Effects of Glutamine for Prevention of Radiation-Induced Esophagitis: A Double-Blind Placebo-Controlled Trial

Abstract

Purpose

Acute radiation-induced esophagitis (ARIE) leads to treatment delays, decreased quality of life (QOL), and secondary adverse events such as weight loss. Grade 3 ARIE occurs in 15%-30% of patients undergoing radiotherapy to the esophagus, leading to disruption or discontinuation of treatment. The purpose of this study was to assess the effects of glutamine, a common nutritional supplement, on ARIE in patients with thoracic malignancies.

Patients and Methods

This double-blind, placebo-controlled trial enrolled patients with advanced thoracic malignancies receiving concurrent chemotherapy/radiotherapy or radiotherapy alone, with radiation doses to the esophagus ≥45 Gy. Patients were randomized (1:1) to receive 4 g of glutamine or glycine placebo twice daily. The primary objective was to determine whether glutamine decreases the severity of ARIE in these patients. Secondary objectives included assessment of the effects of glutamine on other measures of ARIE, weight, symptom burden measure assessed by the MD Anderson Symptom Inventory (MDASI-HN) questionnaire and the toxicity profile of glutamine.

Results

At the time of interim analysis, 53 patients were enrolled: 27 in the glutamine arm and 26 in the placebo arm. There was no difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between the glutamine and placebo arms (74% versus 68%; P=1.00). There were no significant differences between the two arms for time to onset of esophagitis. The duration of ARIE was shorter (6.3 versus 7.1 weeks; P=0.54) and median weight loss was lower (0.9 kg versus 2.8 kg; p=0.83) in the glutamine arm versus the placebo arm. The groups differ significantly in core symptom severity (2.1 vs 1.5, p<.03) but not in head and neck specific symptom severity (1.2 vs 1.1, p<.60) nor in symptom interference (2.1 vs 1.7, p<.22). There was no grade 3 or higher adverse event at least possibly related to glutamine. The study was terminated for futility following interim analysis.

Conclusion

Oral glutamine was not associated with significant improvement in severity of ARIE, weight loss, head and neck specific symptoms or symptom interference compared with placebo in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus.

Clinical trial information:

NCT01952847, and date of registration is September 30, 2013.

INTRODUCTION

More than 1.8 million new cases of cancer are expected to occur in the United States in 2020, which includes 228,820 new cases of lung cancer and 18,440 new cases of esophageal cancer.¹ While the intent of thoracic radiotherapy is to maximize an effective dose to the tumor while sparing as much healthy tissue as possible, complications such as acute radiation-induced esophagitis (ARIE) may cause significant morbidity, affecting quality of life (QOL) and causing unplanned treatment delays and treatment ineffectiveness.^2,3 Esophagitis can manifest as odynophagia, dysphagia, nausea, anorexia, or substernal burning sensation.^3-5 ARIE may occur as early as the first week of radiotherapy, and, in most cases, it arises with symptoms within the first 2 months of treatment.^3,4 Furthermore, the incidence of severe esophagitis (≥ grade 3) is significantly higher in patients receiving concurrent chemoradiation (34%) compared with patients treated with standard thoracic radiotherapy (1.3%) or patients receiving induction chemotherapy followed by standard radiotherapy (6%).³ Though precise dose-delivery radiotherapy techniques such as intensity modulated radiotherapy are being used to spare exposure of normal structures,⁶ ARIE is a frequent dose-limiting toxicity in patients treated with thoracic radiotherapy. Therefore, other strategies, such as using radioprotective agents to control ARIE, are under investigation.

Glutamine, the most abundant free amino acid in human body, is the main oxidative fuel of the intestinal epithelium and is necessary for maintaining the integrity of the gut epithelium.⁷ It is primarily stored in the skeletal muscles and is released into the bloodstream for various biochemical functions. In patients with debilitating diseases such as cancer, the continuous glutamine release from skeletal muscles during the hypercatobolic phase of the disease leads to significant glutamine depletion.^8,9 The continuous depletion of glutamine from muscle may lead to cachexia, negatively affecting acid-base balance, patient immune system, epithelial integrity, and microbiomes—all of which reduce radiation tolerance.⁸ Furthermore, depletion of glutathione, a byproduct of glutamine metabolism that has a protective role against oxidative injury in normal cells, may exacerbate the epithelial damage caused by radiotherapy and chemotherapy.^10,11 Additionally, nausea, vomiting, pain, or dysphagia due to ARIE may exacerbate radiation intolerance. Based on the radioprotective properties of glutamine, we hypothesized that oral supplementation of glutamine could prevent or ameliorate the severity of ARIE. Therefore, we conducted a double-blind, placebo-controlled trial to investigate effects of glutamine supplementation on ARIE in patients with thoracic malignancies receiving radiotherapy.

