ONC: Glutamine (2006)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To assess the feasability of oral glutamine supplementation in bone marrow transplant patients receiving high dose cytotoxic therapy and its effect on incidence and severity of gastrointestinal mucositis, diarrhea and hematological indices. If the incidence of mucositis was reduced, to investigate if there would be a decrease in the usage of parenteral nutrition.
Inclusion Criteria:
  • Patients with hematological malignancies including:
    • Acute myeloid leukemia
    • Cronic myeloid leukemia
    • Hodgkins disease
    • Myeloma
    • Non-Hodgkins lymphoma
  • Received autologus bone marrow transplant following 6 days of BCNU (Carmustine), etoposide and melphalan
  • BMI 20-30 Kg/m2
Exclusion Criteria:
Not specified
Description of Study Protocol:

Recruitment: Not Described

Design: 24 patients (BMI 20-30 kg/m2) with hematological malignancies receiving high dose cytotoxic therapy and bone marrow transplant were randomized in pairs to receive 16g of glutamine powder in 4 divided doses or placebo from day 1 post-transplant until resolution of mucositis or discharge. Measurements of type and quantity of bowel movements, amount of intravenous diamorphine, hospital stay, presence of parenteral nutrition, fever, neutropenia, and platelet count as well as a patient self-completed mucositis assessment and a nursing mucositis assessment were recorded daily.

Information on enteral intake was not assessed and parenteral nutrition was initiated when estimated oral intake was < 1,000 Kcal. This typically occured 5-7 days post-transplant. Parenteral nutrition provided 2,000-2,500 Kcal/ day and 12.5g of nitrogen and was provided for 1-2 weeks until oral intake reached 1,000 Kcal.

Mucositis assessment tools (Tables 1 and 2) were utilized daily to assess mucositis score by the patient and observer (nursing). Patients completed this assessment daily from day 1 of supplementation. The nurses of the bone marrow transplant unit completed the more objective Observer Mucositis Assessment, based on a grading system similar to WHO mucositis grading, daily as well. The objectivity of the observer rating was confirmed when 6 independent observers made identical evaluation of mucositis in 6 patients.

Table 1: Patient Mucositis Assessment

How does your mouth feel today?

0    No change from normal
1    Slightly sore mouth/Little or no difficulty in eating
2    Sore mouth/Pain when eating adn swallowing
3    Considerable mouth pain with redness, ulcers and inflammation
4    Severe pain/Unable to eat or drink






Table 2: Observer Mucositis Assessment
0    Normal Mucosa. No inflammation or ulceration
1    "Chewed tongue" syndrome. < 3 sites inflammation/ulceration
2    > 3 sites inflammation/ulceration
3    Overall inflammation/ulceration of the mouth ± throat. Profuse saliva production
4    Overall inflammation/ulceration of the mouth ± throat. Thick stringy saliva requiring manual removal from mouth ± saline nebulizers






Blinding used: Pairing and randomization of subjects was performed by personnel independent of further involvement in the study. Each pair the subjects were matched for their current treatment because the dose of the chemotherapy agent varied as part of a dose intensification protocol. Researchers and patients were blinded as to the allocation to treatment group. Details of the randomization not described.

Intervention: Subjects were asked to consume 16 g of glutamine or placebo (Polycal) in four equal doses throughout the day. The recommended administration schedule was post meals and prior to bed. Each dose was presented in an individual packet and mixed with 150ml of water or cold fluid immediately prior to use. Subjects were instructed to use the mixture as a mouthwash prior to swallowing. Supplementation began day 1 post-transplant and continued until mucositis resolved or discharge from the hospital.

Statistical Analysis:

  • Student's paired t-test 
  • Mean and standard deviation
  • Chi square for response rates


Data Collection Summary:

Timing of Measurements:

Daily measurement of:

  • Patient mucositis assessment (by multiple choice questionnaire) *see below for scoring scale
  • Observer mucositis assessment (completed by nursing) *see below for scoring scale
  • Diarrhea
  • Intravenous diamorphine
  • Parenteral nutrition
  • Hospital stay
  • Neutropenia
  • Platelet count

Dependent Variables

  • Variable 1: Severity of mucositis as measured by "Patient Mucositis Assessment" and "Observer Mucositis Assessment" (0-4 scale)
  • Variable 2: Number of days of diarrhea (>4 loose stools/day) as measured by daily records
  • Variable 3:Intravenous diamorphine use as measured by daily records
  • Variable 4: Parenteral nutrition use as measured by daily records
  • Variable 5: Hospital stay (from day 1 of treatment as measured by daily records
  • Variable 6: Hematological indices as measured by neutrophil count and platelet count

Independent Variables: Amount of glutamine consumed as part of a daily swish-and-swallow regimen.

