Glutamine

The purpose of the study was to determine what role glutamine plays in preventing peripheral neuropathy.

The author searched PubMed from 1990 to May 2008 with the key words glutamine, chemotherapy, peripheral neuropathy, neurotoxicity, safety, paclitaxel, platinum compounds, and vinca alkloids. To be included, studies had to evaluate the role of oral glutamine in preventing and treating chemotherapy-induced peripheral neuropathy (CIPN). Studies were excluded if they used glutamine in the reduction of other radiation or chemotherapy-induced related toxicities such as mucositis, cardiotoxicity, diarrhea, and cachexia.

Three clinical trials were reviewed for sample, inclusion/exclusion criteria, study design, and results given. No type of measurement was used to review the study quality. Of note, the article did not state if other studies were found in the literature review.

• The total sample of the three studies combined was 195 patients.
• Patients in study 1 had stage IV breast cancer, no mention of stage was made in study 2, and patients in study 3 had metastatic colon cancer.
• In study 1, 33 patients on glutamine and 30 not on glutamine received a first cycle of high-dose paclitaxel.
• In study 2, 29 patients were placed in a control group and 17 in a glutamine group receiving first cycle of high-dose paclitaxel.
• In study 3, 42 patients received glutamine and 44 did not, receiving one cycle (two doses) of oxaliplatin.

Study 1 suggested that glutamine helps to decrease symptoms of peripheral neuropathy.  Study 2 suggested that glutamine can help prevent some symptoms of CIPN. And, finally, study 3 suggested that glutamine may reduce the occurrence of CPIN.

Although each study had a small sample size, glutamine did appear to help reduce symptoms of neuropathy. However, the systematic review concluded that a lack of sufficient evidence existed to recommend oral glutamine for the prevention of CIPN. Glutamine could be beneficial in patients receiving high-dose paclitaxel and oxaliplatin.

• Regarding limitations, none of the studies were placebo-controlled and endpoints were subjective.
• Criteria to evaluate CPIN differed among all three studies and no standard tool or measure was used to document CPIN.
• The long-term effect of glutamine was not studied, and the symptoms may have been reversed after chemotherapy discontinuation.
• The use of only one database likely hindered the research, as did the small number of studies included.

The safety and tolerability of glutamine was not mentioned.

To determine if glutamic acid is an effective preventative therapy in children with vincristine-associated neurotoxicity

Before the first treatment of vincristine, patients were stratified into stratum 1 or stratum 2. Stratum 1 included patients with Wilms tumor or rhabdomyosarcoma who were to receive nine weeks of vincristine; stratum 2 included patients with acute lympoblastic leukemia or non-Hodgkin lymphoma who were to receive four weeks of vincristine. Both groups were randomized to receive L-glutamic acid hydrochloride or placebo three times a day until seven days after week 4 or week 9 of vincristine. The placebo was administered in the same manner.

• N = Stratum 1: 16 placebo, 14 glutamic acid. Stratum 2: 84 placebo, 70 glutamic acid
• AGE = 3–21 years
• MALES: 52% (stratum 1), 62% (stratum 2)  
• FEMALES: 46% (stratum 1), 38% (stratum 2)  
• KEY DISEASE CHARACTERISTICS: Patients with Wilms tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, or non-Hodgkin lymphoma
• OTHER KEY SAMPLE CHARACTERISTICS: All were newly diagnosed.

• SITE: Single site
• SETTING TYPE: Not stated
• LOCATION: USA

• PHASE OF CARE: Active treatment
• APPLICATIONS: Pediatrics

A randomized, placebo-controlled, double-blind trial

• Modified Balis Pediatric Scale of Peripheral Neuropathies

Patients who received glutamic acid did not have significantly less neurotoxicity symptoms compared to the placebo group. The subgroup of patients aged 13 years or older experienced more benefits from glutamic acid (0.28, p = 0.055) compared to patients younger than 13 years. Neurotoxicity rated less than 0.02 (p = 1) but was not statistically significant.

Glutamic acid is not considered an effective preventative treatment of neurotoxicities in preadolescents.

• Possible insufficient dosing of glutamic acid
• Variability in neurological exams as well as data collection
• Data were collected only for initial 5–10 weeks of therapy.
• The researchers identified a small sample size.

Glutamic acid is not recommended for the prevention of neurotoxicities in pediatric patients at this time.

The focus of the study was to evaluate the role of glutamate supplementation in preventing paclitaxel-induced peripheral neuropathy.

Patients were randomized to receive daily placebo or 500 mg glutamate supplementation beginning on the first day of chemotherapy. Treatment was continued throughout six cycles of chemotherapy and for an additional three weeks. Patients were assessed for neuropathy with serial electro-diagnostic measurements at baseline and at the end of the study.