PATIENTS AND METHODS

Design

This single-center, double-blind, placebo-controlled trial (NCT01952847) enrolled adult patients with thoracic malignancies receiving radiation or chemoradiation therapy to the esophagus. The study was conducted in the Department of Investigational Cancer Therapeutics and the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas. The protocol was approved by the Institutional Review Board at MD Anderson and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines. All study participants provided written informed consent before enrollment.

Patients

Patients enrolled in this study had confirmed thoracic malignancies and were scheduled to receive radiotherapy alone or concurrent chemoradiation. The radiation dose was ≥ 45 Gy, and induction chemotherapy was allowed. Conventional fraction doses from 180 to 240 cGy per day were given. Radiation was given daily for 5 days per week by one of the following modalities: 3D conformal radiotherapy, intensity-modulated radiation therapy, or proton therapy.

Intervention

Glutamine and placebo glycine powder were provided by Healios Nutrition Oncology (Houston, Texas) and distributed by the investigational pharmacy at MD Anderson. Investigational pharmacists dispensed either glutamine or placebo glycine according to a computer-generated random assignment list. Treatment allocation was blinded to patients, investigators, and the study coordinators who enrolled the participants. The statistician and the investigational pharmacist had access to the assignments. Patients were randomly assigned to receive 4 g of either glutamine or placebo mixed with water twice each day. All patients were counseled with directions on how to suspend glutamine or placebo glycine powder into water and take in several small boluses. Glutamine or placebo glycine was initiated on the first day of radiotherapy or within 10 days of the start of radiotherapy and was continued for 4 weeks after the last day of radiotherapy. The number of weeks of glutamine or placebo glycine treatment was based on the number of weeks of radiotherapy determined by the treating physician.

Treatment of Esophagitis

If patients developed esophagitis of grade 1 for more than 5 days or grade 2 or higher, the treating physician initiated supportive therapy. Supportive therapy included but was not limited to: xyloxylin (1:1:1 ratio of diphenhydramine, Maalox, lidocaine; 10 mL swish/ swallow every 6 hours as needed) and narcotics to alleviate pain.

Assessments

A retrospective review of the electronic medical records of patients enrolled in the study was performed to collect demographic and patient characteristic data including tumor type and histology, sex, age, and race. Medical history including current concomitant medications and prior history of esophagitis were documented at baseline. Weight measurements were performed at baseline, weekly during radiotherapy, and at 1 and 6 months after the completion of radiotherapy to determine weight loss percentage.

All adverse events (AEs) occurring after administration of the study drug that were at least possibly drug-related were followed until resolution, stabilization, death, loss to follow-up, or commencement of new therapy. The AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.¹² Evaluations were performed at baseline, weekly during radiotherapy, and at 1 and 6 months after the completion of radiotherapy for signs and symptoms of esophagitis using a modified version of CTCAE version 4.03.¹² The modified CTCAE used for grading esophagitis symptoms followed by physicians and mid-level providers is described in Table 1. When a patient experienced the same AE but at different grades, the patient was counted only at the highest grade experienced for that event.

Table 1. Modified Common Terminology Criteria for Adverse Events for Esophagitis.

Adverse Event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Esophagitis	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic; altered eating/swallowing; oral supplements indicated. aPatients are initiated on xyloxylin.	Severely altered eating/swallowing; tube feeding, TPN or hospitalization indicated. aPatients are initiated on narcotic intervention. aFeeding tube required secondary to difficulty swallowing rather than uncontrolled nausea.	Life-threatening consequences; urgent intervention indicated	Death

Abbreviation: TPN, total parenteral nutrition.

^aModifications to National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 specific to this protocol.

Symptom burden assessments were conducted using the MD Anderson Symptom Inventory (MDASI) Head and Neck module (MDASI-HN). The MDASI was designed to assist in the 24-hour recall assessment of 13 symptoms common in cancer patients and was referred to as core symptoms (dry mouth, fatigue, pain, disturbed sleep, drowsiness, feeling of being distressed, anorexia, sadness, numbness/tingling, dyspnea, difficulty remembering, nausea, and vomiting).¹³ The MDASI-HN includes 9 additional head and neck specific symptoms (mouth sores, problems with taste, constipation, teeth/gum problems, skin pain, difficulty with voice, choking/coughing, difficulty swallowing, and problems with mucus) specific to head and neck cancers.¹⁴ The severity at the time of assessment of each symptom is rated on a numerical scale from 0 (symptom is absent) to 10 (worst possible severity). The MDASI-HN also asks patients about how their symptoms impact their daily functions and was referred to as symptom interference. The instruments and techniques have been validated in patients with advanced cancer.¹³ The MDASI-HN was administered at baseline; weeks 3, 5, and 7; end of radiotherapy; and 1 and 6 months after the completion of radiotherapy. Linear mixed models were fitted with group, time and group by time interaction terms in the model and assuming an autoregressive variance covariance matrix structure.

The Study Medication Satisfaction Scale was a 7-item scale that asked patients about several areas of satisfaction while taking the glutamine or placebo glycine. The scale included questions about ease or difficulty of taking the medication in general and in its current form, convenience of taking the study medications as instructed, and patient confidence that the study medication is of benefit. The Study Medication Satisfaction Scale was administered and summarized at the end of treatment of radiation by group.

Statistical Analysis

The primary objective of the study was to determine whether glutamine decreases the severity of esophagitis in patients receiving radiotherapy to the esophagus. The secondary objectives were to assess whether the glutamine regimen 1) improves symptom burden (core symptoms, head and neck symptoms and symptom interference); 2) improves other measures of esophagitis including incidence of any grade esophagitis, incidence of grade 3 or higher esophagitis, duration of esophagitis, delay in onset of esophagitis, and interruption of cancer treatment due esophagitis; 3) affects weight loss after completion of radiation therapy; and 4) we also assessed the toxicity profile of glutamine.

Investigators planned to accrue 80 participants, 40 per treatment arm. Power calculations were based on published data that indicated that the distribution of esophagitis grade among patients not given glutamine was grade 0-1: 26%, grade 2: 37%, and grade 3: 37%¹⁵. A sample size of 40 participants per treatment arm would yield 81% power to detect a modest treatment effect (grades 0-1: 50%, grade 2: 38%, grade 3: 12%), assuming a two-sided 5% alpha and using the Wilcoxon rank sum test for analysis. Calculations were made using nQuery Advisor 7.0. Patients were randomly assigned to receive glutamine or placebo glycine at a 1:1 ratio. Randomization was stratified based on the volume of the esophagus that had received a dose of 40 Gy (20%-40%, 41-60%, and 61-80%) and whether the participant received concurrent chemotherapy.

Semi-annual futility analyses were conducted using Bayesian predictive probability methods.¹⁶ Based on the available data at interim analysis, the trial would be stopped early for futility if the predicted probability of observing a significant difference in success (no esophagitis) between the glutamine and placebo groups, i.e. P(glutamine > placebo ∣ data) > 0.99, at trial completion was < 5%. After accruing 53 participants, investigators conducted an interim analysis that compared incidence of esophagitis severity (grade ≥ 2 vs. < 2) between participants on the glutamine versus placebo arm. Interim results suggested that the probability of concluding the trial in favor of the glutamine arm was 0.001 and in favor of the placebo arm was 0.023. Therefore, accrual to the radiation arm was stopped early for futility.

The protocol defined evaluable patients as those who completed at least 60% of the planned doses of glutamine or placebo. The primary endpoint was the highest grade of esophagitis observed within 6 weeks of the start of radiotherapy. Individual MDASI symptom severity scores are the average of all scale items if more than half of the items were not missing. Categorical variables were compared using Fisher exact test and continuous variables using an independent samples t-test. The duration of esophagitis, weight change over time, and MDASI scores were compared between treatment arms using the Wilcoxon rank sum test. The time to develop esophagitis was compared using Kaplan-Meier estimates and the log rank test. P values less than 0.05 were considered statistically significant.

