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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 4  |  Page : 1379-1387

Value of l-alanyl-l-glutamine parenteral formula in patients with head and neck cancer receiving radiotherapy


1 Department of Clinical Oncology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Public Health and Community Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission07-Jul-2020
Date of Decision17-Aug-2020
Date of Acceptance30-Aug-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Mohammed A Shalaby
MBBCh, Department of Demonstrator, Clinical Oncology, Faculty of Medicine, Menoufia University, Menoufia 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_209_20

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  Abstract 


Objective
The aim was to determine the effect of administration of parenteral l-alanyl-l-glutamine-containing formula on occurrence of treatment-related malnutrition and acute radiotherapy (RT)-related toxicities in patients with head and neck cancer.
Background
Studies have shown that glutamine-containing nutritional therapy can improve the nutritional status of adult patients with cancer.
Patients and methods
A total of 40 patients with head and neck carcinoma were randomized to receive either parenteral l-alanyl-l-glutamine-containing formula (0.4 mg/kg) during the first 2 weeks of RT (with or without chemotherapy) or placebo. Nutritional assessment was done for all patients at diagnosis and on weekly basis till end of treatment using subjective global assessment tool and anthropometric measures. Treatment-related toxicity was reported and graded. Quality of life (QoL) was assessed using Functional Assessment of Cancer Therapy for patients with head and neck cancer.
Results
There was a significant difference between the studied groups regarding subjective global assessment tool score from third week till 7th week (P = 0.019, 0.005, <0.001, <0.001, and 0.021, respectively). Low BMI was more frequent in group 2 patients. Conversely, severe weight loss was significantly different between both groups starting from third week (P = 0.020, 0.010, 0.004, 0.031, and 0.044). There was higher frequency and severity of acute RT toxicities in group 2 patients. There was a significant difference between the two groups regarding QoL as well (P = 0.005).
Conclusion
l-alanyl-l-glutamine nutritional supplement resulted not only in better nutritional status but also in improved treatment tolerance and QoL.

Keywords: carcinoma, l-alanyl-l-glutamine, malnutrition, patients, squamous cell


How to cite this article:
Shehata MA, Tawfeek EA, Elkhouly EA, Soliman SS, Shalaby MA, Gohar SF. Value of l-alanyl-l-glutamine parenteral formula in patients with head and neck cancer receiving radiotherapy. Menoufia Med J 2020;33:1379-87

How to cite this URL:
Shehata MA, Tawfeek EA, Elkhouly EA, Soliman SS, Shalaby MA, Gohar SF. Value of l-alanyl-l-glutamine parenteral formula in patients with head and neck cancer receiving radiotherapy. Menoufia Med J [serial online] 2020 [cited 2021 Apr 18];33:1379-87. Available from: http://www.mmj.eg.net/text.asp?2020/33/4/1379/304536




  Introduction Top


Patients with cancer are more likely to be malnourished than patients treated for many other diseases[1]. Patients with head and neck cancer (HNC) are one of the most vulnerable groups to cancer-related malnutrition during and after cancer treatment[2].

Unfortunately, many patients with HNC are diagnosed at an advanced stage (stage III/IV) and experience conditions of nutritional vulnerability, with a high risk of malnutrition. These tumors directly affect patients' oral intake, taste, and appetite and intensify the effects of treatments toxicity while increasing the risk of severe malnutrition, cachexia, persistence of symptoms, and weight loss[3].

Moreover, antineoplastic treatments, like radiotherapy (RT) and chemotherapy (CT), or a combination of these concomitant chemoradiotherapy (CRT) may also cause multiple symptoms that compromise oral intake[3].

The adverse effects of malnutrition on physical performance, quality of life (QoL), and cancer treatment tolerance and effect should be minimized by appropriate nutrition interventions[2].

Nutrition support therapy is appropriate in patients receiving active anticancer treatment who are malnourished and who are anticipated to be unable to ingest and/or absorb adequate nutrients for a prolonged period of time[4].

Use of specific substances for effects beyond their nutrition role is referred to as nutritional pharmacology. Four nutrients especially have been the subject of research: glutamine, arginine, nucleic acids, and essential fatty acids[4].

Glutamine is the most abundant amino acid in the blood and the free amino acid pool in the body. It is a nonessential amino acid in normal healthy individuals, as it can be produced in enough amounts in vivo and does not need to be supplied in the diet. Cells that utilize glutamine are immunocompetent cells, enterocytes, and hepatocytes[5].

