Omega 3 Fatty Acid and Oncology
To evaluate the influence of preoperative administration of EPA/arginine/RNA-containing nutritional supplement on inflammatory and immune response in patients undergoing major surgery for cancer.
- Written informed consent
- Patients with bile duct, gastric, pancreatic and esophageal cancers
Exclusion criteria included:
- ages younger than 18y or older than 80y,
- body mass index lower than 16kg/m2 or higher than 30kg/m2 pregnancy
- hyperthyroidism
- hypertriglyceridemia
- diabetes mellitus
- human immunodeficiency virus
- hepatitis
- pancreatitis
- iron deficiency anemia
- emergency surgery
- severe cardiac status (higher than New York Heart Association class III)
- severe renal status (serum creatinine > 2mg/dl), or liver failure (bilirubin> 2 mg/dL)
- medication with insulin or corticoids.
Recruitment: not specified
Design: randomized clinical trial. Type of randomization not indicated.
Blinding used: not specified
Intervention: Patients were randomly assigned to receive a preoperative oral nutritional supplement containing omega-3 fatty acids, arginine and RNA (Impact[Japan]) or not. The supplement group was asked to consume 1L/d of Impact(Japanese) for 5 days before surgery. Before and after surgery total calories was approximately 1600 kcal/day for both groups.
| Nutrient | Composition |
| free L Arginine |
1.28g |
|
RNA |
0.13g |
|
Total Lipids |
2.88g |
|
Omega-3 fatty acids |
0.40 g |
|
Omega-6 fatty acids |
0.33 g |
|
nitrogen content |
1.10g |
|
carbohydrates,mineral,vitamins |
13.4g |
Subjects were requested to fill in a food diary, where they recorded all food consumption during the study. Compliance with the study product consumption was confirmed by doctors or nurses.
After surgery, all patients received total parenteral nutrition (TPN) and enteral nutrition (EN).
TPN was administered through the central vein. The amount of non-protein calories was 500 kcal/d after surgery and gradually increased to 1100 kcal/d by postoperative day 3. The amount of nitrogen provided on postoperative day 3 was 8 g/d. The starting solution consisted of a mixture of 12% glucose and 2.072% amino acids and minerals (PNtwin No. 1, Ajinomoto Pharma). The maintenance solution consisted of a mixture of 16.36% glucose and 2.825% amino acids and minerals (PNtwin No.2, Ajinomoto Pharma). Vitamins (Neolamin multi V,Nippon Kayaku Co.,Tokoyo,Japan) and electrolytes were provided as clinically indicated. The perfusion volume was set to 30 to 40 mL/kg/d.
EN was administered by jejunostomy feeding catheter beginning on postoperative day 3. Calories provided, beginning on postoperative day 3, was 300 kcal/d and gradually increased to 1200 kcal/day by post operative day 6. The amount of nitrogen provided was 1.98 g/day beginning on postoperative day 3 and 7.92 g/d on postoperative day 6. Elental (Ajinomoto Pharma), which contained 79.185 carbohydrate,16.40% protein, and 0.64% fat, was used as the EN. Oral food intake began on postoperative day 7.
Statistical Analysis
:(a) Parametric data were expressed as mean±standard deviation, and significance was analyzed by one-way analysis of variance with Fisher's protected least-significant difference test. Parametric data of the two groups were compared by using analysis of two-way repeated measures analysis of variance followed by Scheffe's post hoc test.
(b) Non-parametric data were expressed as medians and quartiles, and differences between groups were tested with the Mann-Whitney U test. P<=0.05 was considered statistically significant. Statistical correlations were performed with Spearman's rank correlation tests.
Timing of Measurements-The times noted for venous blood samples are noted below.
Supplement Group-the venous blood samples were collected 5 days before surgery at the start of supplementation and post operative day-0, the day after the end of supplementation.
Control Group-the venous blood samples were collected postoperative day-0, the day before surgery
Venous blood samples for both groups were collected on post operative days-1-3-and 7, after surgery.
