EAL

ONC: Glutamine (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of the study was to determine the effectiveness and toxicity of oral glutamine therapy in preventing diarrhea in patients receiving pelvic radiation therapy (RT).

Inclusion Criteria:

At least 18 years of age (study meets ADA inclusion criteria since all enrolled subjects were >20 years of age)
Histologically confirmed diagnosis of adenocarcinoma or squamous carcinoma
Pelvic RT at a facility approved by the North Central Cancer Treatment Group
The entire pelvis encompassed by the RT field
Daily dose of RT 1.7-2.1 Gy, with a total cumulative dose of 53.5 Gy (radiation boost allowed to primary tumor)
Patient entered into study before 2nd RT fraction
Written patient informed consent and institutional review board approval required.

Exclusion Criteria:

Pregnant
Allergic to glutamine
Prior history of pelvic RT
History of irritable bowel disease
Stool incontinent
Prior perineal or abdominal resection
Planned use of leucovorin or other cytotoxic chemotherapeutic agents, with the exception of fluorouracil (FU).

Description of Study Protocol:

Recruitment

Subjects were recruited from patients receiving RT at any one of 14 North Central Cancer Treatment Group facilities.

Design

Two-armed, randomized, placebo-controlled clinical trial
Before random assignment to treatment arms, patients were stratified according to:
- History of anterior resection of rectum vs. no history
- Total planned cumulative dose of RT
- Use of FU
- Location of tumor site.
Total study length: February 1998 to October 1999.

Blinding used

Both subjects and researchers were blinded to glutamine intervention.

Intervention

After stratification, patients were randomly assigned to receive one of two study medications:
- Four g (eight mL) oral glutamine, twice per day (morning and evening), for seven days per week during RT and for two weeks afterward
- An identical-appearing placebo administered on the same schedule
- Placebo contained glycine instead of glutamine.
The study medication was provided to subjects in a two-week supply and was presented as a solution made up of:
- 40 mL Ora-sweet (Paddock Laboratories)
- 40 mL Ora-plus (Paddock Laboratories)
- 80 mL water to serve as vehicle
- 112 g of either glutamine or glycine powder

Statistical Analysis

The study was based on an accrual goal of 120 eligible patients, with 60 in each arm of the study
120 subjects provided a statistical power of 97.5% to detect a one-grade improvement level in diarrhea severity of each glutamine-treated subject, when a two-sided 0.05 level Wilcoxon rank sum statistic was applied
An interim analysis was performed when subject accrual was half complete (approximately 30 patients in each arm) in order to stop accrual into the glutamine group if it was more toxic than placebo
Nonparametric Wilcoxon and Fisher's exact tests were used to compare the measures of efficacy and toxicity between treatment arms
Type I error rate was at 5% for all tests.

Data Collection Summary:

Timing of Measurements

Patients were evaluated at baseline and at weekly intervals by a radiation oncologist or a radiation oncology nurse
- Toxicity was assessed according to the National Cancer Institute common toxicity criteria
- Antidiarrheal medication and laxative use were documented
Patients completed a bowel function questionnaire at baseline, at four-week intervals while receiving radiation therapy, for four weeks following radiation therapy, and at 12- and 24-month follow-up intervals
Incidence of toxicity was correlated with individual items on the bowel function questionnaire in order to assess discriminant validity
The UNISCALE quality of life measure was administered concurrent with the bowel function questionnaire.
Patient research records were audited to determine if there were any problems with handling of the study medication such as a failure to refrigerate; no problems were discovered.

Dependent Variables

Diarrhea level
- Measurements:
  - Maximum grade of diarrhea
    - Grades of diarrhea:
      - 0: No diarrhea or increased stool frequency
      - 1: +2-3 stools/day over pretreatment
      - 2: +4-6 stools/day over pretreatment or nocturnal stools
      - 3: +7-9 stools/day over pretreatment or incontinence
      - 4: >10 stools/day or need for parenteral nutrition
      - 5: Diarrhea resulting in death.
  - Incidence of diarrhea
  - Average diarrhea score.
- Measurement tools:
  - National Cancer Institute common toxicity criteria, administered by oncologist or oncology nurse
  - Bowel function questionnaire, completed by patient
  - UNISCALE quality of life measure, completed by patient.

Independent Variables

Four g (eight mL) oral glutamine.

Control Variables

Identical-appearing oral medication.

Description of Actual Data Sample:

Initial N

N=129 (glutamine [E]=64; placebo [C]=65)
E=64 (20 female, 44 male)
C=65 (21 female, 44 male).

Attrition (final N)

There were no cancellations during the initial study.
- Initial study was for duration of RT plus two weeks
At 12 month followup: E=42; C=44
At 24 month followup: E=39; C=35.

Mean age

E=67.5 years
C=65.4 years.

Ethnicity

Data not available.

Anthropometrics (e.g., were groups same or different on important measures)

There were no significant differences between the glutamine group and the placebo group.

Location

All subjects were RT patients from any of 14 different North Central Cancer Treatment Group facilities.

Summary of Results:

Kozelsky summary of results

Variables	Treatment Group (E) in %	Control Group (C) in %	Statistical Significance of Group Difference (P=0.05)
Diarrhea Level
Maximum Grade Diarrhea
0	20	21
1	25	29
2	34	32
3	17	16
4	3	3	0.76
Stools per day (mean)
Physician reported	3.0	3.2	0.64
Patient reported	3.1	3.3	0.56
Maximum stools per day (mean)
Physician reported	5.1	5.2	0.99
Patient reported	5.3	5.7	0.37

[Data analysis is for initial study (RT plus two weeks).]

No significant differences between the two study arms were found with regard to incidence or grade of diarrhea or number of stools per day.
There were no significant differences in bowel function between the E and C groups at 12- and 24-month followup assessments.

Other Findings

There were no significant differences between the E and C groups in:

Tenesmus (E=42%, C=33%; P=0.22)
Abdominal cramping (E=72%, C=61%; P=0.31)
Use of antidiarrheal medications
- Diphenoxylate: E=16%, C=5%; P=0.08)
- Leperamide: E=61%, C=60%; P=0.99.

All subjects were included in data analysis.

Author Conclusion:

The provided formulation of oral glutamine in a dose of four g twice daily was not effective in preventing diarrhea or other treatment related toxicity during pelvic RT. At present, the use of glutamine to prevent diarrhea during RT is not recommended except during a clinical trial.

Funding Source:

Government:	Public Health Service
University/Hospital:	Mayo Clinic Duluth CCOP, Carle Cancer Center CCOP, Siouxland Hematology-Oncology Associates, Iowa Oncology Research Association CCOP, Missouri Valley Cancer Consortium, Ann Arbor regional CCOP

Reviewer Comments:

Well-designed, well-implemented, and well-controlled phase III clinical trial
Patient questionnaires were correlated with physician or nurse assessment of toxicity to validate the gathered data
Evaluation of compliance with medication refrigeration procedures was provided
Patient ethnicity was not recorded
Little patient demographic information provided beyond age and sex
N at 12-month follow-up was 67% of original N
N at 24-month follow-up was 57% of original N.

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?		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?	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?		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%.)	N/A
	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?		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?	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?	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?	???
	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)?	N/A
	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?	Yes
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