Glutamine

STUDY PURPOSE: To assess the effectiveness of glutamine to treat severe mucositis induced by radiation therapy in patients with head and neck cancer

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 5
• TOTAL PATIENTS INCLUDED IN REVIEW = 234 patients with head and neck cancer
• SAMPLE RANGE ACROSS STUDIES: 8–61 patients
• KEY SAMPLE CHARACTERISTICS: Patients receiving radiation therapy for head and neck cancer

PHASE OF CARE: Active antitumor treatment

APPLICATIONS: Elder care

Glutamine treatment had statistically significant benefits: It (a) reduced the risk and severity of OM (grade IV) (RR = 0.17, 95% confidence interval [0.06, 0.47]) and (b) shortened the duration of OM by 2–3 days. The studies reviewed had a low risk of overall bias.

The protective effects of glutamine for radiation and chemotherapy-induced mucositis are promising. Glutamine or alanyl-glutamine accelerated the mucosal recovery through increasing mucosal tissue glutathione stores, reducing inflammatory parameters and speeding re-epithelization.

• Limited search
• Limited number of studies included
• Low sample sizes

Large prospective, comprehensive clinical trials are needed to investigate the effectiveness of glutamine in the prevention of OM induced by radiation therapy or chemoradiotherapy.

STUDY PURPOSE: To review the evidence for use of oral glutamine to prevent treatment-related mucositis in adult patients with cancer

• DATABASES USED: MEDLINE
• KEYWORDS: glutamine; cancer; mucositis; esophagitis; stomatitis
• INCLUSION CRITERIA: Prospective or retrospective design, evaluating the use of oral glutamine for prevention
• EXCLUSION CRITERIA: Pediatric patients, use of glutamine as treatment for mucositis, combining with other interventions, lack of a control or comparison arm

• FINAL NUMBER STUDIES INCLUDED = 15 studies; only data from 11 studies are discussed.
• TOTAL PATIENTS INCLUDED IN REVIEW = Sample sizes and other study details are not provided.
• SAMPLE RANGE ACROSS STUDIES: 21–326 patients
• KEY SAMPLE CHARACTERISTICS: Patients with varied tumor types and treatments

PHASE OF CARE: Active antitumor treatment

Seven studies reported actual mucositis outcomes. Other studies measured outcomes such as weight change or time to onset but not mucositis grades. Various methods of mucositis grading were used. In seven studies, statistical significance of differences observed was not reported. In 10 of 11 studies, the percent of patients with grade 3 mucositis was lower with oral glutamine. In two studies, grade 4 mucositis incidence was lower with glutamine, and in two studies, it was higher with glutamine. Duration of mucositis and time to development findings were inconsistent. Dosage and timing of glutamine varied across studies.

The results of this systematic review are insufficient to provide strong support for the efficacy of oral glutamine for the prevention of oral mucositis.

The authors stated that the study samples were small. High heterogeneity in terms of tumor types and treatments were involved, and no subgroup analysis was done.

The findings do not show a strong evidence of efficacy of oral glutamine to prevent oral mucositis in patients with cancer undergoing a variety of treatments. Oral glutamine did not, however, demonstrate adverse effects, and some evidence suggests that the severity of mucositis might be lower with glutamine. The effect dose and timing of oral glutamine for various patients and treatment types is unclear.

Parenteral nutrition supplemented with 0.57 g/kg glutamine-dipeptide was started on day 6 for a median of 19 days for patients in the treatment group.

• The sample consisted of 32 patients receiving allogenic stem cell transplantation.
• Median age in the treatment group was 49 years old with a range of 25–64 years. Median age in the control groupw as 48 years old with a range of 28–57 years.

The study was conducted between July 1999 and July 2002.

This was a randomized, double-blinded, placebo-controlled pilot study.

Oral assessment was conducted daily. Lesions, erythema, edema, pain, bleeding, dryness, and the production of viscous mucous were scored on a 0–3 scale and summed to produce a daily oral mucositis score (DMS).

• DMS was 8.1 (SD = 3.5) in the glutamine group versus 9.3 (SD = 3.1) in the placebo group; results were not significant.
• No difference was found in mean daily dose of morphine to alleviate mucositis-related pain.

• The sample size was small.
• Multiple other measures were used; most were not significant.

Patients were randomized to receive IV L-alanyl-L-gluatime 0.3 g/kg (30 infusions in 5 patients) or 0.4 mg/kg (25 infusions in 5 patients), administered at a rate of 0.1 g/kg body weight/h. The principal endpoint was incidence of mucositis (mean of three highest scores by Objective Mucositis Assessment Score (OMAS) and highest grade on World Health Organization [WHO] scale).

• The sample consisted of 29 patients, 15 in the placebo group and 14 in the treatment group.
• All patients had unresectable head and neck cancer and received cisplatin and fluorouracil (5-FU) followed by concurrent chemotherapy and radiation.
• Patients with severe renal or hepatic insufficiency were excluded from the study. 
• No patients received steroids or antimicrobials prior to the study. No patients received any measure intended to prevent mucositis, although the authors did not indicate what standard oral care included.

