ONC: Surgery (2006-2007)


de Luis, D.A., Izaola, O., Cuellar, L., Terroba, M.C., Aller, R. Randomized clinical trial with an enteral arginine-enhanced formula in early postsurgical head and neck cancer patients. Eur J Clin Nutr. 2004 Nov;58(11):1505-8.

PubMed ID: 15138461
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
The purpose of the study was to determine whether postoperative enteral  nutrition of head and neck cancer patients could improve nutritional variables and clinical outcomes.
Inclusion Criteria:
  • Oral and laryngeal cancer
Exclusion Criteria:
  • Severely impaired hapatic function (total bilirubin > 3.5 mg/dl)
  • Severely impaired renal function (serum creatinine > 2.5 mg/dl)
  • Ongoing infection
  • Autoimmune disorder
  • Steroid treatment
  • Nutritional oral supplementation in previous 6 months
  • Severely malnourished (weight loss > 10% body weight)
Description of Study Protocol:


    Subjects were oral and laryngeal cancer patients, Medicine School, Valladolid University, Institute of Endocrinology and Nutrition, Spain


    Prospective randomized trial

Blinding used:

    Patients were randomly allocated to groups; use or method of blinding was not mentioned.

Intervention (if applicable):

  • Baseline studies completed on all patients
    • Medical history
    • Physical examination
    • Nutrition assessment: Height, weight, body mass index
  • At surgery, patients were randomly allocated to 2 groups:
    • Group 1: Enteral dietary supplement with arginine and dietary fiber
      • 125 kcal/100 ml; 6.22 g pro/100 ml; 4.86g lipid/100 ml; 13.58 g carbohydrate/100 ml; dietary fiber 0.9g/100 ml
      • 0.625 g arginine/100 ml
    • Group 2: Isocaloric, isonitrogenous enteral formula with dietary fiber
      • 125 kcal/100 ml; 6.25 g pro/100 ml; 4.86g lipid/100 ml; 14.11 g carbohydrate/100 ml; dietary fiber 0.9g/100 ml
  • Enteral feeding was started within 12 hours of surgery at a rate of 20 ml/h via nasogastric tube
    • Infusion rate was increased every 24 hours until the nutritional goal was reached (32 kcal/g; 1.7 g protein/kg) on postoperative Day 4
    • Mean duration of enteral nutrition was 21 + 10 days
    • All patients reached goal rate; there were no dropouts
    • Endpoint to discontinue enteral feeding was oral intake of 1500 kcal/day and 1g/kg/day protein without supplementation, with a minimum 10 days enteral support
  • All patients received prophylactic antibiotics for 7 days following surgery (ceftazidime 500 mg tid i.v.; clyndamicine 300 mg tid i.v.)
  • Selected parameters were measured on postoperative Day 14 and compared to baseline
  • Data was analyzed for statistical and clinical significance

Statistical Analysis:

  • Sample size was calculated at 90% power and 5% significance
  • Distribution of variables was analyzed using the Kolmogorov-Smirnov test
  • Quantitative variables were analyzed using the two-tailed paired or unpaired Student's t-test
  • Nonparametric variables were analyzed with the Friedman and Wilcoxon tests
  • All randomized patients were included in statistical analysis (intention-to-treat analysis)
  • The level of statistical significance was defined as p = 0.05


Data Collection Summary:

Timing of Measurements

    Perioperatively and on postoperative Day 14 the following parameters were evaluated:

  • Serum prealbumin (mg/dl)
  • Serum transferrin (mg/dl)
  • Serum albumin (g/dl)
  • Postoperative complications

Dependent Variables

  • Variable 1: Weight
    • Measured at nutritional assessment
  • Variable 2: Lymphocytes (1.2-3.5 x 10l)
    • Analyzed using an analyzer (Beckman Coulter Inc, LA, CA, USA)
  • Variable 3: Albumin (3.5-4.5 g/dl)
    • Fasting blood samples were drawn
    • Measured with an autoanalyzer (Hitachi, ATM, Mannheim, Germany)
  • Variable 4: Prealbumin (18 - 28 mg/dl)
    • Fasting blood samples were drawn
    • Measured with an autoanalyzer (Hitachi, ATM, Mannheim, Germany)
  • Variable 5: Transferrin (250-350 mg/dl)
    • Fasting blood samples were drawn
    • Measured with an autoanalyzer (Hitachi, ATM, Mannheim, Germany)
  • Wound complications
    • Fistula
    • Wound infection
  • General infections
    • Respiratory infections were diagnosed by radiographic exam, temperature above 38.5° C, and isolation of pathogens from sputum or blood culture
    • Urinary tract infections were diagnosed if urine culture showed at least 105 of a pathogen
  • Diarrhea (> 5 liquid stools/24 hrs or > 2000 ml/day)
  • Length of stay
  • All complications were assessed with standard methods by the same investigator.