Dependent Variables: baseline values were measured 5 days before surgery. After surgery,samples from both the supplemented group and the control group were collected on postoperative days 1-3 & 7. All samples were measured unless otherwise indicated.
- n-3 fatty acid family-eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA)
- n-6 fatty acid family-linoleic acid (LA); (arachidonic acid) AA -measured by gas chromatography.
- Amino acid derived eicosanoids thromboxane B 2(TXB2) and prostaglandin E2(PGE2). TXB2 , and PGE2, were measured with a commercial available enzyme linked immunosorbent assay kit. Minimum detectable level of TXB was 0.5pg/mL. Minimum detectable level of PGE2 was 0.5 pg/Ml.
- Nutrition Markers: serum transferrin (TRF), serum prealbumin, serum retinol-binding protein(RBP), and plasma albumin
- Inflammatory markers: high-sensitivity C-reactive protein (hsCRP), polymorphonuclear leukocyte-elastase (PMN-elastase), a 1-acid glycoprotein (AAG). PMN-elastase was measured with a commercial available enzyme linked immunosorbent assay kit. Minimum detectable level of hsCRP was 0.02mg/dL. Minimum detectable level of PMN elastase was 25.0 pg/mL. Minimum detectable level of AAG was 19 mg/dL.
- Cytokines: TNF-a, interleukin-6 (IL-6) and interleukin-8 (IL-8). Minimum detectable levels of TNF-a was 5.0 pg./mL. Minimum detectable levels of IL-6 was 18.1 pg/mL. Minimum detectable levels of IL-8 was 1.0 pg/mL.
- tumor necrosis factors: (sTNF-RI&sTNF-RII). Minimum detectable levels of sTNF-RI was 1.0 pg/mL. and sTNF-RII was 1.0 pg/mL.
- length of hospital stay (days)
- incidence of postoperative-complications.
Independent Variables: Impact(Japanese)- supplement included arginine, omega-3 fatty acids, and RNA.
Control Variables-Ordinary diet without Impact.
Initial N: 22 men and 4 women
Attrition (final N): same as above
| Supplement Group* | Control Group* | P-value | |
|
| |||
|
Male/female |
11/1 |
11/3 |
NS |
|
Age(y) |
52-71 (64±10) |
43-79 (64±15) |
NS |
|
BMI(kg/m2 ) |
17-24 (19±3) |
17-26 (19±8) |
NS |
|
Duration of operation(min) |
550-645 (598±58) |
305-640 (476±52) |
NS |
|
Blood loss(mL.) |
450-1870 (952±412) |
435-1890 (934±372) |
NS |
BMI=body mass index; NS=no significant difference between the supplement group and control group.
*Range (mean±standard deviation).
Age: 64±11 years
Ethnicity: Not identified
Other relevant demographics: There were no significant differences between groups at entry. No episodes of bleeding, failure of sutures, infection, or death were found in the 7-day observation period before surgery.