During critical illness, the body is unable to produce enough amounts of glutamine, causing its depletion in plasma and tissue, making it a conditionally essential amino acid, and low plasma and tissue levels of glutamine have been associated with poor clinical outcomes[5].

Some studies have highlighted the use of oral glutamine supplementation to reverse cancer-related cachexia and other debilitating conditions. The clinical role of glutamine in the prevention of CT and RT-induced toxicity is suggested[6],[7]. The effects were strongest when patients with HNC were administrated intravenous glutamine (dose 0.4 g/kg/day)[8].

Arginine and nucleotides are being studied as immune-supporting ingredients in enteral feeding formulas in surgical and radiation patients. The endogenous production of arginine from citrulline is supported in the presence of enough supply of its substrate glutamine. Glutamine-containing dipeptides (alanyl-glutamine or glycyl-glutamine is more stable and soluble) now provide the opportunity to restore or even enhance the content of parenteral nutrition (PN) amino acid solutions[9].

The published data on the use parenteral glutamine dipeptide product (i.e., l-alanyl-l-glutamine and glycyl-l-glutamine) formulas are too limited to make recommendations on the use of these formulations[4].

The aim of this study was to determine the prophylactic effect of administration of parenteral l-alanyl-l-glutamine-containing formula on occurrence of treatment-related malnutrition (subjective global score B or C, BMI ≤18.5 and weight loss ≥5 kg in 1 month) and acute RT-related toxicities (primary end point) and its effect on treatment response (secondary end point) in patients with squamous cell carcinoma (SCC) of the head and neck.


  Patients and methods Top


This prospective study was carried out at Department of Clinical Oncology, Menoufia University Hospitals. All patients who presented to the Department of Oncology, Menoufia University, during the period of January 2019 to September 2019 and accepted to participate in the study were included if they met the inclusion criteria.

The inclusion criteria were patients who were pathologically diagnosed with SCC of head and neck (T2-4, N1-3, M0) and then received radical dose of RT with or without CRT. They all had good performance status (≥2), no nutritional problems, and adequate caloric intake (30–35 kcal/kg).

Patients with malnutrition at presentation, treated on palliative base, received altered fractionation schedule, with poor performance status (>2), with head and neck tumors of other histology than SCC, had hypersensitivity for the formula, or refused to participate were excluded.

The study protocol was approved by the Institutional Review Board of faculty of medicine at Menoufia University. After signing informed consent, all patients were initially subjected to thorough history taking; clinical examination; and investigations in the form of complete blood count, complete liver and kidney functions, MRI neck with contrast, computed tomography chest, abdomen and pelvis and endoscopy.

The baseline information collected included patients' demographics, tumor characteristics (size, regional node status, histological characteristics, and grade), and staging, which was based on clinical TNM classification.

The basic anthropometric nutritional assessment measurements based on the main parameters adopted by the Fédération nationale des centres de luttecontre le cancer (French Federation of Cancer Centres) ('standards')[10] including measurement of height and current weight, estimation of involuntary weight loss and the rate of weight loss, and calculation of the BMI [ratio of weight (kg) over height squared (m2)] were measured at baseline before the start of RT and weekly till the end of RT.

Patients were nutritionally screened using a validated screening tool [subjective global assessment (SGA)][11] at diagnosis, then repeated weekly during RT, and after one month and 3 months of RT.

Subjective Comprehensive Nutritional Status/SGA was used to evaluate patients undergoing radiation therapy. SGA tool included patients' medical history (weight change, changes in diet, the last 2 weeks of the digestive tract symptoms, and functional capacity) and physical examination (muscle, ankle and sacrum edema, and ascites). This instrument consists of only a few simple questions that can also be easily answered by nursing personnel[12].

Via history taking and physical examination, a clinician can then determine the patients' nutritional status degree: well nourished (A), moderately malnourished (B), or severely malnourished (C). The patients were also given a numerical score.

All patients were treated with curative dose of 3-D conformal RT (the prescription dose was 70 Gy in 35 fractions over 7 weeks for patients treated on radical dose and from 60 to 66 Gy in 30–33 fractions over 6–6.5 weeks in adjuvant setting). RT was combined with concurrent systemic therapy when indicated, particularly, with cisplatin, comprising weekly cycles of 30 mg/m2.