The study used a two-step design. Patients were randomized first to different doses of the glutamine intervention, then to placebo (double-blind).

OMAS and WHO grading scale were used.

• OMS values were lower in the treatment group (1.33 in the placebo group versus 0.82 in the glutamine group) (p = 0.044).
• The mean WHO score was lower in the treatment group (2 versus 3) (p = 0.035).
• The OMS and WHO score correlation was significant (r = 0.83, p < 0.0001).
• Nine patients in the placebo group required feeding tubes compared to two patients in the treatment arm (p = 0.020).
• Patients in the treatment arm reported less pain (p = 0.008) and required fewer opioids (p = 0.025).

Measurement using both mucositis scales indicated a significant difference in intensity of mucositis.

• The study sample was small.
• Intensive nutritional support was used in both groups.
• All patients were supplemented with oral formulas containing no glutamine.
• Some question exists regarding whether glutamine can be a fuel for rapidly proliferating tumors; other studies have failed to demonstrate this effect.

• Glutamine (Saforis, MGI Pharma) was administered at 2.5 g per 5 ml, three times per day, for a total daily dose of 7.5 g. Treatment began on the first day of chemotherapy and continued for 14 days after the last dose in patients who did not develop oral mucositis or until 5 days after resolution of oral mucositis. Glutamine was orally swished for 30 seconds, then swallowed.
• Oral hygiene consisted of gently brushing teeth twice per day, 30 minutes or more after each study drug treatment, with a soft toothbrush and fluoride toothpaste. Daily flossing and alcohol-free fluoride rinse was recommended.
• All patients were treated with 200 mg oral acyclovir twice per day.

• Patients were eligible for the study if they
  • Were age 18 or older.
  • Had European Cooperative Oncology Group (ECOG) scores of 2 or less.
  • Had histopathologically confirmed breast cancer to be treated with anthracycline-based chemotherapy.
  • Experienced World Health Organization (WHO) grade 2 or higher mucositis during the first cycle of chemotherapy.
  • Were scheduled to receive at least two more cycles without dose reduction.
• In cycle 1, 163 patients received glutamine and 163 received placebo.
• In cycle 2, 150 patients received glutamine and 155 received placebo.

The study was conducted in Russia.

This was a randomized, double-blind, placebo-controlled, crossover, phase III trial.

• Oral mucositis was measured with regard to incidence, severity, ability to eat solid food, and pain.
• The WHO scale and Oral Mucositis Assessment Scale (OMAS) were used.

• Some nausea was reported.
• In treatment cycle 1, incidence of WHO grade 2 or higher was 38.7% in the treatment group and 49.7% in the placebo group (p = 0.026).
• Incidence of grade 3 or higher was 1.2% in the treatment group versus 6.7% in the control group (p = 0.005).
• Ability to eat solid food was 97.5% in the treatment group versus 91.9% in the control group (p = 0.039).
• No differences were observed in oral pain intensity or difficulty swallowing.
• In treatment cycle 2, incidence of WHO grade 2 or higher oral mucositis among patients in the placebo group was significantly lower than cycle 1 (31.9 versus 49.7; p = 0.0269); this was considered to be a carryover effect.

Glutamine is easy to use, has a favorable safety profile, and is low in cost. The total daily dose was within the range of dietary glutamine consumed by an adult on a high-protein diet (about 8 g per day). This treatment should be tested in higher intensity chemotherapy regimens.

To investigate whether L-glutamine (glutamine) decreases the severity of mucositis in the oral cavity, pharynx, and larynx induced by chemoradiotherapy (CRT)

Patients with squamous cell carcinoma of the nasopharynx, oropharynx, hypopharynx, or larynx (HNC) receiving CRT were randomized to orally receive either glutamine (group G) or placebo (group P) at a dose of 10 g three times per day throughout the CRT course.

• N = 40
• AGE RANGE = 38–77 years
• MALES: 34 (85%), FEMALES: 6 (15%)
• KEY DISEASE CHARACTERISTICS: Primary squamous cell carcinoma of the nasopharynx, oropharynx, hypopharynx, or larynx

• SITE: Single-site    
• SETTING TYPE: Inpatient  
• LOCATION: Osaka University Hospital, Japan

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

Double-blinded, randomized, placebo-controlled trial that excluded patients with active mouth or throat soreness before treatment, uncontrolled diabetes mellitus, or severe renal or hepatic insufficiency.

• Images of laryngoscope using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3
• Hematologic and blood chemistry tests were performed at baseline, once per week during the study treatment (weeks one to six), and after treatment (weeks seven to nine) or until patient discharge, whichever occurred first.
• Pain score according to a numerical rating scale (NRS) 
• The primary treatment outcome was evaluated 10 weeks after the completion of treatment using computed tomography (CT), positron emission tomography-CT (PET-CT), and biopsy.

The study demonstrated that glutamine significantly decreased the severity of CRT-induced mucositis in patients with HNC. Patients (group G) receiving glutamine had a decreased the incidence of grade 4 mucositis. The mean duration of supplemental nutrition because of severe mucositis was significantly shorter in group G than in group P (group G, 18 ± 13; group P, 27 ± 11; p = .046). Treatment delay caused by mucositis was observed in zero patients in group G and in 15% of patients in group P. In addition, NRS scores were significantly lower in group G than in group P at weeks 4, 5, and 6 (p = .049, p = .019, p = .032, respectively).