Anthropometrics -not identified
Location: Kagoshima University, Kagoshima,Japan
|
P | ||
|
EPA & DHA |
After supplementation, post operative day 0, levels of of EPA and DHA in the supplement group significantly increased compared with those at baseline. | <0.001 |
|
EPA & DHA
|
After supplementation, postoperative day 0, the levels of EPA and DHA were significantly higher than those in the control group | <0.001 |
| LA & AA | After supplementation, postoperative day 0, levels of LA and AA in the supplement group significantly decreased compared with those of baseline values. | <0.05 |
| LA & AA | After supplementation, postoperative day 0, levels of LA and AA in the supplement group were significantly lower than those in the control group. | <0.05 |
|
P | ||
| Levels of total omega-3 fatty acids | After supplementation, postoperative day 0, level of total omega-3 fatty acids in the supplement group significantly increased when compared to those of baseline values. | <0.001 |
| Levels of total omega-3 fatty acids | After supplementation, postoperative day 0, level of total omega-3 fatty acids in the supplement group was higher than in the control group. | <0.05 |
| Ratio of Omega -6 fatty acids to omega-3 fatty acids | After supplementation, postoperative day 0, the ratio of omega 6 fatty acids to omega 3 fatty acids was significantly lower than at baseline. | <0.001 |
| Ratio of Omega -6 fatty acids to omega-3 fatty acids | After supplementation, postoperative day 0, the ratio of omega 6 fatty acids to omega 3 fatty acids was significantly lower than in the control group. | <.0.001 |
| Ratio of Omega -6 fatty acids to omega-3 fatty acids | Significant changes in total omega -3 fatty acids and the ratio of omega -6 fatty acids to omega-3 fatty acids compared with baseline values in the supplement group continued until postoperative day-1 | <0.05 |
|
P | ||
| TXB2 | In the supplement group, there was a marked decrease after supplementation. | <0.001 |
| PGE2 | In the supplement group, there were no significant differences in PGE2 levels before and after supplementation. |
NS |
|
P | ||
| TRF, prealbumin, RBP | In the supplement group, on postoperative day 0, TRF, prealbumin, and RBP significantly increased compared to those at baseline. |
<0.01(TRF) <0.05(RBP) |
| TRF, RBP | In the supplement group, on postoperative day 0, TRF and RBF levels were significantly higher in the supplement group than those in the control group. |
<0.01(TRF) <0.05(RBP) |
| Albumin | No significant differences were found in albumin levels in the supplement group and the control group. |
NS |
| hsCRP, PMN-elastase, and AAG | In the supplement group, on postoperative day 0, levels of hsCRP, PMN-elastase, and AAG were significantly lower in the in the supplement group than in the control group. |
<0.05(hsCRP) <0.05(AAG) <0.01(PMN-elastase) |
| PMN-elastase | In the supplement group, on postoperative days 1 and 3, PMN-elastase levels were significantly lower in supplement group than in the control group | <0.001 |
| IL-8 | In the supplement group, on postoperative day 3, levels of IL-8 were significantly lower than than those in the control group. | <0.001 |
| IL-6 | No significant differences in IL-6 levels was found at any time. |
NS |
| STNF R-I, STNF R-II | In the supplement group, on postoperative day 0, levels of sTNF R-I & sTNF R-II significantly decreased when compared with those of baseline values. | <0.05 |
| STNF R-I, STNF R-II | In the supplement group, on postoperative day 1, levels of sTNF R-I and sTNF R-II were significantly lower than those in the control group. |
<0.05(STNF R-I) <0.01 (STNF R-II |
| TNF-a | In the supplement group, on postoperative day 0, TNF-a in the supplement group was detected in 3 of 12 patients, with a mean level 5.4 ±4.2 pg/mL, and in 5 of 14 patients in the control group with a mean level of 4.8±5.6 pg/mL. | |
| TNF-a | In the supplement group, on postoperative day -1, TNF-a was found in all patients. | |
| TNF-a | In the supplement group, on postoperative day 1, levels of TNF-a in the supplement group (14±12.5 pg/mL) were similar to those in the control group(16.5±13.8 pg/mL). Thereafter, TNF-a traces were detected in the plasma. | |
Other Findings
|
Spearman's r |
P | |
|
sTNFR-I vs total omega-3 fatty acids |
-0.734 |
<0.0001 |
|
sTNFR-II vs total omega-3 fatty acids |
-0.519 |
<0.001 |
|
sTNFR-I vs EPA |
-0.703 |
<0.0001 |
|
sTNFR-II vs EPA |
-0.477 |
<0.01 |
|
sTNFR-I vs DHA |
-0.646 |
<0.0001 |
|
sTNFR-II vs DHA |
-0.439 |
<0.01 |
|
IL-8a vs PMN-elastase |
0.799 |
<0.0001 |
|
Spearman's r |
P | |
| hsCRP vs IL-6 |
0.800 |
<0.0001 |
| IL-8 vs PMN-elastase |
0.532 |
<0.001 |
|
Supplement Group |
Control Group |
P | |
| Days of hospital stay |
49.0±18.3 |
46.1±15.0 |
NS |
Postoperative hemorrhage was not found in any patients.