The patients were equally randomized (by simple random numbers generated by a computer) to receive either l-alanyl-l-glutamine parenteral with dose of 0.4 mg/kg, diluted with normal saline and infused over 4 h daily from the first day of RT for two weeks (to void concerns regarding its stimulatory effects on malignant growth)(experimental group) or receive placebo (control group).

Nutritional counseling was provided to every patient from the start of RT. It consisted of a personalized dietary prescription by a specialized dietician to achieve estimated protein-calorie requirements and to consider chewing and swallowing abilities. Regular consultation by a registered dietician was also provided weekly during RT and at the time of the scheduled follow-up visits (1 month and 3 months after the end of RT).

Nutrition support via tube feeding was provided if patients were unable to eat adequately (<60% of requirement for >1–2 weeks). EN or oral nutritional supplement was provided if the gastrointestinal tract is functional and PN if EN was not enough or feasible.

PN was defined as nutrients administered intravenously that contain a combination of amino acids, carbohydrate, or fat with nonprotein calories, with at least 15 kcal/kg/day for at least 6 days. EN was defined as oral nutrient supplements and tube feeding, providing calories with at least 15 kcal/kg/day for at least 6 days.

Serum albumin levels, white blood cells counts, and hemoglobin level were done weekly. All patients were examined weekly, for the presence and severity of treatment complications and evaluated according Radiation Therapy Oncology Group (RTOG) / European Organization for Research and Treatment of Cancer (EORTC) Radiation Toxicity Grading[13].

All the patients who develop RT-related complications, for example, mucositis, anorexia, and xerostomia, were accordingly treated. Treatment gaps and irregularities owing to treatment-related complications were reported in both groups.

QoL was assessed at baseline, at the end of RT, and after 3 months of end of RT using Functional Assessment of Cancer Therapy for patients with Head and Neck cancer (FACT-H and N)[14].

Statistical analysis of the collected data

Results were collected, tabulated, and statistically analyzed by an IBM compatible personal computer with SPSS statistical package version 23 (Released 2015, SPSS Inc. IBM SPSS statistics for windows, version 23.0; IBM Corp., Armonk, New York, USA).

Two types of statistical analysis were done

  1. Descriptive statistics were expressed in number, percentage, mean, and SD
  2. Analytic statistics used were as follows:


    1. Student t test is a test of significance used for comparison of quantitative variables between two groups of normally distributed data, whereas Mann–Whitney test was used for comparison of quantitative variables between two groups of not-normally distributed data
    2. Paired t test was used to compare different readings of normally distributed data in the same group (i.e., before and after treatment), and Wilcoxon test was used to compare different readings of not-normally distributed data in the same group
    3. χ2 test was used to study association between qualitative variables. Whenever any of the expected cells were less than five, Fischer's exact test was used
    4. Z test was used to compare two proportions in two groups.


A logistic regression was performed to ascertain the effects of potential risk factors on the main outcome.

Two-sided P value of less than 0.05 was considered statistically significant.


  Results Top


This study included 40 patients: 20 patients in experimental group received nutritional supplement and 20 patients in control group.

There was no significant difference between the two studied groups regarding the patients' characteristics at the beginning of the study, including age, BMI, sex, PS, or comorbidities [Table 1]. Included patients mostly presented with stage III. A total of 36 patients received concomitant chemoradiotherapy (CCRT), and four patients received RT alone on adjuvant base. There was no significant difference between the two groups regarding disease characteristics including cancer subtype, TNM classification, stage, or treatment [Table 1].
Table 1: Patients' and disease characteristics

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All over the weeks of treatment, although the BMI was numerically higher in experimental group, the difference was not significant. Conversely, severe weight loss (>5% during the treatment period) was significantly different between both groups starting from third week (P = 0.020, 0.010, 0.004, 0.031, and 0.044) [Table 2].
Table 2: Nutritional Parameters in Both Groups throughout Treatment Period

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Regarding SGA scoring by third week, there was a significant difference between the studied groups regarding SGA score (P = 0.019, 0.005, <0.001, <0.001, and 0.021, respectively). By the end of RT, 16 (80%) patients in control group vs seven (41.2%) patients in experimental arm developed severe malnutrition (score C) [Table 2].

During treatment, no nutritional intervention was needed in 13 (65%) patients of control group and 18 (90%) of experimental group. However, four (20%) patients of control group required nasogastric tube and three (15%) required total parenteral nutrition (TPN). Only one patient of experimental group required TPN.

