Glutamine

Glutamine

PEP Topic 
Radiation-Induced Diarrhea
Description 

Glutamine is the most abundant amino acid in the body, comprising 60% of the free amino acid pool. Glutamine requirements increase during periods of metabolic stress and, therefore, glutamine is considered a conditionally essential amino acid. Glutamine is the primary fuel for rapidly dividing cells, including enterocytes, colonocytes, fibroblasts, and lymphocytes. Individuals deficient in glutamine often present with changes in gastrointestinal (GI) morphology, resulting in bacterial translocation, malabsorption, and diarrhea. Individuals deficient in glutamine also may present with impaired wound healing or immune function. Glutamine is available as a dietary supplement without prescription. Glutamine has been examined for management of diarrhea, mucositis, and peripheral neuropathy.

Effectiveness Not Established

Guideline/Expert Opinion

Gibson, R.J., Keefe, D.M., Lalla, R.V., Bateman, E., Blijlevens, N., Fijlstra, M., … Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). (2013). Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Supportive Care in Cancer, 21(1), 313–326.

doi: 10.1007/s00520-012-1644-z
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Purpose & Patient Population:

To systematically review current evidence for prevention and treatment of gastrointestinal (GI) mucositis in adults and children receiving cancer treatment and to update relevant Multinational Association of Supportive Care in Cancer (MASCC) guidelines

Type of Resource/Evidence-Based Process:

This was an evidence-based guideline developed based on a systematic review of the literature with rating of levels of evidence and identification of study flaws.

Database searched was MEDLINE.

Search keywords were numerous and included all known possible interventions tested.

Inclusion and exclusion criteria were not stated in this article but provided elsewhere in the journal.

Phase of Care and Clinical Applications:

  • Patients were undergoing the active treatment phase of care.
  • The study has clinical applicability for pediatrics.

Results Provided in the Reference:

A total of 1,336 papers were initially retrieved; of these, 146 were reviewed for development of the guidelines.

Guidelines & Recommendations:

  • Probiotics with Lactobacillus spp. may be beneficial for prevention of chemotherapy- and radiotherapy-induced diarrhea in patients with pelvic malignancies. Two studies with positive results were cited.
  • Amifostine may reduce esophagitis because of concomitant radiation and chemotherapy. It is not recommended in other situations because of conflicting evidence.
  • Mesalazine, 5-aminosalicylic acid (5-ASA), and olsalazine are not recommended because they have been associated with increased diarrhea compared to placebo.
  • Sucralfate is not recommended for diarrhea prevention because it is associated with increased GI side effects, including rectal bleeding.
  • Oral sulfasalazine given at 500 mg twice daily is recommended to reduce incidence and severity of radiation-induced enteropathy.
  • No guideline was provided for glutamine, but three new studies were sited that showed promising results.
  • If loperamide has not resulted in diarrhea control with standard or high-dose chemotherapy in HCTY patients, 100 mcg or greater of subcutaneous octreotide twice daily is recommended.

Limitations:

This review had a limited search strategy, as only one database was searched. In addition, most of the suggestions and recommendations provided were based on low-level evidence by the rating system used.

Nursing Implications:

These guidelines provide some suggestions for management of oral mucositis and diarrhea in patients with cancer. They also provide information regarding evidence for mucositis in the entire GI tract.

Research Evidence Summaries

Kozelsky, T.F., Meyers, G.E., Sloan, J.A., Shanahan, T.G., Dick, S.J., Moore, R.L., … North Central Cancer Treatment Group. (2003). Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. Journal of Clinical Oncology, 21(9), 1669–1674.

doi: 10.1200/JCO.2003.05.060
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Intervention Characteristics/Basic Study Process:

The study design was based on a goal of 120 patients, so that the two-sided, 0.05-level Wilcoxon rank sum would have a power of 97.5% to detect an improvement in diarrhea severity. After stratification, patients were randomly assigned to the experimental group (4 grams of glutamine twice per day for 7 days per week during radiation and for 2 weeks thereafter) or an identically appearing placebo (glycine) for the same time period.

