Sun, J., Wang, H., & Hu, H. (2012). Glutamine for chemotherapy induced diarrhea: a meta-analysis. Asia Pacific Journal of Clinical Nutrition, 21(3), 380–385.

To investigate if prophylactic glutamine administration in patients receiving chemotherapy is effective for diarrhea prevention and control with the two major outcomes of duration and severity of diarrhea

• Databases searched were Embase, MEDLINE, Cochrane Library, and BIOSIS.
• Search keywords were glutamine, diarrhea, chemotherapy, meta-analysis, and prophylactic.
• Studies were included in the review if they used randomization, with one group receiving glutamine and one group serving as control, and if they included patients receiving bone marrow transplant.
• Studies were excluded if they were not written in English or Chinese or did not clearly report results.

• A total of 20 references were retrieved.
• Studies were graded using the Jadad 5-point scale with 1 point assigned to each of the following: description of study as randomized, description of appropriate method of randomization, description of double-blind, description of appropriate method of double-blinding, and statement addressing study withdrawals.
• Review Manager Software was used for quantitative analysis to calculate the odds ratio for the weighted mean differences (WMDs) for continuous data between the study drug group and the control group. The software also was used to perform heterogeneity analysis; data that was not significantly heterogeneous (p > 0.05) were analyzed using a fixed effects model, and heterogeneous data (p < 0.05) were analyzed using a random effects model.
• Common toxicity criteria grades for diarrhea were defined as follows.
  • Grade 0: No diarrhea
  • Grade 1: An increase of fewer than 4 stools per day from pretreatment
  • Grade 2: An increase of 4–6 stools per day or nocturnal stools
  • Grade 3: An increase of more than 6 stools per day, incontinence, or need for parenteral support for dehydration
  • Grade 4: Physiological consequences requiring intensive care or death.  
     

• A total of eight studies were included in the review.
• The total sample size was 298 patients, with 147 in the treatment groups and 151 in the placebo groups. Sample ranges across all studies were 8–33 in the treatment groups (n = 18) and 8–33 in the placebo groups (n = 19).
• Cancer diagnoses were gastrointestinal, acute myeloid leukemia, colorectal, advanced breast, autologous and bone marrow transplant, and hematologic.

Patients were undergoing the active treatment phase of care.

• An overall statistically significant difference was found in duration of diarrhea with glutamine recipients versus patients receiving placebos (WMD, -1; 95% confidence interval [CI], -1.73, -0.26). Oral glutamine scored higher (WMD, -1.06, 95% CI, -2.01, -0.11) compared to intravenous glutamine (WMD, -0.89; 95% CI, -2.07, 0.28).
• Study findings indicated that glutamine did not improve the severity of diarrhea (WMD, 0.49; 95% CI, -1.36, 0.39).
• Statistical heterogeneity was found for overall rates (p < 0.00001) with the random effects model (p < 00001).

According to the results of this meta-analysis, prophylactic administration of glutamine (ranging from 16–30 g oral form daily for periods of up to 20 days and 20-40 g IV administration daily for periods of up to 21 days) reduced the length of chemotherapy-induced diarrhea (CID). However, results did not show reduction in the severity of the diarrhea. Oral glutamine was found to be more effective than IV glutamine.

• Endotoxin levels were used to assess permeability levels instead of the standard lactulose-mannitol test.
• Although this was a meta-analysis, the individual RCTs were small.
• Doses and administration were not standardized across studies, making it difficult to combine results for statistical analysis.

This meta-analysis provided evidence that glutamine, as the most abundant amino acid in humans, could reduce the duration of CID and intestinal permeability and may stimulate mucosal recovery. However, glutamine has not been shown to be beneficial in reducing or limiting the severity of CID. Larger trials are needed.

Prophylactic oral glutamine in patients receiving chemotherapy may be useful in lessening the duration of chemotherapy-related diarrhea. However, without further large trials with standardized doses, routes, and length of administration, glutamine should not be recommended for practice.