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ONC: Glutamine (2006)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
The purpose of this study was to evaluate if oral glutamine could help prevent intestinal toxicity, measured by changes in intestinal absorption (IA) and intestinal permeability (IP), and the clinical counterpart of these changes which is diarrhea, induced by chemotherapy with 5-Fluorouracil (FU) / folinic acid (FA) in patients with colorectal cancer.
Inclusion Criteria:

Patients who were scheduled to receive chemotherapy with FU/FA as treatment for advanced or metastatic colon cancer or as adjuvant therapy, as a precautionary adjunctive treatment after surgical resection for colon cancer.

  • All patients had a performance status (PS) not worse than 2 according to the Eastern Cooperative Oncologic Group scale (PS 0=normal activity; PS 1= symptoms but fully ambulatory; PS 2=some bed rest, but in bed < 50% of normal daytime).
  • Patients were scheduled to receive chemotherapy with FU/FA. 
  • Patients had not received chemotherapy previously.
  • Creatinine clearance was normal.
  • Patients gave informed consent to participate in the study.
Exclusion Criteria:
This study did not list any specific exclusion criteria.
Description of Study Protocol:

Recruitment: 70 patients entered the study between June 1996 and April 1998 who were scheduled to receive chemotherapy with FU/FA as treatment for advanced or metastatic colon cancer or as a precautionary adjunctive treatment after surgical resection for colon cancer.  Chemotherapy consisted of daily administration 100 mg/m2 FA followed by 450 mg/m2 FU for 5 days.

Design: A double blind, two arm,  randomized controlled trial comparing oral glutamine with placebo.  Patients were randomized by telephoning the clinical trials office where clinicians used a computer driven procedure with stage of treatment as the stratifying variable. 

Blinding used (if applicable): Patients, clinicians, and statistians were blind to the assigned treatment.

Intervention (if applicable): Glutamine and placebo were obtained as crystalline powders in sachets, each containing 3g of either glutamine or placebo (maltodestrins).  Patients were instructed to consume the contents of 6 sachets (18g) / day dissolved in water.  To assess compliance, patients were instructed to record the number of sachets consumed each day and return unused sachets.  Glutamine or placebo was administered for 15 consecutive days, starting 5 days before the first day of chemotherapy.

Statistical Analysis:  Overall effect of chemotherapy on IA and IP was assessed by comparing pre- and post-treatment values for the whole group using the Wilcoxin signed rank test.  For each pt., differences between IP and IA tests before and after treatment were calculated.  Differences were then compared between the 2 study arms by the non-parametric Mann-Whitney test.  Daily assessments of diarrhea were summarized for each patient by means of AUC (area under the curve) using the trapezoidal rule.  All p values were two-sided. 

 

Data Collection Summary:

Timing of Measurements:  Baseline evaluations of IA and IP were performed 2 and 1 day before starting the study treatment.  Post-treatment IA and IP tests were performed 1 and 2 days stopping the study treatment.

Dependent Variables

  •  Intestinal absorption (IA) was assessed by the D-xylose absorption test. 
  •  Intestinal permeability (IP) was assessed by the cellobiose-mannitol permeability test.

To obtain data on toxicity, patients were provided with a diary to record the following daily:

  • nausea (yes/no)
  • vomiting (yes/no; #of episodes
  • number of stools; consistency of stool (normal; soft; watery)
  • presence of fecal blood (yes/no)
  • abdominal pain (yes/no)
  • number loperamide tablets consumed (pts. were instructed to take loperamide tablets, 4 mg. dose after the first watery stool followed by a 2 mg. doses every 4 hours.)

For diarrhea, common criteria grades were defined as follows:

  • grade 0 - none
  • grade 1 - increase of <4 stools/day over pretreatment
  • grade 2 - increase of 4-6 stools/day or nocturnal stools
  • grade 3 - increase of >7 stools/day, incontinence, or need for IV hydration
  • grade 4 - physiological consequences requiring intensive care or hemodynamic collapse

Independent Variables: 18 g glutamine or placebo for 15 consecutive days, starting 5 days prior to the first day of chemotherapy.  

Control Variables: Daily chemotherapy administration.

 

Description of Actual Data Sample:

Initial N: 70 (35 glutamine, 35 placebo)

Final N: 62 (29 glutamine / 17 males, 12 females; 33 placebo / 19 males, 14 female)

Mean Age Range: 63 years (44-76) glutamine; 61 years (35-75) placebo

Ethnicity: not specified  

Anthropometrics: There were no differences in baseline clinical and functional characteristics between the two arms.  Only 7 patients (11%) were severly malnourished with a body mass index <20 kg/m2. 

 

 

Summary of Results:

 

  • For the whole group, chemotherapy induced significant worsening of IA and IP. 
  • Mean values for D-xylose and mannitol absorption dcreased by absolute values of 5.5% (relative decrease 23%; p<0.0001) and 7.0% (relative decrease 33%;p<0.0001), respectively.
  • Mean values for cellobiose absorption and the cellobiose/mannitol ratio increased by absolute values of 0.14% (relative increase 50%;p=0.003) and 0.025 (relative increase 167%; p<0.0001), respectively.
  • Differences between pre- and post-treatment showed reduction in IA was more marked in the placebo arm (7.1% vs. 3.8%; p=0.02).  Reduction in IP to mannitol was higher in the placebo arm (9.2% vs. 4.5%; p=0.02).
  • One case of grade4 diarrhea was observed in the placebo and none in the glutamine arm.
  • Diarrhea lasted longer in patients receiving placebo compared with glutamine.
  • The AUC for diarrhea was larger in the placebo group.
  • Patients in the placebo group consumed significantly higher mean number of loperamide tablets than pts. in the glutamine group (2.6 vs. 0.4; p=0.002).
  • Glutamine did not prevent severe stomatitis; however, grade >2 stomatitis was observed in 5 (17%) patients who received glutamine and in 7 (21%) who received placebo.
  • The mean duration of stomatitis was similar in the glutamine and placebo arms (4.2 and 3.4 days, respectively). 
  • There was no difference in nausea, vomiting between groups.
Author Conclusion:

 

  • An oral supplement of 18 g. glutamine significantly reduced the degree of impairment of IA and IP in patients treated with FU/FA chemotherapy.
  • Chemotherapy with FU/FA reduced IA and increased IP in both the glutamine and placebo groups, consistent with the damaging effect of chemotherapy on the gut mucosa; however, changes in both IA and IP were significantly more marked in the placebo group.
  • Our clinical data suggest that glutamine can significantly reduce the duration and severity of diarrhea (diarrhea was was a secondary endpoint of interest).
  • The aurthors concluded the effect of glutamine on chemotherapy induced stomatitis remains to be established.
Funding Source:
Reviewer Comments:

 

Exclusion criteria was not indicated and location of the study was not specified.

The tests used to assess IA and IP appeared to be reliable to measure changes in small intestinal mucosa.

Overall in this study, 18 g. of oral glutamine did have a protective effect on intestinal mucosa in patients treated with FU/FA chemotherapy.

This study did not indicate how stomatitis was assessed or graded.

The effect of diarrhea was only a secondary endpoint in this study that was under powered to identify small clinical differences.  The authors suggest their clinical data showed that glutamine can significantly reduce the duration and severity of diarrhea. However, the significantly higher consumption of loperamide in the placebo group could have diluted the differences in severity of diarrhea.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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? ???
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? ???
  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? N/A
  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? 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? N/A
  6.6. Were extra or unplanned treatments described? Yes
  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? N/A
  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? N/A
10. Is bias due to study's funding or sponsorship unlikely? No
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? Yes