Independent Variables

  • Presence of oral or laryngeal cancer
  • Surgery
  • Enteral feeding

Control Variables

  • isocaloric, isonitrogenous enteral formula


Description of Actual Data Sample:

Initial N:

  • Group 1(arginine-enhanced enteral formula): n = 45 (3 females, 42 males)
  • Group 2 (isocaloric, isonitrogenous enteral formula): n = 45 (3 females, 42 males)

    There were no significant differences between the groups regarding gender, mean age, body weight, location, and stage of tumor

Attrition (final N):

    No dropouts were present in this study.


  • Group 1:  60.2 + 12.5
  • Group 2:  60.6 + 11.5


    Not mentioned

Other relevant demographics:

    Tumor stage:

  • Group 1: Stage 1 (0); Stage 2 (5); Stage 3 (14); Stage 4 (26)
  • Group 2: Stage 1 (0); Stage 2 (5); Stage 3 (11); stage 4 29



  • Group 1: 25.2 + 3.3
  • Group 2: 25.1 + 3.3

    Weight (kg):

  • Group 1: 69.8 + 11
  • Group 2: 69.3 + 10.2

    Weight loss prior to surgery:

  • Group 1: 2.5%
  • Group 2: 1.4%,

    Diagnosis of disease:

  • Group 1: 23 oral cavity, 22 larynx
  • Group 2: 20 oral cavity, 25 larynx


    Institute of Endocrinology and Nutrition, Medicine School, Valladolid University, Simancas, Valladolid, Spain


Summary of Results:

Variables (Serum protein and anthropometric parameters)

Base measurement

Day 14


Statistical significance of difference

Weight (kg)    

Group 1: 69.7 + 11.1

Group 2: 69 + 10.9

Group 1: 68.9 + 10.2

Group 2: 67.8 + 10.8



Lymphocytes (103 µl/mm3)

Group 1: 1531 + 522

Group 2: 1205 + 684

Group 1: 1878 + 1168

Group 2: 1548 + 841

p < 0.05

p < 0.05

Albumin (g/dl)

Group 1: 2.43 + 0.5

Group 2: 2.49 + 0.4

Group 1: 3.17 + 0.88

Group 2: 3.1 + 0.57

p  < 0.05

p < 0.05

Prealbumin (mg/dl)    

Group 1: 14.5 + 7.2

Group 2: 12.2 + 4.7

Group 1: 22.5 + 6.6

Group 2: 21.4 + 7.4

p < 0.05

p < 0.05

Transferrin (mg/dl)

Group 1: 135.6 + 39.3

Group 2: 145.9 + 56

Group 1: 181.1 + 48.8

Group 2: 182.9 + 37.5

p < 0.05


p < 0.05    

 Patient Complications

 Group 1    

 Group 2

 Statistical significance of difference

 Fistula of wound



 P < 0.05

 Infection of wound




 General infection







 P < 0.05

 Length of stay

 25.8 + 15

 35 + 24.6

 P < 0.05

Other Findings

    There were no significant intergroup differences in the plasma proteins and interleukins.

    Group 1 had a significantly higher rate of diarrhea than Group 2.

    Group 1 had a significantly shorter length of stay than Group 2.

Author Conclusion:

    The authors concluded that arginine-enhanced enteral formula improves the rate of fistula in postoperative head and neck cancer patients, and shortens the length of stay.

    The authors stated that arginine was the only difference between their two formulas; therefore, the authors think it likely that arginine was the key to improved outcomes.

Funding Source:
University/Hospital: University of Valladolid
Reviewer Comments:

Well designed, well implemented randomized controlled trial

Longer time period of enteral nutrition (average 21 days) than other studies; longer time period to demonstrate effects

Use and/or method of blinding unknown

Albumin may not be an accurate indicator of serum protein status at Day 14 postoperatively, due to albumin's long half-life

Unknown if subject population is representative of the study's target population


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? ???
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%.) 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? N/A
  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.) 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
  5.5. 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? 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)? 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? ???
  10.2. Was the study free from apparent conflict of interest? ???