None of the patients had oral mucositis (OM), RT dermatitis, dysphagia, dysgeusia, or xerostomia at the first week of the study. As treatment weeks passed, there was a significant difference between the studied group regarding OM, which was more frequent in control group. By the end of week 7, 15 (75%) patients developed grade III mucositis (vs seven patients in experimental group) and one (5%) patient developed grade IV mucositis vs no patients in experimental group [Table 3].
Table 3: Treatment-related toxicities in both groups

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It is important to document that the patient who had grade IV mucositis was hemodynamically unstable and needed ICU admission.

Moreover, there was a significant difference between the two groups regarding radiation dermatitis at end of RT; six (30%) patients of control group vs four (23.5%) patients of experimental group had grade III radiation dermatitis. Other RT-related toxicities such as dysphagia, dysgeusia and xerostomia were also significantly higher in the control group compared with the experimental group (P = 0.005, 0.03, and 0.004, respectively) [Table 3].

Regarding unplanned admissions, eight (40.0%) patients of control group and three (15%) of experimental group were admitted to the hospital. The proportion of patients completing planned RT treatment was 100% in both groups, although three patients in control group (15%) were obligated to withhold RT sessions owing to high-grade toxicity.

FACT-H and N quality-of-life assessment revealed that the initial score of experimental group was 111.90 ± 6.55 and was not significantly different from that of the control group (115.45 ± 6.09), with P value 0.084. At the end of treatment, FACT-H and N of control group was reduced significantly to 69.55 ± 11.27 (P < 0.001) and that of experimental group was reduced significantly to 80.25 ± 11.42 (P < 0.001), with significant difference between the two groups as well (P = 0.005).

There was no significant difference between the two groups regarding the response to treatment (P = 1.00) or the SGA at 3 months (P = 0.121) after end of treatment. Complete response (CR) was reached in 13 (65.0%) patients in each group, partial response (PR) in three (15.0%) patients of experimental group and four (20.0) patients of control group, progressive disease (PD) in three (15.0%) patients in each group, and stable disease (SD) in one (5.0%) patient in experimental group and none in control group.

Multivariate regression model revealed that glutamine intake was not a significant determinant of moderate or severe malnutrition (SGA score B or C); however, glutamine intake was a significant determinant of weight loss percentage. Glutamine intake was significantly inversely related to weight loss (P < 0.001), with unstandardized coefficient B of -7.195 (CI: -10.748 to -3.642). The modality of treatment was also significantly related to weight loss percentage, with unstandardized coefficient B of -6.825 (CI: -13.574 to -0.076) [Table 4].
Table 4: Linear regression of determinants of weight loss among the studied patients

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There were no reported toxicities of l-alanyl-l-glutamine formula among experimental group.


  Discussion Top


Malnutrition is frequent comorbidity in patients with HNC as food intake may be significantly reduced in these patients owing to chewing and swallowing difficulties associated with tumor location, poor dietary intake, and tumor-related inflammation and may be aggravated by treatment-related adverse effects[15].

Nutritional problems such as weight loss, low body mass index, and reduced protein-calorie intake before and/or during RT have been associated with worse prognosis (e.g., reduced survival and locoregional treatment failure), impaired QoL, greater treatment toxicity, and severe mucositis[15].

Nutrition interventions in patients with HNC should aim to maintain or improve dietary intake and nutritional status, including maintenance or build-up of skeletal muscle mass, and to minimize the adverse effects of malnutrition on physical performance, QoL, and treatment tolerance[16].

In patients with cancer, marked glutamine depletion develops over time as cancer cachexia is marked by massive depletion of skeletal muscle glutamine. This can have a negative effect on the function of host tissues dependent upon adequate stores of glutamine (e.g., intestinal epithelial cells and lymphocytes). The extent of normal tissue damage from radiation or CT may be influenced by the presence of adequate tissue glutamine stores. This supports a possible therapeutic role for glutamine in the prevention of host normal tissue toxicity during cancer treatment[6].

Glutamine-containing dipeptides (alanyl-glutamine or glycyl-glutamine) are more stable and soluble, and over the years, an extensive evidence base for their safety has been established[9].