The total sample consisted of 43 women with a median age of 59 years (range of 35–80 years) who were diagnosed with gynecologic cancers and were receiving paclitaxel.

The study was conducted in multiple outpatient sites throughout Israel.

Phase of care

• Active antitumor treatment

The study had a double-blind, placebo-controlled randomized trial design.

• Various electro-diagnositic measurements were used to assess nerve conduction and sensory conduction velocity.
• The National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) was used for assessment, as was a 0–3 scale to measure change in symptoms.

An indication of peripheral neuropathic toxicity was lower in patients receiving glutamate, but the difference was not statistically significant. However, significantly lower pain levels were noted in the glutamate group (p = 0.011). No differences were found between groups regarding electro-diagnostic measurements.

The study does not provide strong support for the benefit of glutamate in the prevention of peripheral neuropathy in patients receiving paclitaxel. No firm conclusions can be drawn due to study limitations.

• A small sample size (less than 100).
• The questionable validity and reliability of the three-point assessment scale.
• Findings may not be generalizable to patients receiving other chemotherapeutic agents.
• Of the 67 patients randomized, the consort diagram shows a final sample of 43; however, results are only reported for 38 patients. Actual sample and reasons for withdrawal are not well explained.

The findings suggest that glutamate does not prevent peripheral neuropathy during treatment with paclitaxel. Conclusions are limited due to study deficiencies.

The aim of the study was to evaluate the value of glutamic acid as a modifier in vincristine-induced neurotoxicity.

Children were randomized to treatment or placebo groups during adjuvant treatment with vincristine. Patients were evaluated weekly by physical examination. The treatment group received glutamic acid 1.5 g orally per day in three divided doses during a four-week induction with vincristine.

• The sample consisted of 94 pediatric patients (72% male and 28% female) with a mean age of 7.1 years (range of 3–18).
• The patients had acute lymphoblastic leukemia, non-Hodgkin lymphoma, or Wilms tumor.

The study was conducted at a single site in Egypt.

Phase of Care

• Active antitumor treatment

Clinical Applications

• Pediatrics
   

The study had a double-blind, randomized, placebo-controlled design.

• Achilles tendon reflex and patellar reflex were graded as normal, decreased, or absent.
• Parasthesis was recorded as absent, mild, moderate, and severe.
• Strength was assessed as normal, mild decrease, moderate decrease, and severe decrease.
   

Achilles and patellar reflexes were decreased at weeks 3 and 4 in more patients receiving placebo. Prevalence of mild parasthesias was greater in the placebo group at week 4. No severe parasthesias were recorded in the glutamic acid group compared to an incidence rate of 7.5% in the placebo group. The differences were not statistically significant.

The findings suggest that glutamic acid may be helpful in reducing vincristine-induced peripheral neuropathy symptoms in pediatric patients.

• Limitations include the small sample size (less than 100), measurement validity and reliability, and the findings not being generalizable.
• The method of grading reflexes and symptoms was not shown to be reliable, and physical examinations and grading were done by different physicians.
• Although the article states that patients were randomly assigned, it also states that the oncologist decided on the treatment, so assignment method is unclear.
• It is not stated whether there were any chemotherapy dose adjustment or delays.
• The article notes that “other treatments” were at the physician's discretion, so it is unclear if only glutamic acid was given for neuropathic effects.

 The findings suggest that glutamic acid may be helpful in managing peripheral neuropathy from vincristine; however, several study limitations exist. Additional well-designed research in this area is warranted.

To examine the efficacy and safety of glutamine to reduce vincristine-induced neuropathy in children and adolescents

Patients expected to receive a cumulative dose of 6 mg/m² over a 30-week period were randomized to receive glutamine or placebo. Participants' families were contacted weekly to answer questions and monitor compliance and monitor adverse effects. Study medications were provided in a powder formulation to be mixed in juice for oral administration. Study measures were obtained at baseline, after 21 days, and on day 42 after a wash-out period. Glutamine was given at a dose of 6 g/m² twice daily up to a maximum dose of 10 g.

• N = 49   
• MEDIAN AGE = 11 years
• AGE RANGE = 4–19 years
• MALES: 48.2%, FEMALES: 51.8%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Hematologic malignancies; acute lymphoblastic leukemia was the most common.
• OTHER KEY SAMPLE CHARACTERISTICS: More than 50% were Hispanic.