Sample Characteristics:

  • The study reported on 129 patients from 14 institutions.
  • Patients were stratified by
    • History of anterior resection of the rectum versus no prior rectal surgery
    • Total planned cumulative radiation dose
    • Use of fluorouracil (FU)
    • Primary tumor site (rectal versus prostate versus gynecological versus other).

Study Design:

This was a two-arm, placebo-controlled, randomized clinical trial.

Measurement Instruments/Methods:

The primary measure of treatment efficacy was diarrhea levels, which were evaluated using a bowel function questionnaire that was derived from previous studies on radiation therapy and bowel functioning. Participants completed the questionnaire weekly for 4 weeks, then at 12- and 24-month follow-up intervals. Toxicity was measured using National Cancer Institute (NCI) Common Terminology Toxicity Criteria for Adverse Events: Diarrhea.

Results:

No significant differences were found in incidence of diarrhea (p = 0.99), stools per day, maximum stools per day, antidiarrheal agent used, or use of loperamide.

Limitations:

  • This study was inconsistent with other studies which found a significant effect (improvement) in diarrhea with glutamine supplementation. Further research is needed to determine whether a lower dose of glutamine was used in this study.
  • The authors did not report on the validity or reliability of the bowel function questionnaire.
  • No dose-response data was provided to assess whether higher doses or longer pretreatment use of glutamine would have been more effective in treating or preventing diarrhea.

Kucuktulu, E., Guner, A., Kahraman, I., Topbas, M., & Kucuktulu, U. (2013). The protective effects of glutamine on radiation-induced diarrhea. Supportive Care in Cancer, 21(4), 1071–1075.

doi: 10.1007/s00520-012-1627-0
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Study Purpose:

To investigate the protective effects of glutamine on radiation-induced diarrhea

Intervention Characteristics/Basic Study Process:

Patients were divided into two groups. One group received 15 g oral glutamine each day beginning one week prior to radiotherapy and continuing until one week after radiation therapy completion. The other group was given an oral glucose solution.

Sample Characteristics:

  • The study consisted of 36 patients with a mean age of 66 years.
  • The sample was 62% male and 38% female.
  • Renal, prostate, bladder, and gynecologic were the most common cancers.
  • All were receiving radiation therapy in the range of 45–70 Gy. Some also had received concomitant chemotherapy with 5 fluorouracil (5FU) or cisplatin.

Setting:

The study was conducted at a single outpatient site in Turkey.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Study Design:

This was a two-group prospective trial.

Measurement Instruments/Methods:

  • Patient diaries were used. 
  • The National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 3.0, for diarrhea was used.
     

Results:

No between-group differences were found in overall incidence of diarrhea. None of the patients in the glutamine group developed grade 3–4 diarrhea, compared to 69% of those in the placebo group (p = 0.0000). More patients in the placebo group required loperamide and parenteral supportive therapy.

Conclusions:

Findings suggest that oral glutamine may be helpful in the prevention and management of severe radiation-induced diarrhea.

Limitations:

  • The sample size was small with fewer than 100 patients.
  • A risk of bias exists because no blinding or random assignment was used.
  • More patients in the placebo group received 5FU and had rectal cancer. 
  • Diarrhea grading depends on patient recall of stool frequency, so reliability and accuracy may be questionable.
  • The authors did not clarify how the criteria were applied and what toxicity value was used in analysis, because grading was apparently done twice weekly. 
  • A 10% drop-out rate occurred because of a lack of compliance with the oral medication. 
  • The glucose solution used as placebo was not well described. The nature of this solution could have worked as an osmotic laxative in the placebo group. 
  • The authors did not explain how patients were assigned to study groups.

Nursing Implications:

Findings suggest that oral glutamine may help in the prevention of severe radiation-induced diarrhea. However, study design issues limit the quality of this study. Use of glutamine warrants further investigation in large, well-designed randomized studies.


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