Arginine and Gastrointestinal cancers

Citation:

McCarter, M.,Gentilini,O.,Gomez,M,Daly,J. Preoperative oral supplement with immunonutrients in cancer patients. Journal of Parenteral and Enteral Nutrition. 1998;22(4)206-210.

PubMed ID: 9661120
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

The aim of this study was to evaluate the effectiveness of arginine and arginine plus omega-3 fatty acids on post-operative immune function in supplements given preoperatively one week before cancer surgery. 

Inclusion Criteria:
  • Patients scheduled to undergo major gastrointestinal surgery for carcinoma of the esophagus,stomach,or pancreas
  • 18 years of age or older
  • Able to consume an oral diet,and
  • Informed consent

 

                                   

Exclusion Criteria:
  • Evidence of active infection (temperature >=38.5oC; leucocytosis >=12x109/L)
  • Renal failure (serum creatinine >=3mg/dL)
  • Hepatic failure (serum bilirubin >=3 mg/dL)
  • Human immunodeficiency virus
  • History of immunosuppressive therapy (including steroids,chemotherapy,or radiation therapy within 3 months of surgery)
  • Uncontrolled diabetes (fasting blood glucose,>=200 mg/dL),and
  • Pregnancy.   
Description of Study Protocol:

Recruitment -The recruitment procedures were not identified by researchers. IRB approval obtained from Cornell University Medical Center.

Design: Randomized double blinded study with patients randomized at least 7 days before the planned elective procedure. The eligible patients were randomized to 1 of 3 blinded groups: group 1 received a standard nutritional supplement; group 2 received a similar supplement with added arginine; and group 3 received the same supplement with added arginine and omega-3 fatty acids.

Blinding :The supplements, distributed to each of the 3 groups of patients, were coded such that both investigators and patients were blinded to the content.

Intervention: group 1=standard, isocaloric, isonitrogenous nutritional supplement; group2=supplement+arginine; group3=supplement+arginine+omega-3 fatty acids.

All of the supplements were fortified with>=100% of of the recommended dietary allowance for vitamins A, B6, B12, C, D, E, thiamine, riboflavin, niacin, calcium, iron, folic acid, phosphorus, iodine, magnesium, zinc, copper, biotin and pantothenic acid.

Composition of dietary supplements
Variable Group 1 Group 2 Group 3
Energy(kcal/d)

750

750

750

 % from protein

45

34

34

  % from fat

16

16

16

  % from carbohydrtae

39

50

50

Total nitrogen(g/d)

13

13

13

Total arginine(g/d)

2.4

20

20

EPA/DHA(g/d)

0

0

2.6

Dietary fiber(g/d)

15

15

18

EPA= eicosapentanoic acid; DHA= docosahexanoic acid; group 1=standard nutritional supplement;v group2=supplement+arginine; group3=supplement+arginine+omega-3 fatty acids.

Statistical Analysis:

  • Chi square analysis of discontinous variables
  • Analyses of variance (ANOVA) with Tukey's post hoc test for significance for the continous variables, where appropriate
  • Data are represented as mean ±SEM.

 

Data Collection Summary:

Timing of Measurements: The patients blood was collected at three time points:

  1. upon enrollment in study, supplements had not been provided
  2. the morning before the operation (after one week of supplement)
  3. postoperative day 1.

Each patient, during the preoperative period, maintained a diary of signs and symptoms (eg, nausea, bloating, cramping and diarrhea) associated with supplement intake.

Dependent Variables: Patients were followed clinically for postoperative infectious complications and length of hospital stay.

  • Infectious complication:

          -urine,

         -blood-serum was analyzed for arginine and ornithine content, and peripheral blood mononuclear cells   (PBMCs were isolated for lymphocyte mitogenesis, tumor necrosis factor alpha (TNF-a) interleukin -6 (IL-6), prostaglandin E2(PGE2),and leukotriene B (LTB) production.

         -sputum,

         -abcess,

         -wound,

         -other.

  • Total no. of infections
  • Number of patients with infection
  • Number of infectious complications: leak, wound healing
  • Total number of other complications
  • No. of patients with other complications
  • No. of patients with any complications
  • No. of patients with any complications
  • Mortality (30 day)
  • Length of hospital stay (days)     

Control Variables: Group 1-standard nutritional supplement

Independent Variables: Group 2-supplement+arginine;Group 3-supplement+arginine+omega-3 fatty acids.

 Compliance with study protocol and maintaining a food diary (tracking when and how much supplement consumed) was reinforced by phone calls to the patients.

 

Description of Actual Data Sample:

Initial N:51

                                                                       Patient demographics

 

Variable

Group 1

Group 2

Group 3

N

11

14

13

Age(y)

66.0±4.4

64.5±4.1

62.0±2.3

>10% weight loss

2(18)

3(21)

3(23)

% of usual weight

94.5±2.3

97.8±1.5

94.0±1.8

Serum albumin(g/dl)

3.8±0.2

3.9±0.3

3.6±0.3

Gender(M/F)    

5/6

9/5

7/6

Cancer

Esophagus

2

5

3

Stomach

3

2

4

Pancreas

6

5

6

Attrition (final N):

38 (13 patients were excluded from the final analysis becuase of inadequate of oral supplement( <4500 mL total)and cancellation or rescheduling of surgery.

Age: ranged 62.0±2.3 years to 66.0±4.4 years .

Ethnicity: not identified

Other relevant demographics: none were identified.

There are no significant differences between groups in terms of age, weight loss, type of cancer and previous operations.

Anthropometrics -not identified.