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: New York

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics

Double-blind, placebo-controlled, randomized, controlled trial

• Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
• Purdue Pegboard test
• Grip strength
• Symbol Digit Modalities Test
• Pedatric quality of life

Seventy-eight percent developed peripheral neuropathy as defined by CTCAE. There was no correlation between CTCAE and other testing results. A higher number of those receiving placebo had increased CTCAE sensory neuropathy scores compared to those on glutamine (p = 0.02) on day 21. There was no difference between groups on day 42. There were no differences between groups in motor neuropathy scores.

Glutamine had a protective effect for sensory neuropathy in this study. Varied measures for peripheral neuropathy were not correlated, pointing to the need for ongoing research to identify the most valid and reliable measures for assessment.

• Small sample (< 100)
• Baseline sample/group differences of import
• The glutamine group had lower sensory neuropathy scores at baseline.

There have been mixed findings regarding the benefits of glutamine for the prevention of chemotherapy-induced peripheral neuropathy. This study demonstrated some benefit, although limited by sample size. Ongoing research is needed for determination of any potential role of glutamine for the prevention of neuropathy with agents associated with this side effect.

The study examined the neuroprotective effect of glutamine.

Seventeen patients received 10 g of glutamine administered three times daily for a total of four days beginning 24 hours after completion of paclitaxel. The remaining 29 patients made up the control group. Neurologic assessments and electrodiagnostic (nerve conduction) studies were carried out at baseline and at least two weeks (median 32 days) after treatment by a neurologist. Neurologic signs and symptoms also were assessed.

The study sample consisted of 46 patients who received high-dose paclitaxel prior to stem cell transplantation.

The study had a retrospective, non-randomized design.

Patients who received glutamine developed less weakness, less loss of vibratory sensation, and less toe numbness compared to those in the control group. A trend toward reducing symptoms of finger numbness was noted. In the comparison group, three patients developed foot drop and four patients developed tibialis weakness.

The mechanism of neuroprotection conferred by glutamine is unclear; some evidence suggests a correlation between treatment-induced reduction in nerve growth and severity of neurotoxicity.

The limitations of this study include it not being randomized or blinded as well as the fact that no placebo control group was used.

Results of this study should be interpreted with caution because of the small sample size and the non-randomized, retrospective design.

Female participants were were admitted for cyclophosphamide (6,000 mg/m²), thiotepa (500 mg/m²) and carboplatin (800 mg/m²) over 96 hours seven and four days prior to stem cell transplantation. Mesna (7,400 mg/m²; 1,500 mg/m² per day) was administered by continuous infusion over 120 hours. After December 1998, women enrolled in the study received glutamine (10 g orally three times daily) for four days starting 24 hours after the completion of paclitaxel. Data were collected at baseline and two weeks after completion of chemotherapy. In addition, paired pre- and post-paclitaxel evaluations were performed on all women.

• The study had a sample size of 45 women with advanced breast cancer, 12 who received glutamine 10 g orally three times daily for four days starting 24 hours after the completion of paclitaxel, and 33 women placed in the historical comparison group.
• Women were eligible to participate they were to receive high-dose chemotherapy (paclitaxel 825 mg/m² via continuous infusion over 24 hours four days before transplantation and melphalan 90 mg/m² per day for two consecutive days after recovery) with stem cell support.
• Women with stage IV breast cancer also were eligible if their disease had responded (partial or complete response) to conventional dose chemotherapy.
• Those with central nervous system metastases, prior progression while on a taxane, compromised organ function, or baseline neuropathy from chemotherapy that was disabling were excluded.

• A detailed neurologic history and neuropathy assessment instrument was used.
• Questions assessing symptoms were asked separately for fingers and toes and were graded as mild, moderate, or severe as well as their interference with functioning.
• Evaluation of reflexes, vibration sense, pin prick, and proprioception were performed on upper and lower extremities.
• Cerebellar function, gait, and motor weakness also were evaluated.
• Nerve conduction studies were performed in four nerves, with motor responses recorded.
• Serial sensory nerve conduction studies were performed on three nerves.

Women who received glutamine had fewer symptoms, with 8% of women who received glutamine reporting dysesthesias in the fingers and toes, as compared to 40% of the women who did not receive glutamine. In addition, the frequency of moderate to severe numbness was observed less often in the glutamine-treated group than in the non-glutamine group for both fingers and toes. Moderate to severe parasthesias also were observed less frequently in those who received glutamine.

• A non-randomized design.
• Unbalanced treatment and comparison groups.
• The grading of myalgias was not collected prospectively.
• Retrospective chart reviews were performed.
• Neurologic examinations can vary in their findings, even when performed by one examiner.

The purpose of the study was to evaluate whether oral glutamine reduced the incidence and severity of peripheral neuropathy in patients receiving oxaliplatin.