The study showed that glutamine significantly decreases the severity of CRT-induced mucositis in patients with cancer, which in turn will improve quality of life for patients.

• Small sample (< 100)

This study could not provide conclusive results of glutamine in the prevention and treatment of oral mucositis. The study indicated the need for an integrative and multidisciplinary approach in patient care, which could result in substantial advances in the outcomes of cancer therapy and the improvement in patient quality of life. However, there is no known specific dose for glutamine, and it has not been approved by the U.S. Food and Drug Administration for the treatment of mucositis during chemoradiotherapy.

To evaluate the effect of oral glutamine on the prevalence and severity of acute radiation-induced oral and esophageal mucositis

Data were collected retrospectively for patients receiving radiation therapy. Findings were compared between those who did and did not receive glutamine. Outcomes between those who were given glutamine early (prior to radiation therapy) versus late (after radiation therapy was begun) in the course of radiation therapy were compared. Data on nutritional status and interruptions in treatment were evaluated.

• The sample was composed of 117 patients, including 79 cases with oral mucositis.
• Mean patient age was 62.2 years (SD = 13.6 years) in the experimental group.
• The sample was 81.2% male and 10.8% female.
• Diagnoses were head and neck, lung, esophageal, and lymphoma.
• The majority of patients (73.5%) were also receiving chemotherapy.

The study was conducted at a single site outpatient setting in Spain.

Patients were undergoing the active antitumor treatment phase of care.

This was a retrospective study.

The World Health Oragnization (WHO) mucositis grading scale was used.

• In the final sample, 27.4% of patients received early glutamine, 49.5% received glutamine late, and 23.1% of patients did not receive glutamine.
• Analysis showed that prevalence of mucositis was lower among patients who received early glutamine compared to those who either did not receive glutamine or were given glutamine late (p ≤ 0.02).
• After correction for sex, age, chemotherapy, radiation dose, and previous surgery, only glutamine use was predictive of risk for development of oral mucositis (risk difference = -9.0%; 95% CI = -18%, -1%).
• For patients receiving radiation to the head and neck region, severity of oral mucositis was higher among those who did not receive early glutamine (p = 0.039).

Provision of oral glutamine prior to the beginning radiation therapy may be of benefit in the prevention of oral mucositis. Firm conclusions cannot be made because of multiple study limitations.

• Differences in the baseline sample group and variations in chemotherapy regimens, which could have affected the development of mucositis, could have influenced results.
• A risk of bias exists because of the lack of a control group, blinding, and random assignment.
• Unintended interventions or applicable interventions that were not described could have influenced results.
• Measurement and methods were not well described.
• No information about the oral care used was provided.
• The timing of mucositis evaluation and how evaluations were done was not reported. 

This study has numerous limitations and risks of bias, and it attempted to draw conclusions across a very heterogenous population of patients. Findings suggest that oral glutamine may be helpful in preventing oral mucositis in patients receiving radiation to the head and neck area, and it appears that glutamine treatment may be most beneficial if treatment is begun prior to the initiation of radiation therapy.

To determine if 0.65 g/kg enteral glutamine daily for 7 days is effective in reducing the incidence and severity of mucositis in pediatric oncology patients when given with chemotherapy

Patients received one course of chemotherapy with glutamine and an identical course without. Alternate patients were given glutamine with course 1 or with course 2.

• The study was comprised of 76 patients, aged 1–21 years.
• The sample was 56% male and 44% female.
• Cancer diagnoses were acute myelogenous leukemia (AML), B-cell non-Hodgkin lymphoma (NHL), Ewing’s sarcoma/primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, osteosarcoma, and other.

The study was conducted at a single site at Yorkshire Regional Centre for Pediatric Oncology and Hematology in the United Kingdom.

Patients were undergoing the active treatment phase of care.

This was a randomized study using the patients as their own controls.

• Patient/parent diaries were used from day 1-21 using Common Toxicity Criteria for nausea, vomiting, diarrhea, oral mucositis, and abdominal pain.   
• Plasma ammonia and glutamine levels were recorded.
• Clinical measurements of weight, height, percentage weight/height, mid-upper arm circumference, total parenteral nutrition (TPN) use, enteral feeding, and other complicatios that could affect eating tolerance during enteral feeding.

No difference was found between the five symptoms or for the total number of children with each symptom.

Oral glutamine did not improve the nutritional status of patients in the study. Even though subjective toxicity scores showed more problems if glutamine was not used, because of the small sample size, the difference was not significant. In addition, 62% took glutamine via enteral feeding tube, therefore eliminating the local effect on the oral mucosa.

• The sample size was small with fewer than 100 patients.
• The study lacked a placebo.
• A number of patients were unable to complete the study.
• Randomizing all potential patients was not possible because of the need to urgently start treatment for some patients.

Further study into what factors resulted in the decreased use of TPN could be of benefit. Further studies are needed to investigate the use of oral glutamine using larger and more diverse populations.