EAL

ONC: Glutamine (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine whether glutamine could decrease 5-FU-associated mucositis.

Inclusion Criteria:

Chemotherapy naïve and scheduled to receive a 5-day course of 5-FU-based chemotherapy in the North Central Treatment Group (NCCTG) treatment clinical trial.
Study entry on first day of first chemotherapy cycle.
Adult patients

Exclusion Criteria:

None specified.

Description of Study Protocol:

Recruitment

Participants in the NCCTG between November 1995 and March 1997.

Design

Placebo RCT

Intervention

Patients randomized to receive 4 g glutamine or an identical-appearing placebo twice daily for 14 days beginning on the first day of their first chemotherapy cycle.
Patients were to swish the medication in their mouths for 10 seconds and then swallow it.
Patients were not to take anything by mouth for 15 minutes after using the mouthwash.

Statistical Analysis

Fisher’s exact testing for percentage of severe mucositis
Wilcoxen for average mucositis scoring
Toxicity score = sum of the types of adverse reactions attributed to “glutamine” solution by the patients.
O'Brien global test used: combining data for mucositis area under the curve.

Data Collection Summary:

Timing of Measurements

Daily diary questionnaire for self-report of mucositis

Filled out by patient during the 21 days after the first dose of chemotherapy
Based on NCCTG criteria
Follow-up phone conversations by a nurse were made 7 to 10 days after start of study to address questions and encourage compliance with the study medication and diary reporting.

Physician evaluation of mucositis scores timing unclear, historical means 4 to 5 weeks after the beginning of each chemotherapy cycle.

Dependent Variables

Severity of mucositis

0 = no mucositis

1 = Soreness/erythema

2 = Erythema/ulcers/can eat solids

3 = Ulcers/requires liquid diet only

4 = Alimentation not possible

Independent Variables

Glutamine supplementation

Control Variables

Dentures
Smoking history
Chemotherapy regimen

Description of Actual Data Sample:

Initial N: 134 (66 glutamine, 68 placebo)

Attrition (final N): None lost to ineligibility or follow up

Baseline	Glutamine (n = 66)	Placebo (n = 68)	p
Dentures
Yes	26	26	0.99
No	40	42
Smoking history
None	58	58	0.79
Cigarette or smokeless tobacco	8	10
Chemotherapy regimen
5FU 370 + LCF 100	0	1	0.99
5FU 370 + CF 500	0	1
5FU 370 + CF 20 + LEV	60	60
5FU 425 + CF 20 + LEV	2	3
5FU 450 + LEV	4	3
Sex
Female	30	32	0.86
Male	36	36
Age (yrs)
Median	67.0	60.5	0.01
Mean	64.6	60.8

5FU, 5-fluorouracil; CF, citrovorum factor; LCF, levo citrovorum factor; LEV, levamisole

Summary of Results:

Measures of mucositis evaluated by physician

	Glutamine (n = 66)	Placebo (n = 68)	p
Maximum mucositis (grade)			0.75
None (0)	20	24
Mild (1)	27	24
Moderate (2)	15	15
Severe (3)	2	5
Life-threatening (4)	2	0
Mean	1.08	1.02

Measures of mucositis evaluated by patients

	Glutamine (n = 66)	Placebo (n = 68)	p
Maximum mucositis (grade)	(n = 63)	(n = 68)	0.52
None (0)	25	24
Mild (1)	16	20
Moderate (2)	10	11
Severe (3)	9	6
Very Severe (4)	3	0
Mean	1.19	0.98
Duration of Mucositis	(n = 38)	(n = 37)	0.58
Median (days)	9	9

Other Findings

No significant differences reported by both physician and patients between groups.
Average duration of mucositis who had any incidence of stomatitis was virtually identical.
A multivariate analysis to examine any influence from the different ages (<50 years and >50 years) in the 2 treatment groups failed to demonstrate any benefit of glutamine.
Use of other medications to alleviate mucositis (recorded in diaries) was NS (30% vs. 23%, p=0.4).
Difference of across genders becomes significant when severity of the patient reported maximum mucositis.
- >25% of women and only 6% of men reported marked or severe mucositis
- Similar for the maximum grade by the physician (p = 0.01)
- Mucositis graded as severe or life-threatening by 13% of women and 1% of men (p = 0.01).

Author Conclusion:

This study did not support the hypothesis that glutamine would be able to lessen 5-FU-induced mucositis. The dose and schedule of glutamine may have played a role.

Limitation: All patients were given oral cryotherapy before chemotherapy, possibly blunting effects of oral glutamine.

Age differences deemed clinically insignificant. Analyses redone and age not a confounding factor.

Funding Source:

Government:

Public Health Service Research Grant, Dept. of Health and Human Services

Reviewer Comments:

Funding sources - NCI and PHS grants. This was a trial of NCCTG and Mayo Clinic.

Limitations

blinding indicated but not specified
did not exclude XRT patients
differences in follow-up length for patients (21 days) versus MD (4-5 weeks)
length of follow-up by MD was 4-5 weeks when patients may have been undergoing a second cycle of chemotherapy that was not supplemented with gln
did not list cancer sites/stages
timing of gln/placebo not specific (just twice daily)
make-up and source of gln and placebo not indicated

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?	???
	1.3.	Were the target population and setting specified?	Yes
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?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
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.)	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?	Yes
	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.)	Yes
	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?		N/A
	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?	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?		???
	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.)	No
	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?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	Yes
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?	???
	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?	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?	???
	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?	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?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes