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ONC: Glutamine (2006)

Citation:

Decker-Baumann C, Buhl K, Frohmüller S, Herbay Av, Dueck M, Schlag PM. Reduction of chemotherapy-induced side-effects by parenteral glutamine supplementation in patients with metastatic colorectal cancer. Euro J Cancer, 1999;35(2): 202-207.

PubMed ID: 10448260
 
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:
To investigate the effects of parenteral glutamine supplementation on 5-fluorouracil (5-FU)/calcium-folinate (CF) chemotherapy-associated alterations of the gastrointestinal mucosa in humans.
Inclusion Criteria:
  • Metastatic colorectal carcinoma, none otherwise specified.
  • Informed consent.
Exclusion Criteria:
None specified.
Description of Study Protocol:

Recruitment

  • Not specified. Approved by the Medical Ethical Committee of the University of Heidelburg. 

Design

  • Prospective, controlled and randomized study.

Blinding used

  • The endoscopist did not know to which group each patient belonged.
  • Otherwise, no blinding used.

Intervention

  • Parenteral Glutamine intervention group
    • Received parenteral glutamine supplementation in combination with 5-fluorouracil (5-FU)/calcium-folinate (CF)
    • Glutamine administered as glycyl-L-glutamine (GlyGln) i.v. over eight hours in a 10% solution
    • Supplementation occurred one day before and during chemotherapy at a dosage of 0.4 g/kg body weight per day of GlyGln (14-22 g Gln/day).
  • Control group
    • Chemotherapeutic treatment without glutamine supplementation.
  • Patients observed over three courses of cytostatic therapy
    • 5-FU (550 mg/m2/day) was given continuously for five days
    • CF (170 mg/m2/day) given as intravenous bolus on each of five days
    • Above repeated every four weeks.

Statistical Analysis

  • Results expressed as mean ± standard deviation
  • Wilcoxin Rank Sum test for comparison before and after treatment in groups
  • Mann-Whitney U-test for group comparisons for statistical significance
  • P-values below 0.05 were considered significant.
Data Collection Summary:

Timing of Measurements

  • Effectiveness of supplementation by gastroscopy and duodenoscopy
    • Before and after the first and third chemotherapy courses.
    • Biopsies of the distal duodenum for intracellular gln concentrations and histomorphometric exam.
  • Venous blood samples
    • Before and after the second chemotherapy course
    • Plasma amino acids
    • Pre-albumin
    • Retinol binding protein (RBP)
    • Routine biochemical parameters.
  • Food intake during chemotherapy
    • Precise weighing method
    • Nutrient intake calculated using the software program Prodi 3.2 Plus, on the basis of the German food composition table.
  • Chemotherapy-induced side-effects
    • Documented during the whole study course
    • Graded according to World Health Organization (WHO) criteria.
  • Mucositis (oral and anal)
    • Assessed by observation
    • One day before and one day after each chemotherapy course
    • Classification scale
      • 0: No abnormalities
      • 1-2: Mucositis
      • 4-5: Ulcerations.
    • Findings before and after chemotherapy compared and scored with a range +4 to -4.

Dependent Variables

  • Villus height and crypt depth
  • Duodenal glutamine mucosal concentration
  • Plasma glutamine
  • RBP
  • Pre-albumin
  • WHO criteria of chemotherapy-induced side effects
  • Mucositis.

Independent Variable

  • Glutamine supplementation.

Control Variables

None

Description of Actual Data Sample:

  • Initial N: 24
  • Attrition (final N): 24.

 

Glutamine group (N=12)

Controls (N=12)

Age (Mean±SD)

56.1±9.6 years
(Range 40-67 years)

58.4±7.2 years
(Range 44-66 years)

Sex

4 female, 8 male

5 female, 7 male

Response (classification by WHO guidelines)

 

 

     Partial response

3

4

     No change

5

5

     Progressive disease

4

3

Summary of Results:
  • Both groups comparible in age and resonse to chemotherapy
  • Due to severe side effects, chemo dose reduced:
    • Two cases in control group
    • One case in the glutamine group.
  • No significant difference between the two groups before or during the study and all were in the normal range
    • Mean body weight
    • Mean plasma pre-albumin
    • Mean plasma RPB concentration.
  • Energy and protein ingestion
    • No differences between groups during first and second therapy courses
    • Control group had a significantly higher mean energy (P=0.01) and mean protein (P<0.05) intake during third course of therapy.
    • Mean total protein intake remained significantly higher in glutamine group (oral plus GlyGln) (first chemo course P=0.001; second chemo course P=0.01; third chemo course P<0.05).
  • Plasma glutamine concentration remained unchanged, but intracellular glutamine in the duodenal mucosa was higher in the intervention group after the third course of chemotherapy.
  • No significant differences in ratio of villus height to crypt depth (v:c ratio) between groups.
  • V:c ratio decreased slightly in controls before first and third chemotherapies and increased in glutamine group after the first (P=0.01) and third (P=0.03) chemotherapy courses.
  • Mucositis and ulcerations of gastric and duodenal mucosa lower in glutamine group than controls (P<0.05).
  • In total, no significant differences between the groups regarding clinical side-effects according to WHO criteria.

[Note: Technical problems occurred with the suction biopsy capsule led to a decreased number of biopsies and endoscopic examinations. Problems were solved and described.]

Author Conclusion:
  • The protective effect of the gastrointestinal mucosa shown in this study using glutamine supplementation can be expected in in patients receiving 5-FU/CP chemotherapy.
  • These results are encouraging and should be confirmed in larger trials.
Funding Source:
Industry:
Reviewer Comments:

Limitations

  • The small sample size
  • Did not exclude for prior chemotherapy, concurrent or prior XRT
  • Did not look at length of disease as a possible confounding factor
  • Study funding/paid patients: Patients seemed to undergo some pretty extensive testing with no drop out.

Positive points

  • Used WHO grading for mucositis
  • Gln dosing per body weight
  • Addressed many potential issues with gln administration
  • Evaluated effect of gln over more than one round of chemotherapy.
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? ???
  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? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? ???
  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? ???
  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? ???
  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? ???
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? ???
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? ???
  5.5. In diagnostic study, were test results blinded to patient history and other test results? ???
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? ???
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? ???
  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? ???
  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? Yes
  10.2. Was the study free from apparent conflict of interest? ???