RESULTS

Patients

A total of 53 patients with confirmed thoracic malignancies, who were scheduled to receive radiotherapy alone or concurrent chemoradiation, were enrolled in this study between August 2014 and October 2016. Of the 53 patients, 27 were randomly assigned to the glutamine arm and 26 to the placebo arm. After randomization, 2 patients in each arm did not receive treatment (glutamine arm: 1 withdrew, reason unknown and 1 was later found ineligible; placebo arm: 1 withdrew, reason unknown and 1 withdrew due to lack of insurance coverage). Of the 25 patients treated on the glutamine arm and 24 on the placebo arm, 19 patients in each arm received at least 60% of planned doses of the study drug (glutamine or placebo). Therefore, there were 38 response-evaluable patients (Figure 1). Most patients (87%) were white. There were no significant differences in the baseline patient characteristics or radiation dose to the esophagus between patients in the 2 arms (Table 2). Final results suggested that the probability of concluding the trial in favor of the glutamine arm was 0.036 and in favor of the placebo arm was 0.003.

Figure 1. Flow chart of patients enrolled in the study.

Table 2. Baseline Patient Characteristics (n = 53).

Characteristic	Glutamine (n = 27)		Placebo (n = 26)		Total		a P-Value
	No.	(%)	No.	(%)	No.	(%)
RANDOMIZATION STRATIFICATION							1.00
20%-40% XRT only	4	(15)	4	(15)	8	(15
20%-40% XRT + chemotherapy	9	(33)	9	(35)	18	(34)
41%-60% XRT only	4	(15)	4	(15)	8	(15)
41%-60% XRT + chemotherapy	6	(22)	7	(27)	13	(25)
61%-80% XRT only	2	(7)	1	(4)	3	(6)
61%-80% XRT + chemotherapy	2	(7)	1	(4)	3	(6)
DEMOGRAPHIC & CLINICAL CHARACTERISTICS
Age, mean (SD), y	27	67.6 (9.8)	26	64.9 (11.8)	53	66.3 (10.8)	b 0.36
Gender							0.41
Male	14	(52)	17	(65)	31	(58)
Female	13	(48)	9	(35)	22	(42)
Race & Ethnicity							0.05
Black	1	(4)	6	(23)	7	(13)
White	26	(96)	20	(77)	46	(87)
Cancer type							0.67
Esophageal	2	(7)	4	(15)	6	(11)
Head & Neck	1	(4)	0	(0)	1	(2)
Lung	23	(85)	22	(85)	45	(85)
Sarcoma	1	(4)	0	(0)	1	(2)
BMI, mean (SD), kg/m2	27	27.0 (5.1)	26	28.2 (4.7)	53	27.6 (4.9)	b 0.35
SCREENING MDASI							---
Collected	26	(96)	25	(96)	51	(96)
Not collected	φ1	(4)	φ1	(4)	2	(4)
Baseline MDASI scores, median (minimum, maximum).
Total symptom severity	1.0	(0.1, 4.0)	1.0	(0, 3.4)	1.0	(0, 4.0)	c 0.93
Core symptom severity	1.4	(0.2, 5.3)	1.3	(0, 4.3)	1.3	(0, 5.3)	c 0.50
Head & neck symptom severity	0.4	(0, 2.3)	0.6	(0, 3.4)	0.5	(0, 3.4)	c 0.73
Symptom interference severity	0.5	(0, 7.0)	0.5	(0, 7.2)	0.5	(0, 7.2)	c 0.87

Abbreviations: BMI, body mass index; MDASI, MD Anderson Symptom Inventory; XRT, external-beam radiotherapy.

^φ2 randomized patients did not complete the screening MDASI: 1 in the placebo arm and 1 in the glutamine arm.

^aP values are from Fisher exact test unless otherwise noted.

^bIndependent samples t-test

^cWilcoxon rank sum test

Severity of Esophagitis

Of the 38 response-evaluable patients, 27 (71%) developed esophagitis during the first 6 weeks of radiotherapy. The maximum grade of esophagitis during the 6 weeks was grade 1 in 2 (5%), grade 2 in 13 (34%), and grade 3 in 12 (32%) patients (Table 3, Figure 2). There was no significant difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between patients in the glutamine arm (14 of 19, 74%) (95% CI 48.80, 90.85) and those in the placebo arm (13 of 19, 68%; Fisher exact test P =1.00) (95% CI 43.45, 87.42). Twelve (32%) of the 38 response-evaluable patients experienced grade 3 esophagitis, including 7 of 19 (37%) in the glutamine arm (95% CI 16.29, 61.64) and 5 of 19 (26%) in the placebo arm (95% CI 9.15, 51.20; Fisher exact test P = 0.73).