The current study was conducted in Menoufia University, Clinical Oncology Department, on 40 patients who were recruited and randomized by simple randomization into two groups: group 1 received parenteral l-alanyl-l-glutamine formula vs placebo in group 2. There was no significant difference between two groups regarding epidemiological and disease features, indicating homogeneity of the groups.

At randomization, all patients were well nourished (SGA tool score A, BMI greater than 18.5, and no history of significant weight loss). Despite nutritional support along the RT period, patients experienced moderate and severs malnutrition (SGA score B and C, reduced BMI less than or equal to 18.5, and significant weight loss =5% in 1 month).

Occurrence of malnutrition, reduced weight, and reduced BMI in patients with HNC during RT with or without CT despite nutritional care has been reported by some studies, such as Arribas et al., Orell et al., Citak et al., and Hofto et al. However, in the current study, it seems that administration of l-alanyl-l-glutamine formula significantly protected experimental group patients from developing severe malnutrition, marked weight loss, and abnormal BMI [17],[18],[19],[20] .

This affected patients' need for nutritional intervention like need for nasogastric tube insertion and TPN and unplanned treatment gaps. Cerchietti et al.[21] also reported that patients who received l-alanyl-l-glutamine formula experienced less pain and had fewer percutaneous endoscopic gastrostomy tube insertions for nutritional support compared with patients who received placebo.

There was a higher incidence of patients with OM in the placebo group compared with l-alanyl-l-glutamine formula group. This goes with the results reported by Cerchietti et al.[21] and Elfeky et al.[22], who assessed the value of l-alanyl-l-glutamine administered intravenously in patients with HNC receiving definitive RT with or without CT and concluded that l-alanyl-l-glutamine formula had protective effects against OM.

The role of glutamine in prevention of radiation dermatitis in patients with HNC was reported by LopezVaquero et al.[23], who found a significant benefit of oral glutamine in reducing the incidence and severity of dermatitis. Moreover, Pathak et al.[24] found that patients receiving oral glutamine delayed the onset of OM and dysphagia and reduced its severity in patients with oropharynx and larynx carcinoma.

In our study, we found that parenteral l-alanyl-l-glutamine formula significantly reduced the incidence and severity of radiation dermatitis together with other acute effects such as dysphagia, xerostomia, and dysgeusia.

So, unplanned admissions owing to severe toxicity or malnutrition and subsequent treatment gaps were less frequent in this arm. This is like what was reported by Elfeky et al.[22], who indicate that patients who received parenteral glutamine-containing formula tolerated treatment in a better way.

Although there was no significant difference between two groups in QoL score at the start of treatment, it was significantly reduced at the end of treatment period, and this can be expected as a result of treatment-related adverse effects and reduction in nutritional parameters. However, placebo group had worse QoL score than glutamine-enriched formula group. Sari et al.[25] also reported that quality-of-life score using FACT-H and N was lower in patients treated with intensity modulated radiotherapy.

So, despite the QoL being negatively affected with RT; the use of glutamine-enriched formula may mediate this negative effect.

Regression analysis revealed that glutamine administration was an independent risk factor for maintaining weight during RT period, augmenting its protective value against malnutrition, and patients who received CRT with RT were at higher risk for weight loss. This can be explained by higher rate of acute toxicities in these patients, which affects swallowing and food intake.

Glutamine can be a principal fuel for a group of rapidly proliferating tumor. These tumors described are as glutamine traps, which in turn may contribute to depletion of glutamine stores and cancer-related wasting[26]. This raised concerns regarding possible stimulation of malignant growth in tumor-bearing hosts supplemented with glutamine. On the contrary, some evidence suggests that glutamine may decrease tumor growth by several mechanisms including immune-mediated tumor cell killing and intra-tumoral glutathione depletion[27].

In our study, response evaluation after 3 months revealed there was no significant difference regarding two studied groups. This goes with that detected by Cerchietti et al.[21], but the evaluation of this relation requires a larger trial and long-term follow-up.

It is important to document that in this study and in studies conducted by Cerchietti et al.[21] and Elfeky et al.[22], there was no reported toxicities related to parenteral l-alanyl-l-glutamine formula administration.


  Conclusion Top


Parenteral l-alanyl-l-glutamine formula administration reduced the frequency and severity of malnutrition and rate of weight loss in patients with head and neck SCC and improved tolerability of treatment and QoL with no reported toxicities. Parenteral l-alanyl-l-glutamine formula may be a valid option for patients receiving RT with or without CT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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