Location: Cornell University Medical College

 

Summary of Results:

Infectious complications

Group 1

Group 2 Group 3
Infectious complication

0

1

1

   Urine

0

0

1

   Blood

0

0

1

   Sputum

0

0

2

   Abcess

0

0

1

   Wound

0

1

2

   Other

2

3

0

Total no. of infections

2

5

7

No. of patients with infection*

2(18)

4(29)

5(38)

Noninfectious complications
     Leak

0

2

1

     Wound healing

1

2

3

      Total no. of other

1(9)

4(29)

4(31)

       complications*
      No. of patients with

1(9)

3(21)

4(31)

      other complications*
       No. of patients with

2(18)

6(43)

7(54)

        any complications*
 Mortality (30 day)*

0

1(8)

0

     Length of hospital stay(d)

13 ±1.7

15±2.4

17±3.7

       

 *Values in parentheses are percentages

Production of TNF,IL-6,PGE2, and LTB4 by stimulated PBMCs
Cytokine

DAY

Group 1

Group 2

Group 3

TNF Baseline

307±37

1078±385

637±128

Preop

640±147

514±194

402±102

POD1

576±137

675±240

825±193

IL-6 Baseline

3503±419

3424±427

2841±833

Preop

3401±366

3901±543

2853±537

POD1

3081±245

2914±180

2636±282

PGE2 Baseline

6437±1585

2377±214

6721±2208

Preop

4769±1647

5205±1136

6615±1615

POD1

13802±4065

8919±2171

7342±2189

LTB4 Baseline

130±19

125±58

203±70

Preop

158±52

79±41

127±46

POD1

95±56

219±61

66±26

Isolated PBMCs were stimulated with 10 µg/ml lipopolysaccharide. n=5 for groups 1 and 2,and n=7 for group 3. There were no statistically significant differences in mean cytokine production among groups. Preop= preoperative; POD=postoperative day, TNF=tumor necrosis factor, IL-6=interleukin 6, PGE 2 = prostaglandin E2; LTB4 = leukotriene 4, PBMC=peripheral blood mononuclear cells.

Tolerance of dietary supplements

Variable

Group1

Group 2

Group 3

Volume Consumed

4692±378

4572±270

4407±373

% of target

93

91

87

Missed supplement*

                

Any day

4(36)

6(46)

7(54)

  Day before surgery

4(36)

4(29)

3(23)

Symptoms*

Cramping

6(55)

1(7)

5(38)

Distention

6(55)

4(29)

8(62)

                       Gas

7(64)

4(29)

3(23)

                       Other

3(23)

1(7)

3(23)

No significant differences were noted between groups for the amount of supplements consumed and the number of missed days.

Reports of symptoms among groups were slightly less for group 2, but this did not reach significance.

Other Findings

There were no significant differences in mean arginine in any of the three randomized groups despite the fact that each group consumed nearly equal amounts of of oral supplements during the properative period. The groups 2 and 3) that had received arginine in the supplement did manifest a significant increase in the level of a major metabolite of arginine, serum ornithine [70 µmol/l increased to 103 for group 2 (p<0.05) and 88 for group 3 (non-significant)].

1. The study did not demonstrate any differences among the three groups relative to cellular immune function reported.

2. The addition of supplements (arginine or arginine with omega-3 fatty acids) had no effect on the suppression of lymphocyte  proliferation after a major surgery.

3. No significant differences for infections and complications.

4. No significant difference for length of hospital stay.

Author Conclusion:

The author stated that thereby were 3 possible explanations for the differences in serum ornithine levels:

1. Poor patient compliance with the study protocol.

2. Patients were instucted not to consume the supplement on 1 or more days as part of their on-going medical evaluations during the preoperative period.

3.The metabolism of arginine may have been rapid or enhanced in patients with a cancer diagnosis. There is an increased resting energy expenditure and alteration of nutrient metabolism in these patients described as,"the result of of tumor-induced metabolic derangements".

Sample size is small and larger studies are recommended.

Supplementation only one-week preoperatively may not be sufficient to improve immune function.

Because this study was conducted in the outpatient setting, problems with patient compliance may have impacted the results of the study.

 

Funding Source:
Industry:
Novartis Nutrition Corporation
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:

It should be noted that this study was funded by Novartis Nutrition Corporation.

Limitations include:

  • No control group
  • sample size
  • question is longer preop support needed
  • did not measure dietary sources of omega-3 fatty acids and arginine
  • did not use intent to treat analysis
  • question if patients experienced difficulty consuming normal diet plus 750 ml supplement/day or if they replaced supplement for po intake?

 

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) ???
  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? ???
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) ???
 
Validity Questions
1. Was the research question clearly stated? ???
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? ???
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? ???
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? Yes
  2.2. Were criteria applied equally to all study groups? ???
  2.3. Were health, demographics, and other characteristics of subjects described? ???
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  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.) ???
  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? ???
  4.1. Were follow-up methods described and the same for all groups? ???
  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%.) ???
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? ???
  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
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? ???
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? ???
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  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? ???
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? ???
  6.6. Were extra or unplanned treatments described? ???
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? ???
  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? ???
  7.1. Were primary and secondary endpoints described and relevant to the question? ???
  7.2. Were nutrition measures appropriate to question and outcomes of concern? ???
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  7.6. Were other factors accounted for (measured) that could affect outcomes? ???
  7.7. Were the measurements conducted consistently across groups? ???
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? ???
  8.1. Were statistical analyses adequately described and the results reported appropriately? ???
  8.2. Were correct statistical tests used and assumptions of test not violated? ???
  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)? ???
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? ???
  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? ???
9. Are conclusions supported by results with biases and limitations taken into consideration? ???
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? ???
10. Is bias due to study's funding or sponsorship unlikely? ???
  10.1. Were sources of funding and investigators' affiliations described? ???
  10.2. Was the study free from apparent conflict of interest? ???