• Increase Font Size
  • Decrease Font Size
  • View as PDF

ONC: Glutamine (2006)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To study the effect of glutamine in preventing doxifluridine-induced diarrhea as well as its potential impact on tumor growth.
Inclusion Criteria:
  • aged >70 years
  • diagnosed with advanced breast cancer
  • treated with oral doxifluridine (600 mg/m2) plus leucovorin (25 mg dose), both two times per day for 4 consecutive days every 12 days
  • gave oral informed consent
Exclusion Criteria:
  • pretreated with pelvic irradiation
  • had a history of diarrhea
Description of Study Protocol:

Recruitment   From April 1993 to October 1995, 67 patients from the Instituto nazionale in Milan, Italy who were >70 years of age and had advanced breast cancer about to undergo oral doxifluridine (600 mg/m2) plus leucovorin (25 mg dose), both two times per day for 4 consecutive days every 12 days were asked to participate.

Design  Randomized double-blind

Blinding used Randomization was handled in a double-blind manner by an individual who had no further involvement with the study.

Intervention Glutamine was delivered at the dose of 30 g/d for 8 consecutive days during the chemotherapy-free period.  The daily intake was divided into 3 equal doses presented in separate sachets and taken dissolved in 50 ml of cold fluid (nonalcoholic) after the main meals.  The placebo was maltodextrine; it was given on the same schedule. 

Statistical Analysis  Differences between glutamine and placebo were assessed using the chi-square test.

 

Data Collection Summary:

Timing of Measurements:

  • Patients had to complete a daily card reporting the regular or irregular intake of the drugs and supplements. 
  • Evaluation of toxicity, according to National Cancer Institute (NCI) criteria, was made before each cycle of chemotherapy, and patients were asked in particular about the number of episodes of diarrhea and the temporal duration of this side effect. 
  • A complete blood count was performed every 12 days for assessing hematological toxicity, whereas routine serum biochemistry was done every 3 cycles. 
  • Responses were evaluated according to World Health Organization criteria every 5 cycles of chemotherapy.

GRADING of NCI Diarrhea

Diarrhea Score
None     0
Increase of 2-3 stools/day compared with pretherapy 1
Increase of 4-6 stools/day or nocturnal stools 2
Increase of 7-9 stools/day or incontinence 3
Increas of >10 stools/day or grossly bloody diarrhea, or need for parental support 4

Dependent Variables

  • Diarrhea: Incidence was recorded after each cycle of chemotherapy and severity was scored by the NCI classification 
  • Nausea and vomiting
  • Mucositis
  • Gastric pain
  • Body Mass Index

Independent Variables: 30 g / day glutamine for 8 consecutive days during chemotherapy-free period or placebo

Control Variables Chemotherapy twice daily for 4 consecutive days every 12 days.

 

Description of Actual Data Sample:

Initial N: 67 (35 glutamine, 32 placebo)

Attrition (final N): 65 (33 glutamine, 32 placebo)

Age: 73.5 years (70-88 years) glutamine; 73.5 years (70-86 years) placebo

Ethnicity: not specified

Other relevant demographics:

A total of 278 cycles were delivered in the glutamine group with a median of 10 cycles per patient (range 3-15) and with a mean delivered dose intensity (DDI) of 396mg/m2/d-1 of doxifluridine.  The median duration of treatment was 3.5 months (range 1-5 months).

A total of of 259 cycles, with a median of 10 cycles per patient (range 1-15), were performed in the placebo group with a mean DDI of 391 mg/m2/d-1 of doxifluridine.  The median duration of treatment was 3 months (range 1-6 months).

Performance status and disease-free index were similar between groups.

Anthropometrics: not specified 

Location: not specified

 

Summary of Results:

Other Findings

  • The prevalence of diarrhea according to NCI criteria affected 16 patients in each group, with a global prevalence of grade 3-4 of 6% in glutamine group and 16% in placebo (P=NS), whereas considering only the affected patients a grade >3 was registered in 12% and 31%, respectively (P=NS).
  • The registered episodes of diarrhea were 34 in glutamine group and 32 in placebo.
  • No difference in prevalence of diarrhea was observed between glutamine and placebo group even when the analysis was performed cycle by cycle.
  • The median duration of diarrhea was 2 days in glutamine group and 3 days in placebo.
  • Grade 1-2 nausea and vomiting, mucositis, and gastric pain had a similar prevalence in the two groups; only one patient in the placebo group experienced grade 3 nausea and vomiting.
  • There was no significant difference in hematological toxicity.
  • The body mass index decreased in a non-significant manner by one unit in both groups.

 

Author Conclusion:
  • This study fails to demonstrate that oral glutamine supplementation can reduce the diarrhea rate in cancer patients receiving doxifluridine.
  • No difference was found in prevalence or severity of diarrhea and response to classification between those randomized to glutamine and those to placebo.
  • Inefficacy of oral glutamine in preventing intestinal toxicity requires further investigation.
  • A possible explanation for discrepancy between the experimental literature and the results of this study are that changes in circulating glutamine concentration are observed when tumor size is >10% body weight and there is visible evidence of cachexia; however, the patients participating in this study did not appear to be severely depleted.
  • The authors stated that "for the first time in a clinical setting, their data showed that oral glutamine supplementation does not interfere with tumor response in breast cancer patients treated with doxifluridine, and that glutamine is well tolerated and may safely be further investigated in cancer patients."
Funding Source:
Reviewer Comments:

Agree with the authors' conclusion and thought this was an overall good study.

Limitations:

  • No information on ethnicity of participants
  • No assessment of diarrhea prior to study
  • Did not exclude GI disease
  • Did not exclude or account for XRT therapy
  • Did not give source of gln
  • Did not listing funding source
  • Would have been helpful to figure out gln consumed per body weight since there were problems with complicance to prescribed dosage
  • Did not account for other medications interferring with study protocol (ie., patients taking antidiarrheals)
  • It should be noted that gln was only taken as prescribed in 29/32 patients and placebo was only taken as prescribed in 25/32 patients.
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? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  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? 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.) N/A
  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.) No
  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? No
  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? 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? N/A
  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? 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? 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)? 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? 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? No
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? ???