A total sample size of 86 patients with colorectal cancer were enrolled. Forty-two patients received glutamine and 44 did not. Patients received oxaliplatin 85 mgm/m², 5-FU  bolus 500 mgm/m², and folinic acid 20 mgm/m². Patients received glutamine 15 g twice a day for seven days every two weeks starting on the day of treatment. Patients were assessed at baseline for neurological toxicity and electrophysiological toxicity and again assessed at cycles 2, 4, and 6.

The 86 patients enrolled in the study had adenocarcinoma of the colon or rectum.

The study took place from September 2004 to December 2005.

The study had a non-randomized, pilot design.

Glutamine supplementation significantly reduced the incidence and severity of oxaliplatin-induced neuropathy. After two cycles of treatment, grade 1–2 sensory neuropathy was significantly lower in the intervention group versus the control group. The percentage of grade 3–4 sensory neuropathy was lower in the glutamine group after four cycles of treatment and remained that way for six cycles. In addition, glutamine supplements lowered peripheral nerve hyperexcitability and interference with activities of daily living. Glutamine supplementation also reduces the need for oxaliplatin dose reduction without affecting response to chemotherapy and survival.

• Concerns exist concerning glutamine supplements possibly protecting tumor cells from the cytotoxic effects of chemotherapy.
• The study was a non-placebo controlled, non-blinded study with a relatively small sample size; therefore, causality cannot be inferred.
• There was no between-group difference detected. 

Glutamine is a potential neuroprotective agent that needs to be studied in larger populations in a randomized, placebo-controlled trial.

This study outlines the common antineoplastic agents known to cause neuropathy and provides information on incidence, onset dosages, the signs and symptoms, and general course and patterns of resolution. Agents identified include platinum compounds, vinca alkaloids, taxanes, bortezomib, ixabepilone, thalidomide, and lenalidomide. In addition to outlining the mechanisms of neuropathy development in cancer, the study discusses neurophysiologic and objective testing, noting that findings on electromyographic (EMG) and nerve conduction studies (NCS) can lag behind clinical symptoms. The study also identifies commonly used physician-based grading systems, including the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Eastern Cooperative Oncology Group (ECOG) systems, and notes that these two grading systems lack inter-rater reliability. Patient-based instruments for assessment include the Functional Assessment of Cancer Treatment (FACT) and the Patient Neurotoxicity Questionnaire (PNQ). The authors note that the routine assessment of pain secondary to neuropathy, using instruments such as the Brief Pain Inventory (BPI), is useful.

Routine assessment should be conducted and continued throughout therapy. Key points in assessment that should be included are:

• History, related comorbid conditions, alcohol use, symptoms, pain assessment, time course, and treatment delays or discontinuation from CIPN
• Physical examination
• Patient interview questions regarding sensation of numbness or tingling, pain, bothersome sensations, weakness, difficulty walking, falls, and interference with activities of daily living
• Functional skills testing, such as straight-line walking, name writing, buttoning, pegboard tests, and timed pellet retrieval.

Proposed agents for prevention of CIPN identified include:

• Agents with positive findings: vitamin E, calcium, magnesium, glutamine, glutathione, N-acetylcysteine, oxcarbazepine, xaliproden
• Agents with negative findings: amifostine, nimodipine, Org2766, rhuLIF
• Agents being tested in trials: vitamins B12, B6, acetyl-L-carnititne, alpha lipoic acid

Agents used for pain management:

• Those with negative results in CIPN, including gabapentin, amitriptyline, notriptyline
• Other agents commonly used include duloxetine, 5% lidocaine patch, opioids, tramadol

Current literature is inconclusive on the benefits of neurostimulation in treating CIPN. The authors note that evidence is scarce on efficacy of complimentary and alternative medicine (CAM) therapies and the need for appropriately powered and controlled studies in this area. However, acupuncture was identified as a promising adjunct option. The article also provides safety tips and issues for management of functional deficits in PIN, including situations in which to avoid or discontinue physical training, footwear selection, orthosis, and safety aspects of the household environment. Finally, the article addresses how autonomic neuropathy from chemotherapy occurs, but has not been well documented or studied.

• Limitations include a significant lack of evidence regarding effective management and prevention in this area.
• The review did not describe a search strategy or process to determine the quality of evidence used.

The article provides a comprehensive review of current knowledge about CIPN and common approaches toward assessment, prevention, and management. The authors do not make specific recommendations for treatment, research to validate evaluation tools, and exploration of combinations and scheduling of pain medications. In addition, testing of the safety and effectiveness of therapeutic interventions and dietary supplements are needed.