Table 3. Maximum Grade of Esophagitis in the First 6 Weeks of Radiotherapy.

Highest Grade Esophagitis	Treatment Arm				Total
	Glutamine		Placebo
	n (%)	95% CI	n (%)	95% CI
Absent	5 (26)	(9.15, 51.21)	6 (32)	(12.58, 56.55)	11 (29)
Grade 1	2 (11)	(1.30, 33.14)	0 (0)	-	2 (5)
Grade 2	5 (26)	(9.15, 51.20)	8 (42)	(20.25, 66.50)	13 (34)
Grade 3	7 (37)	(16.29, 61.64)	5 (26)	(9.15, 51.21)	12 (32)
Total	19		19		38

Figure 2. Grade of esophagitis by proportion of glutamine/placebo taken.

The median time to esophagitis was 3.4 (95% CI 2.7 to 43) weeks overall, 2.9 (95% CI 2.4 to 4.1) weeks in the glutamine arm, and 4.1 (95% CI 3.1 to 5.9) weeks in the placebo arm. There was no significant difference in time to esophagitis between the treatment arms (Log-rank test P = 0.29). The median duration of esophagitis was 7.0 (IQR 8.6) weeks, ranging from 1 to 44 weeks. There was no significant difference in the median duration of esophagitis between patients in the glutamine cohort (6.3 weeks) and those in the placebo cohort (7.1 weeks; Wilcoxon rank sum test P = 0.54). None of the study participants had treatment interruption due to mucositis/esophagitis.

Symptom Burden over Time

A total of 259 MDASI symptom scores over time were available from 38 response-evaluable participants (Figure 3 [a-d]). No significant group by time interactions were found on core symptoms, head and neck specific symptoms or symptom interference. However, the groups differed significantly in core symptom severity (2.1 vs 1.5, p<.03) with the glutamine group reporting higher core symptom severity. No significant group differences were found in head and neck specific symptom severity (1.2 vs 1.1, p<.60) or in symptom interference (2.1 vs 1.7, p<.22).

Figure 3. Quality of life scores over time.

The lines in each plot were created using locally estimated scatterplot smoothing, a nonparametric regression method, to help visualize the relationship between scores across the 8 time points. Wide confidence bands result from the sparseness of data at each time point. Data points are jittered. a) MD Anderson Symptom Inventory (MDASI) core symptom severity score. b) MDASI head and neck symptom severity score. c) MDASI total symptom severity score. d) MDASI symptom interference score.

The Study Medication Satisfaction Scale showed no significant differences between the 2 arms.

Weight Change over Time

Patients lost a median of 2.8 (IQR 4.7) kg from baseline to the end of the study. The median weight loss was greater in patients in the placebo arm (2.8 kg; IQR 4.2 kg) compared with those in the glutamine arm (0.9 kg; IQR 4.2 kg); however, the median weight loss was not statistically significantly different between the 2 arms (Wilcoxon rank sum test P = 0.83). Weight was recorded at the end of treatment with glutamine/placebo, which was 1 month after the completion of radiotherapy. This value was missing for 12 response-evaluable participants. For these missing values, weight at the end of radiotherapy rather than the end of glutamine/placebo treatment was used to calculate weight change.

Adverse events

A total of 49 patients who received at least 1 dose of the study drug were evaluable for toxicity assessment. All AEs that were at least possibly related to the study drug were collected. Of the 25 patients in the glutamine arm, 3 had grade 1 AEs and 2 had grade 2 AEs possibly related to the study drug. Of the 24 patients in the placebo arm, 1 had a grade 2 AE possibly related to the study drug. There were no grade 3 or 4 AEs or deaths that were at least possibly related to the study drug.

DISCUSSION

Despite the use of novel technologies for targeted delivery of radiation to cancer cells, practical issues such as treatment-related toxicity can hamper the prospects of attaining maximal benefit.¹⁷ Although ARIE is a frequent AE reported in patients receiving radiotherapy for thoracic malignancies,¹⁸ there are currently no standard measures to reduce ARIE. Our results indicate that glutamine does not significantly improve the severity of ARIE, weight loss, or QOL in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus.”