Incidence of postoperative complications-Complications in either group did not occur until postoperative day 14. Two patients in each group postoperative complications i.e., cholangitis(n=1) and bleeding (n=1), respectively, and the incidence of postoperative complications were similar in both groups (16.7% in the supplement group and 14.3% in the control group), P not significant).
The oral administration of a supplement enriched with omega-3 fatty acids, five days before surgery, improved the preoperative state in cancer patients. There was also improvement in the patients' preoperative inflammatory and immune response.
This study consisted of 12 to 16 patients. The number was small for a power analysis of the effects of this nutrient on clinical trial. Suggested that more investigations are required to clarify the benefits of a supplement with omega-3 fatty acids.
| University/Hospital: | Kagoshima University |
Limitations of the study
- the small sample size
- the relationship to the power analysis seem problematic
- "double-blinding" procedure was not utilized.
- no information on staging of cancer, primary or secondary cancer sites, previous treatments
- no information on recruitment, blinding or randomization
- no information on % compliance of supplement
- no information on side effects or not of supplement
- no information on kcal intake total
Even though food diaries were maintained by subjects with protocol compliance verified by doctors and nurses, the relevance of that data was not explained by researchers.
|
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 | |
| 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 | |
| 4. | Is the intervention or procedure feasible? (NA for some epidemiological studies) | Yes | |
| Validity Questions | |||
| 1. | Was the research question clearly stated? | Yes | |
| 1.1. | Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? | Yes | |
| 1.2. | Was (were) the outcome(s) [dependent variable(s)] clearly indicated? | Yes | |
| 1.3. | Were the target population and setting specified? | No | |
| 2. | Was the selection of study subjects/patients free from bias? | ??? | |
| 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? | ??? | |
| 2.2. | Were criteria applied equally to all study groups? | ??? | |
| 2.3. | Were health, demographics, and other characteristics of subjects described? | No | |
| 2.4. | Were the subjects/patients a representative sample of the relevant population? | ??? | |
| 3. | Were study groups comparable? | ??? | |
| 3.1. | Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) | ??? | |
| 3.2. | Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? | ??? | |
| 3.3. | Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) | Yes | |
| 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 | |
| 3.6. | 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? | N/A | |
| 4.1. | Were follow-up methods described and the same for all groups? | N/A | |
| 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%.) | N/A | |
| 4.3. | Were all enrolled subjects/patients (in the original sample) accounted for? | Yes | |
| 4.4. | Were reasons for withdrawals similar across groups? | 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? | ??? | |
| 5.1. | In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? | ??? | |
| 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.) | ??? | |
| 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 | |
| 5.5. | 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 | |
| 6.1. | 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? | Yes | |
| 6.3. | Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? | Yes | |
| 6.4. | Was the amount of exposure and, if relevant, subject/patient compliance measured? | Yes | |
| 6.5. | Were co-interventions (e.g., ancillary treatments, other therapies) described? | Yes | |
| 6.6. | Were extra or unplanned treatments described? | N/A | |
| 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 | |
| 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 | |
| 7.2. | 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 | |
| 7.4. | 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 | |
| 7.6. | Were other factors accounted for (measured) that could affect outcomes? | 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 | |
| 8.1. | 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 | |
| 8.3. | 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)? | N/A | |
| 8.5. | Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? | Yes | |
| 8.6. | Was clinical significance as well as statistical significance reported? | N/A | |
| 8.7. | If negative findings, was a power calculation reported to address type 2 error? | N/A | |
| 9. | Are conclusions supported by results with biases and limitations taken into consideration? | Yes | |
| 9.1. | Is there a discussion of findings? | Yes | |
| 9.2. | Are biases and study limitations identified and discussed? | Yes | |
| 10. | Is bias due to study's funding or sponsorship unlikely? | ??? | |
| 10.1. | Were sources of funding and investigators' affiliations described? | Yes | |
| 10.2. | Was the study free from apparent conflict of interest? | ??? | |