ONC: Arginine (2006)


van Borkhurst-de van der Schueren, M.A.E., Quak, J., von Blomberg-van der Flier, B.M.E., Kuik, D.J., Langendoen, S.I., Snow, G.B., Green, C.J., van Leeuwen, P.A.M. Effect of perioperative nutrition, with and without arginine supplementation, on nutritional status, immune function, postoperative morbidity, and survival in severely malnourished head and neck cancer patients. Am J Clin Nutri 2001; 73: 323-32.

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

To determine whether preoperative enteral nutrition, with or without arginine, could improve nutritional status, reduce postoperative morbidity and surgery induced immune suppression and improve survival in malnourished head and neck cancer patients undergoing major surgery.

Inclusion Criteria:
  • Patients from 1 January 1994 through 31 December 1997, entering the Department of Otolaryngology/Head and Neck Surgery of the University Hospital Vrije Universiteit
  • Histologically proven squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx.
  • Malnourishment ( wt loss >10% of body weight)
Exclusion Criteria:
  • Well nourished (wt loss < 10% of body weight)
  • Receiving investigational drugs or steroids
  • Had renal insufficiency, hepatic failure, or any genetic immune disorder
  • Had a confirmed diagnosis of AIDS
Description of Study Protocol:


Patients meeting the inclusion criteria stated above that agreed to participate in the study after giving written, informed consent. 


Randomized Controlled Clinical Trial

Blinding used (if applicable)

Blinding of patients was only possible in Groups 2 and 3 (enterally fed groups)

Intervention (if applicable)

Nutritional needs were met by 1.5 x their basal energy expenditure (BEE) calculated with the Harris Benedict Equation. 

Patients were randomly assigned to 1 of 3 treatment groups:

    1.  received no preoperative nutrition support

    2.  received preoperative enteral nutrition with a special formula that closely mimics a standard formula

    3.  received preoperative enteral nutrition in which 41% of the casein is replaced with arginine.

- Patients in group 2 and 3 received the enteral nutrition 7-10 days preoperatively thru a nasogastric tube.

- Group 1 was instructed to consume their usual diet.

- Group 2 and 3 met all their nutritional with the enteral feeds but were allowed pleasure eating.

- Postoperatively, all patients received enteral nutrition (1.5 x BEE) until a swallow X-ray performed 10 days post-op showed no leakage from anastomoses.  Groups 1 and 2 received the standard formula, while group 3 received the arginine supplemented formula. 

Statistical Analysis

  • One-way analysis of variance (ANOVA) was used to compare continuous variables
  • Chi-square tests were used to compare discrete variables
  • Two-factor repeated measures ANOVA was applied to analyze group and time interactions.
  • The overall CV was computed for the cytokine production data
  • All P values </= 0.05 was considered statistically significant.



Data Collection Summary:

Timing of Measurements

Nutritional assessment, immunological evaluation, and assessment of clinical outcome and survival were tested at: recruitment into the study, 1 day preoperatively, 1 day postoperatively, 4 day postoperatively, 7 day postoperatively, and on day of discharge.

Patients had at least one telephone contact with the research dietitian during the preoperative period.

Follow-up time for survival was >16 months.

Dependent Variables

  • Weight (kg)
  • Fat mass (kg) - skinfold thickness and midarm muscle circumference
  • Fat free mass (kg) - bioelectrical impedance analysis
  • Grip Strength (right/left hands) - dynamometer
  • Albumin - biochemical assessment
  • immune variables: absolute number of leukocytes and lymphocytes, the total lymphocyte count, percentage of monocytes, CD3+, CD4+, CD8+, CD19+, CD16/CD56+/CD3-, CD16/CD56+/CD3+

Independent Variables

Standard enteral formula vs. Arginine-supplemented formula

Table 1 from article - Composition of the nutritional formulas
Composition per liter Standard formula Arginine-supplemented formula
Protein (g) 62.50 36.85
    free arginine (g) 0.00 12.50
    Glutamine (g)     6.30 3.70
    Nitrogen (g) 9.80 9.80
Fat (g) 48.61 48.61
Carbohydrate (g) 140.63 153.77
Energy (kJ) 5250 5250

Control Variables

Regular oral diet with group 1

Description of Actual Data Sample:

Initial N:

49; 30 males, 19 females

Attrition (final N):

49, no patients were lost in follow-up; patients lost at survival analysis are noted in the results. 


Group 1, 55 +/- 10 yrs; group 2, 60 +/- 8 yrs; group 3, 59 +/- 12 yrs



Other relevant demographics:


The groups did not differ significantly in age, tumor stage, tumor localization, comorbidity, or weight loss.


Department of Otolaryngology/Head and Neck Surgery of the University Hospital Vrije Universiteit, Amsterdan


Summary of Results:

Table 3; Anthropometric measurements at baseline and after the preoperative intervention:

Baseline Baseline Baseline Mean change after the intervention Mean change after the intervention Mean change after the intervention

Group 1


Group 2


Group 3


P for differences between groups

Group 1

Group 2

Group 3
Weight (kg) 62.8 +- 8.4 55.3 +- 8.1

61.6 +- 8.5






Fat Mass (kg) 12.2 +- 8.7 10.5 +- 6.7

13.0 +- 5.8




Fat-free mass (kg) 42.1 +- 16.8 36.3 +- 17.0 47.5 +- 6.9 0.14 -0.3 2.5 0.7

Grip Strength    




35.3 +- 10.6

27.9 +- 13.9


26.7 +- 9.5

26.4 +- 11.0


33.6 +- 10.9

29.2 +- 14.6













Albumin (g/L) 37.3 +- 4.0 32.9 +- 6.4

35.9 +- 4.0





Other Findings

  • No significant changes in nutritional status were noted between the 3 groups as a result of nutritional intervention
  • In the week of preoperative intervention, albumin concentrations decreased in group 1.  Postoperatively, albumin concentrations decreased as a result of surgery, but no significant differences were noted between groups. 
  • Patients in all 3 groups showed immunologic disturbances in response to surgery with a clear drop in total lymphocyte count and an increase in the number of leukocytes. 
  • the HLA-DR expression on monocytes was comparable between groups at all time points. 
  • the type and severity of the complications did not differ significantly between groups
  • no significant differences between groups were found in the postoperative use of blood products or antibiotics or in any of the other recorded clinical indexes.
  • At the time of survival analysis, 32 patients had died of recurrent disease.  Overall survival rate was 35%.
  • Disease specific survival was 49%.   No significant difference in survival was noted between the 3 groups, although the trend was for better survival for patients in group 3. 
  • 3 patients in group 1 and 5 patients each in groups 2 and 3 never resumed swallowing
  • Author Conclusion:

    "The results of this study failed to support the hypothesis that preoperative feeding, either with or without arginine supplementation, improves clinical outcome, intermediate markers of immune function, or nutritional status compared with ad libitum oral food intake.  No conclusions can be made about the value of perioperative feeding per se because all 3 groups of patients received tube feeding postoperatively."

    Additional author comments:

  • disease-related malnutrition may simply be a marker of the severity of the disease and not purely as a result of diminished intake or altered metabolism
  • it was assumed that group 1 was going to have depressed food intake, when results showed that the average daily consumption was ~ 80% of their estimated nutritional needs
  • nutritional intervention may not have been aggressive enough
  • final consideration, that the length of nutritional support was not sufficient for repletion of these extremely malnourished patients

    Suggestions for future studies:

    "More work is required to determine whether earlier, more aggressive, or differently composed nutritional support may be more effective in extremely malnourished patients undergoing a major catabolic event."

  • Funding Source:
    University/Hospital: Vrije University, University of Southern Denmark,
    Reviewer Comments:
    • The study by Van Bokhorst-De Van Der Schueren is a well-constructed prospective, double-blind, randomized trial to study the effect of preoperative enteral nutrition on postoperative morbidity and late mortality in severely malnourished head and neck cancer patients. 
    • Although the results are not promising, the author does a thorough job in determining possible flaws within the study, such as possibly inadequate aggression of nutrition intervention and inadequate length of time, as well as providing several suggestions for further research. 
    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? 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
      2.2. Were criteria applied equally to all study groups? 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
    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) Yes
      3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
      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? 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%.) Yes
      4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
      4.4. Were reasons for withdrawals similar across groups? Yes
      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? 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? Yes
      6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
      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
      6.8. 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? ???
      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)? Yes
      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? Yes
      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? No
      10.2. Was the study free from apparent conflict of interest? ???