Glutamine is a radioprotectant found abundantly in human tissues. Several studies have evaluated the role of systemic glutamine to prevent or delay ARIE.^2,8,15,19-22 In a randomized study, Chang et al. reported that patients with advanced non–small cell lung cancer (NSCLC) benefitted from glutamine supplementation during concurrent chemoradiotherapy.¹⁹ The incidence of grade 2 or 3 ARIE was significantly decreased in patients randomly assigned to receive glutamine (6.7%) compared with patients who did not receive glutamine (53.4%), and the onset of ARIE was significantly delayed in patients who received glutamine. Though few other studies have reported decreased incidence of ARIE with glutamine,^8,20-22 Jazieh et al. had reported that patients with locally advanced NSCLC who received glutamine were not protected against esophagitis in a phase 1 clinical trial of paclitaxel and carboplatin with concurrent radiotherapy.² Similarly, in our single-center, double-blind, placebo-controlled study in adult patients with thoracic malignancies receiving radiation or chemoradiation therapy to the esophagus, there was no significant difference in the proportion of patients who had ARIE between the glutamine and placebo arms. Though the onset of esophagitis was earlier in patients in the glutamine arm, the duration of esophagitis was shorter compared with those in the placebo arm; neither of these differences was statistically significant. Despite the occurrence of ARIE in 71% of the patients in the first 6 weeks of radiotherapy, there was no interruption to radiotherapy in patients in our study, probably due to intense supportive care. However, following interim analysis, the study was terminated for futility.

Symptoms associated with ARIE such as dysphagia and pain are cumulative, resulting in weight loss, dehydration, and malnutrition. However, with glutamine supplementation, patients have been reported to have a median weight gain of 1.2 kg compared with weight loss of 4.6 kg in the control group.¹⁹ Other investigators have reported that weight loss was higher in NSCLC patients treated with chemoradiation who did not receive glutamine supplementation.^20,21 This is an important finding because weight loss is negatively associated with QOL and survival.^20,23,24 In a study of 1999 patients treated in 9 RTOG trials with thoracic irradiation with or without chemotherapy, weight loss greater than 8% was significantly associated with poor survival.²⁴ In our study, though the median weight loss in patients treated in the glutamine arm was less (0.9 kg) compared with those in the placebo arm (2.8 kg), the difference was not statistically significant. As reported by Algara et al.,⁸ glutamine was well tolerated in our cohort except for some mild toxicities.

Symptoms related to ARIE can significantly impact QOL. For example, difficulty in swallowing and pain can limit food intake and result in weight loss and malnutrition. The morbidity associated with weight loss and its impact on QOL can be debilitating, resulting in treatment delays or discontinuation of treatment resulting in progression of cancer.^2,3 In our study, we found that glutamine did not reduce the head and neck specific symptoms or symptom interference as assessed by MDASI-HN.

Though we did not observe the beneficial efforts of glutamine in preventing or reducing the severity of ARIE, our study was double-blind, placebo-controlled study, the gold standard of epidemiologic studies. Most of the studies that had earlier reported improvement in the severity of ARIE with glutamine supplementation were either retrospective studies ^15,20-22 or non-randomized studies.⁸ Similar mixed results have been reported with amifostine, an intravenously administered radioprotectant, which was also evaluated for its efficacy to reduce ARIE. Several small randomized trials reported that amifostine reduced the rates of esophagitis in advanced NSCLC patients;^25-27 this result, however, was not reproducible in a large cooperative group trial or randomized, phase 3 trials.^28-30

Our study hade a few limitations. First, the occurrence of esophagitis was based on symptoms and clinical evaluation. Endoscopy was not done to confirm or grade esophagitis. Second, patients in the glutamine arm received 4 g of glutamine twice each day compared with 10 g of glutamine 3 times a day in all other studies.^2,8,19-21 Third, although there was no statistically significant difference in the baseline characteristics of patients between the 2 groups, the wide range of radiation doses may have had an impact on the study.

In conclusion, results of our double-blind, placebo-controlled study indicate that use of glutamine did not significantly decrease the severity, delay the onset of esophagitis or improve QOL, but may prevent weight loss in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus. In view of these mixed results, a meta-analysis may help to determine the effect of glutamine supplementation on ARIE.