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ONC: Glutamine (2006)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To evaluate if oral glutamine could prevent or minimize stomatitis in patients experiencing stomatitis after chemotherapy.
Inclusion Criteria:
  • Patients who just experienced stomatitis after their last course of chemotherapy.
  • Patients who are planning to receive the same chemotherapy doses during the next course of treatment as during the previous treatment.
  • All patients patients gave written informed consent.
Exclusion Criteria:

Not indicated

Description of Study Protocol:

Recruitment Patients experiencing stomatitis after a course of chemotherapy were offered the opportunity to enter this study if no other parameters precluded receiving the same chemotherapy doses during the next course of treatment. IRB approval from the University of Minnesota Hospital and Clinics.

Design Non-randomized pilot study.

Intervention All patients received the same chemotherapy regimen as during the previous treatment but in addition received a suspension of L-glutamine, 4 gm swish and swallow orally twice a day, from day 1 of chemotherapy for 28 days or for 4 days past the resolution of any post-chemotherapy stomatitis.  The suspension of glutamine was prepared by mixing 50 gm L-glutamine, supplied as a crystalline powder, with 2 parts of ORA-Sweet, 1 part ORA-Plus, and 1 part water to yield a suspension of 500 mg/ml L-glutamine.  Thus the final suspension contained 500 mg/ml glutamine, 30% sucrose, 2.5% glycerin, 2.8% sorbitol, 0.04% citric acid, 0.36% NaPO4, 0.16% cellulose and carboxymethylecellulose, 0.04% carrageenan, and 0.04% xanthum gum.  The suspension was stored in a refrigerator until use for less than 4 weeks.

Statistical Analysis Maximum grade of mucositis and total number of days of mucositis were compared by the Mann-Whitney (mucositis grade) or paired t test (days of mucositis).

 

Data Collection Summary:

Timing of Measurements  were reported by patients to the investigators at the end of each course of chemotherapy.

Dependent Variables

  • Total number of days of mucositis (reported to investigators by the patients) 
  • Severity of mucositis (number of days at each grade). The severity of mucositis was graded as follows (a modified CALGB criteria):
    • 0, no mucositis
    • 1, painful mucositis not necessitating a change in oral intake
    • 2A, painful mucositis restricting oral intake to soft foods
    • 2B, painful mucositis restricting oral intake to liquids
    • 3,  mucositis restricting oral intake
    •  Mucositis grade were determined by the patient according to tolerance and were reported by patients to investigators.
  • The patient's subjective impression as to whether the mucositis was more severe, the same, or less severe with glutamine supplementation.
  • The nadir neutrophil count.

Independent Variables Glutamine supplementation

 

 

Description of Actual Data Sample:

Initial N: 17 (not differentiated for sex of patients)

Attrition (final N): 14 (8 male, 6 female)

*It is important to note that this study started out as a placebo-controlled trial. The first 3 patients assigned to the placebo group refused to continue the study since the placebo would not relieve their mucositis. Intent-to-treat analysis was not completed in this study, resulting in the 14 patients as the final n.

Age: not indicated

Ethnicity: not indicated

Other relevant demographics: 8 patients were given a 9 day continuous infusion of doxorubicin, docarbazine, and cyclophosphamide (starting doses: 60 mg/m2, 1000 mg/m2, and 250 mg/m2, respectively) 7 of these patients had a soft tissue sarcoma and 1 patient a mesothelioma. One patient with AIDS and Kaposi's sarcoma was given 45 mg/m2 doxorubicin by constant iv infusion over 5 days, 400 mg/m2 dacarbazine iv bolus, and 2mg vincristine iv push.  One patient with breast cancer was given 60 mg/m2 doxorubicin, 600 mg/m2 cyclophosphamide, and 600 mg/m2 5-fluorouracil, iv bolus.  One patient with osteosarcoma received 75 mg/m2 of doxorubicin over 3 days by continuous infusion and 1.5 gm/m2/day of ifodfamide by bolus administration on days 1,2,3,4, and 5. One patient with a soft tissue sarcoma receive 50 mg/m2/day of etoposide orally for 21 days.  One patient with osteosarcoma received 7.5 gm/m2 of ifosfamide and 500 mg/m2 of VP-16 over 5 days and 900 mg/m2 of carboplatin over 2 days by bolus infusion. And a patient with squamous cell carcinoma of the head and neck received 55 mg/m2 of doxorubicin and 25 U of bleomycin by continuous infusion over 5 days.

Anthropometrics not indicated

Location: not specific

 

Summary of Results:
  • The maximum grade of mucositis decreased in 12 of 14 patients with glutamine supplementation (median score 2A vs 0.5, p < 0.001) and remained the same at grade1 in 2 of 14 patients (the median score 0.5 is arbitrary, because half of the patients had a score of 1 and half a score of 0).
  • The total number of days of stomatitis decreased in 13 of 14 patientss with glutamine supplementation (2.7 + 0.8 (mean + SEM) vs 9.9 + 1.1, p < 0.001).
  • 13 0f the 14 patients felt that the mucositis was less severe with the addition of glutamine.
  • No change in the nadir neutrophil count was noted with the addition of glutamine.
Author Conclusion:
  • This report demonstrates that simple oral supplementation with glutamine can significantly decrease the severity of chemotherapy-induced stomatitis in ambulatory patients.
  • The glutamine supplementation allowed for higher chemotherapy doses to be administered when typically doses are reduced as a result of chemotherapy-induced mucositis.
  • 4 patients received more than 1 glutamine intervention with subsequent chemotherapy treatment and 2/4 were able to tolerate an increase in chemotherapy dose with less mucositis then pre-study chemotherapy-induced mucositis.
  • Further studies are needed to find the appropriate dosing and schedule needed for glutamine supplementation.
Funding Source:
Industry:
Vikings Children's Fund
Other:
Not-for-profit
0
Foundation associated with industry:
Reviewer Comments:
  • Sample size was very small
  • Data collected was subjective (recorded by patient not by nurse/investigator) and did not use standardized mucositis grading (WHO or NCI)
  • Did not appear to evaluate mucosa at start of study to have a baseline for comparison
  • Outcome measures could be biased since this was not a randomized, double-blind, placebo-controlled study.
  • There was a conflict of interest associated with this study; the authors have a financial interest in a company that is developing oral glutamine as treatment for mucositis.
  • Authors changed study design and some patients went through more than one round of glutamine supplementation, but unsure if additional glutamine treatments are included in these study results or if it is just the first glutamine intervention
  • Demographics on patients not described
  • Start not the same for all participants
  • Mixed cancer sites and chemotherapy agents/dosing used
  • Timing of glutamine supplementation not specified (just twice a day)
  • Did not check compliance with glutamine supplementation
  • Did not exclude for XRT to oropharyngeal region
  • Did not find out if patients were using other techniques to treat mucositis (oral cryotherapy or other medications)
  • Overall, this study did not present as very reliable.
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? 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? N/A
  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? N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  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.) 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? ???
  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? No
  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? No
  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? N/A
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? N/A
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? No
  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? No
  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? Yes
  10.2. Was the study free from apparent conflict of interest? No