Effect of Arginine- and Glutamine-based Oral Formulations on Salivary Biomarkers and Clinical Severity of Radiation-induced Oral Mucositis in Head and Neck Cancer: A Randomized Controlled Trial

Overview

This triple-blinded, randomized controlled clinical trial investigates the effectiveness of L-arginine and L-glutamine oral suspensions in managing radiation-induced oral mucositis (RIOM) in patients with head and neck cancer (HNC) undergoing radiotherapy. A total of 69 patients are randomly assigned to three groups: L-arginine + maltodextrin, glutamine + maltodextrin, or maltodextrin alone (control). The interventions are administered as a swish-and-swallow solution three times daily from the second to seventh week of radiotherapy. Key outcomes assessed include oral mucositis severity (WHO scale), pain intensity (VAS), body mass index (BMI), oral health-related quality of life (OHIP-14), and salivary epidermal growth factor (EGF) levels. The study aims to determine whether L-arginine offers superior mucosal healing and symptom relief compared to glutamine or placebo.

Radiation-induced oral mucositis (RIOM) is recognized as a frequent and severe complication among patients with head and neck cancer (HNC) who undergo radiotherapy (RT) 1. It manifests as damage to healthy tissues, specifically inflammation and/or ulceration of the oral mucosa, affecting over 80% of these patients receiving radiation therapy 2. RIOM manifests as a normal tissue injury lasting from 7 to 98 days, initiated by acute inflammation in the oral mucosa, tongue, and pharynx following RT exposure 1. This inflammation is accompanied by the accumulation of various inflammatory cells and the secretion of cytokines, chemotactic agents, and growth factors. RIOM may escalate into a life-threatening condition due to significant blockages that restrict the intake of food and water, leading to weight loss and septic issues from the loss of protective epithelial and basement membrane layers. Consequently, these complications can disrupt cancer treatment and necessitate changes in the radiation dose, thus impacting local tumor control.3 The pathogenesis of RIOM associated with RT for HNC unfolds through a complex, multi-stage process. Initially, ionizing radiation directly damages cellular DNA within the radiation field, resulting in lethal double-strand breaks. When these breaks are not repaired accurately, it leads to programmed cell death or apoptosis. Concurrently, this radiation exposure stimulates various cells such as endothelial cells and fibroblasts to produce reactive oxygen species (ROS). These ROS further exacerbate DNA damage and disrupt cellular functions by modifying protein and lipid membrane structures, leading to escalated inflammation 4. When excessive ROS accumulate, they cause oxidative stress, managed by antioxidants like superoxide dismutase and glutathione peroxidase. Disruptions in this balance lead to oxidative damage, increasing the risk of cancer and inflammatory conditions. Chemoradiation activates NF-kappa B, heightening pro-inflammatory cytokine levels that drive the progression to mucosal ulceration characteristic of OM. This condition severely impacts patients' nutrition and oral hygiene and increases the risk of secondary infections due to deeper tissue damage 5. L- glutamine is L-alpha-amino acid. It is the most abundant free amino acid in human blood. L- glutamine is needed for several functions in the body including for the synthesis of proteins as well as an energy source. L-glutamine can be synthesized by the body and can also be obtained from the diet if needed.6 L- glutamine is crucial for powering lymphocytes and the gastrointestinal tract, helping to protect against infections and maintaining the mucosal barrier. It's important in cellular metabolism and acts as a nitrogen carrier across various tissues. Although its plasma levels remain stable, glutamine is predominantly stored in muscles and regulated by the liver 7. Several studies indicated that glutamine could decrease both the frequency and intensity of OM 8-13. L-arginine, a conditionally essential amino acid, is primarily metabolized by enzymes such as nitric oxide synthase (NOS), arginine decarboxylase, and arginase (ARG), contributing to the synthesis of proteins and various bioactive molecules like nitric oxide (NO), proline, creatine, and polyamines 14. There is growing interest in enhancing the physiological roles of arginine, particularly in reducing intestinal inflammation and oxidative stress 15. Previous research has shown that L-arginine supplementation in both animals and humans with intestinal disorders can lessen intestinal damage, alleviate oxidative stress and inflammation, and help reestablish mucosal immune balance. Notably, Coburn et al. have documented that L-arginine supplementation reduced intestinal inflammation in mouse models of dextran sulfate sodium (DSS)- induced colitis, an experimental model of IBD.16 L-arginine significantly enhances wound healing through various mechanisms. It is crucial for collagen synthesis, which is fundamental for new tissue development and the formation of strong connective tissue. This amino acid also has anti-inflammatory effects that regulate the body's response to injury, reducing the risk of chronic inflammation that can impede healing. Additionally, l-arginine promotes fibroblast proliferation, which is essential for producing collagen and other extracellular matrix components that aid in wound repair. Indirect benefits of l-arginine include improved circulation and blood flow to the wound area, supplying necessary oxygen and nutrients, and bolstering the immune system to fight infections and support healing processes 17-20. Based on the various physiological properties of L-arginine, its anti-inflammatory effects, and its capacity for wound healing and tissue repair, this study aim to evaluate the effect of L-arginine oral suspension versus glutamine oral suspension on salivary EGF, and on management of radiation-induced oral mucositis (RIOM) and its associated symptoms, as well as assessing their effects on the oral health related quality of life in HNC patients.