Description of Actual Data Sample:

Initial N: 24 [Experimental Group 12, Placebo Group 12] (Sex not specified)

Attrition (final N): 16 [Experimental Group 8, Placebo Group 8] (Sex not specified)

Age: Not specified

Ethnicity: Not specified

Other relevant demographics: Not specified

Anthropometrics: Not Specified

Location: Addenbrooke's Hospital, Hills Rd, Cambridge UK

Summary of Results:



Glutamine (n=8)

Placebo (n=8)

Statistical Significance of Group Difference

Total Mucositis Score (Patient)

17.0 ± 11.5

26.6 ± 18.6


Total Mucositis Score (Observer)

 31.1 ± 11.4

 32.3 ± 12.1






Days with Mucositis Score > 3 (Patient)

 1.4 ± 2.1

2.1 ± 4.2


Days with Mucositis Score > 3 (Observer)

5.9 ± 5.1

7.0 ± 6.1


Days of Diarrhea

3.1 ± 3.5

3.3 ± 3.7


Days of Temperature > 37.5° C

2.9 ± 2.6

3.5 ± 3.8


Days of Neutropenia

(<0.5 x 109/L)

28.4 ± 11.5

25.4 ± 11.4


Days of Low Platelets

 (<50 x 109/L)

53.6 ± 57.1

43.6 ± 22.9


Days of Parenteral Nutrition

11.3 ± 5.0

6.6 ± 4.2


Days of IV Diamorphine

5.0 ± 4.6

6.6 ± 7.7


Hospital Stay

25.6 ± 2.2

28.3 ± 5.5


Other Results:

  • Mean consumption of treatment, NS for group difference:
    • 69% ± 15% of total 16g dose, Glutamine group
    • 76% ± 15% of total 16g dose, Placebo group
  • Disease outcome assessed at 6 months post discharge indicated no significant difference in response rates.
Author Conclusion:

No improvement in clinical course of bone marrow transplantation as measured by severity of mucositis, incidence of diarrhea, hematological indices, and hospital stay with supplementation of 16g of glutamine daily.

"Glutamine supplementation may be ineffective in the management of cytotoxic-induced oral mucositis."

The absence of any significant differences between glutamine and placebo groups may be a result of the study design and/or the dose of glutamine used since other studies used larger doses.

Additional confounding factors include patient's performance status and prior chemotherapy treatments, both of which could have an impact on mucositis.

Finally, the large volume of fluid required to consume the glutamine (600 ml/day) may have impacted the consumption of glutamine/placebo in those with mucositis. The authors recommend using soft-solids to mix the glutamine/placebo.

Larger trials are needed, especially those in which all patients receive the same treatment.

Funding Source:
University/Hospital: Addenbrook's Hospital
Foundation associated with industry:
Reviewer Comments:

This study provided no information on the demographics or specifics about the anticancer treatment for these subjects. There was no information  on the adequacy of diet to suggest if the glutamine was utilized to meet daily requirements.


  • No information on:
    • Patient demographics
    • Exclusion Criteria
    • Enteral Intake
    • Nutritional Needs
    • Percentage of Nutritional Needs met by Parenteral Nutrition
    • Tolerance of treatment
  • Too few statistical tests
  • Small sample size
  • No information on validation of mucositis assessment tools
  • 33% of the patients were excluded from analysis because of  non-compliance
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? No
  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? No
  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) No
  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? No
  4.1. Were follow-up methods described and the same for all groups? No
  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%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  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? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  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.) Yes
  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? No
  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? ???
  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? No
  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? No
  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? No
  8.1. Were statistical analyses adequately described and the results reported appropriately? No
  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)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  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? No
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? ???