= 13

Anthropometrics:

Study Entry: median percent weight loss:
- 13% compared with pre-illness stable
- Loss over a median of four months
- Median rate of weight loss 2.0 kg/month

Location: Edinburgh, Scotland and Birmingham, United Kingdom

Summary of Results:

Table 1. Changes in anthropometrics, performance status, and caloric intake in patients with advanced pancreatic cancer after commencement of EPA

Duration of EPA supplementation, week	n	Body weight, kg	Rate of weight change, kg/mo	Arm muscle circumference, cm	Triceps skinfold thickness, mm	% Total body water	Daily caloric intake, kcal
0	26	66.8 (56.0-75.1)	-2.0 (1.4-2.8)	23.8 (22.9-25.3)	11.2 (8.7-14.1)	50.9 (46.4-53.9)	1,777 (1345-2215)
4	21	66.0 (55.0-73.2)	0.5 (1.5-2.0)*	23.5 (22.4-26.1)	11.8 (8.9-16.1)	49.5 (45.4-52.9)	1,828 (1562-2203)
8	16	65.2 (57.7-76.0)	0.2 (1.4-0.9)*	23.9 (22.4-25.4)	12.1 (7.6-13.2)	49.3 (45.4-51.0)
12	14	65.0 (52.3-80.2)	0.3 (0.2-0.8)*	24.5 (22.4-26.1)	12.6 (8.8-14.0	49.1 (45.2-52.1)

Values presented are medians, with interquartile range in parentheses; n = number of patients; * Statistical significance is p < 0.005 vs. 0 week.

Other Findings

No significant change in median body weight for patients surviving at 4, 8, and 12 weeks after starting EPA.
No significant change in MAMC, TSF, or total body water (expressed as a percentage of total body weight in table 1) in patients surviving at 4, 8, and 12 weeks after starting EPA.
APPR remained stable during the study.
No statistically significant change in the WHO performance status occurred.
A small, but non-significant increase in caloric intake occurred.
Over the initial four weeks of EPA supplementation, the percentage of EPA in plasma phospholipids increased significantly (10%, p = 0.03).
Median values for full blood count, electrolytes, urea, glucose, and liver function test did not change significantly during the study.
Toxicity: Symptoms such as nausea and steatorrhea were possibly associated with the administration of the high-purity EPA capsules.
Survival: Majority of the study population (25 of 26) died. The surviving patient remains alive at 36 months from the time of diagnosis. Median survival from the time of diagnosis for all patients was 203 (152-380) days. The median survival from the time of commencement of EPA treatment for all patients was 173 (85-339) days.

Author Conclusion:

Conclusion

EPA is well-tolerated and may stabilize weight in or alter the progress of cachexia in persons with advanced pancreatic cancer.
Up to 6 g/day of EPA does not appear to be associated with or produce any anticachectic effects.

Limitation

Not all the patients who entered the study completed the three-month study period due to the advanced nature of the disease and subsequent poor survival of patients with pancreatic cancer.

Funding Source:

Industry:

Scotia Pharmaceuticals Ltd

Pharmaceutical/Dietary Supplement Company:

University/Hospital:

Royal Infirmary of Edinburgh (UK), Cancer Research Campaign, University of Edinburgh Wilkie Research Fellowhip

In-Kind support reported by Industry:

Yes

Reviewer Comments:

The 2 gram daily dose of EPA appears to be the efficacious dose in stabilizing weight loss for cachectic patients with pancreatic cancer.

Strengths

The findings from this study suggest that high doses of EPA would appear to be an effective anticachetic agent.
Adherence to the protocol was likely due to the plasma EPA response

Limitations

No control or intervention group used in this study. A placebo group would be useful to make comparisons.
Participants were terminally ill, most died at 12 weeks, making it difficult to generalize findings.
Difficult to determine if EPA would be effective in patients with less severe cachexia.
Need more information about patient characteristics.
Need additional and more in-depth dietary/nutrition information from patients such as macro- and micro-nutrient intake as well as an assessment of EPA from food sources.
EPA and fish oil have a variety of side effects that include insulin resistance, adverse glucose metabolism, prolonged bleeding time, inhibited platelet function, and the immunomodulatory effects of fish oil may cause dangerous immunosuppression.
Researchers ran out of fish oil capsules mid-study, so 12 patients received fish oil capsules after the study period.

Project support

Scotia Pharmaceuticals provided the EPA capsules for this study.
The University of Edinburgh and the Cancer Research Campaign supported this study.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	3.	Were study groups comparable?	N/A
3.	Were study groups comparable?		N/A
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
	4.	Was method of handling withdrawals described?	No
4.	Was method of handling withdrawals described?		No
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	No
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	???
	4.4.	Were reasons for withdrawals similar across groups?	???
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
	5.	Was blinding used to prevent introduction of bias?	No
5.	Was blinding used to prevent introduction of bias?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	No
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	No
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?	Yes
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	No
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	No
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	???
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	???
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	No
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.6.	Were extra or unplanned treatments described?	No
	6.6.	Were extra or unplanned treatments described?	No
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
	7.	Were outcomes clearly defined and the measurements valid and reliable?	Yes
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.7.	Were the measurements conducted consistently across groups?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
	8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	No
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	No
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	No
	9.	Are conclusions supported by results with biases and limitations taken into consideration?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	10.	Is bias due to study's funding or sponsorship unlikely?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes