ONC: Arginine (2006)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To determine if postoperative feeding of head and neck cancer patients, using an enteral diet supplemented with arginine, improves immunological and nutritional status, and clinical outcome; for example, reducing postoperative infectious/wound complications and length of stay, when compared with an isocaloric, isonitrogenous control diet.

Inclusion Criteria:
  • Adult patients with oral, pharyngeal and laryngeal cancer
  • Exclusion Criteria:
  • Severely impaired renal function (serum creatinine concentration > 2.5 mg/dl)
  • Severely impaired hepatic function (total serum bilirubin concentration > 3 mg/dl)
  • autoimmune disorders
  • insulin-dependent diabetes mellitus
  • ongoing infections



  • Description of Study Protocol:




    Prospective, randomized, controlled clinical trial

    Blinding used (if applicable)


    Intervention (if applicable)

    At the time of surgery, patients were randomly assigned to the study group or the control group. 

    • In all patients, the enteral diet was infused via a nasogastric tube. 
    • The feedings were started within 24 hours of surgery at 40 ml/hr and advanced 20 ml/hour every 24 hours until at goal rate on post-operative day 4.  All patients received calories and nitrogen by PN to achieve nutritional goals during post-operative day 1-3. 
    • Goal rate was determined by calculating 31.0 total kcal/kg, 25 non-protein kcal/kg, and 1.5 g pro/kg for each patient

    Study group:  received an enteral diet supplemented with arginine (Nutrison Intensive)

    Control group:  received an isocaloric, isonitrogenous enteral formula

    In addition, every patient received a prophylactic antibiotic treatment for 7 days post-operatively.

    Statistical Analysis

    Where appropriate, one-way analysis of variance (ANOVA), Student's t-test and x2 test was used.

    Data Collection Summary:

    Timing of Measurements

    Preoperatively and postoperatively on days 1, 4, and 8.

    Dependent Variables

    • serum level of albumin (g/dl)
    • prealbumin (mg/dl)
    • transferrin (mg/dl)
    • total number of lymphocytes (106/ml)
    • lymphocyte subsets (CD3, CD4, CD8, and CD4/CD8 ratio; %)
    • serum immunoglobulin concentrations (IgG, IgA, IgM; mg/dl)

    Independent Variables

    Enteral diet supplemented with arginine vs. standard enteral formula.

    Composition of formula (per 100 ml) from Table 1:

    Enriched Controlled

    Total proteins (g)

    6.22 6.25
            Casein 5.595 6.25
            Free L-arginine 0.625 ------
    Total lipids (g) 4.86 4.86
            Linoleic acid 1.18 1.25
            alphalinolenic acid 0.23 0.25
            omega-6/omega-3 ratio 5:1 5:1
    Carbohydrates (g) 13.58 14.11
    Total energy (kcal) 125 125
    Osmolarity (mosm/L) 300 255

    Control Variables

  • Prophylactic antibiotic treatment (amoxicillin/clavulanate, 2.2g bid I.V.) was given for 7 days postoperatively


  • Description of Actual Data Sample:

    Initial N: 44 patients (39 males / 5 females)

    Attrition (final N):  unknown; only states that 44 patients were examined.  Further states that there were no dropouts secondary to formula intolerance. 

    Age: Study group: 60.8 +/- 9.1; Control group: 63.2 +/- 5.7

    Gender: Study group: 21 males/2 females;  Control group: 18 males/3 females

    Ethnicity: unknown


    No significant difference between groups in regards to mean age, gender, body weight, malnutrition state, disease type and stage, or mean duration of operation.

    Weight loss >10% in one year:  enriched group 6 out of 23 patients; control group 7 out of 21 patients

    Location: unknown


    Summary of Results:




    Measures and standard deviation

    POD 1

    Measures and standard deviation

    POD 4

    Measures and standard  deviation

    POD 8

    Measures and standard deviation





    4.1 +/- 0.5

    3.9 +/- 0.3


    3.7 +/- 0.5*

    3.5 +/- 0.5*


    3.2 +/- 0.5*

    3.0 +/- 0.4*


    3.4 +/- 0.5*

    3.2 +/- 0.4*





    28.2 +/- 4.8

    29.7 +/- 4.5


    22.1 +/- 7.6*

    24.0 +/- 7.8*


    23.9 +/- 5.1

    25.1 +/- 6.2


    25.5 +/- 7.9

    26.7 +/- 6.7





    250.1 +/- 39.2

    242.0 +/- 28.7


    201.4 +/- 46.0*

    210.0 +/- 39.9*


    210.4 +/- 51.0*

    204.5 +/- 45.8*


    215.7 +/- 3501

    209.1 +/- 38.8*

    * p < 0.05 compared with preoperative value


    Other Findings

  • Gastrointestinal tolerance of both formula diets was good, no significant differences between groups.
  • Immunological variables dropped in both groups on POD 1
  • Only the enriched group had a significant increase (P<0.05) in total number of lymphocytes, CD 4 and CD4/CD8, on POD 4. 
  • Postoperative complication rate showed no difference (P=0.059)
  • Length of postoperative stay was 25 +/- 11.6 days, enriched; 28.0 +/- 12.6 days, control

    In malnourished patients only:

  • the enriched formula, malnourished, reduced both postoperative infection/wound complications and length of stay compared to control (p<0.05)
  • the enriched formula showed a significant increase (P<0.05) in CD4, CD4/8 on POD 4 and POD 8.


  • Author Conclusion:

    "In conclusion, arginine improves postoperative immunological response to head and neck cancer patients.  We stress the importance of preoperative nutritional assessment to identify malnourished patients (weight loss > 10% during the six months before surgery).  Our results suggest that these patients could benefit from an immunonutrient-enriched enteral diet."

  • unable to find any association between total lymphocyte number and nutritional status.
  • results demonstrate that an enteral diet supplementation with arginine speeds up recovery from the immunodepression following surgical trauma.
  • with a separate analysis on malnourished patients, results demonstrate that administration of a supplemented formula reduces major post-operative complications and length of post-operative stay significantly
  • Funding Source:
    University/Hospital: Maggiore della carita Hospital (Italy)
    Reviewer Comments:
    • This is a well-designed study by Riso et al with positive findings supporting the use of enteral immunonutiriton in head and neck cancer patients. 
    • Specific details on handling of study dropouts were not included. 
    • The authors separated the findings between malnourished and well-nourished patients, thus opening another avenue for 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) ???
      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? ???
      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? 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? 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? 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? 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)? N/A
      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? ???