From Radiation to Weight Loss: The Self-perpetuating Cycle of Oral Mucositis: Insights from a Pilot Institutional Study

Abstract

Introduction:

Globally, head-and-neck cancers are the sixth most prevalent type of cancer, most frequently found in developing countries. Treatment modalities include surgery, radiotherapy (RT) or chemotherapy, either alone or in combination. Approximately two-thirds of these patients receive radiation therapy as part of their treatment approach. The pathological changes at the tumour site, along with acute toxic reactions to radiation therapy, can result in decreased taste sensitivity and harm to the oral mucosa can lead to conditions such as mucositis, xerostomia, pain and difficulties in swallowing and decreased mouth opening. Our aim is to evaluate the correlation between increasing weight loss and the escalating severity of mucositis, as this vicious cycle significantly affects patient outcomes and quality of life, as discussed in this paper.

Materials and Methods:

We conducted a prospective pilot study from February 2024 to July 2024, during which we observed and gathered data from 50 consecutive patients with oral cancer and its various subsites with proven histopathology of squamous cell carcinoma who underwent adjuvant radiation or chemoradiation therapy (CRT) three to 6 weeks following surgical tumour resection.

Results:

The sample size consisted of patients who received adjuvant CRT and adjuvant RT only. The incidence of weight loss and the severity of mucositis is directly linked with each other.

Discussion:

The inference of this study is that weight management during adjuvant therapy leads to lesser radiation toxicity.

INTRODUCTION

Head-and-neck cancers (HNCs) represent the sixth most common type of malignancy worldwide, with a higher incidence in less developed regions. These cancers encompass tumours of the tongue, oral cavity, pharynx, larynx and thyroid gland. Treatment strategies often include surgery, radiotherapy (RT), chemotherapy or a combination of these modalities. Radiation therapy is utilised in about two-thirds of cases and may be employed either with curative intent or for palliative care, depending on the cancer type and treatment objectives. RT primarily works by damaging DNA, thereby preventing cellular replication and division. While cancer cells are generally less efficient at repairing radiation-induced DNA damage, normal healthy tissues are usually more capable of recovery.

Nevertheless, radiation therapy, along with tumour-related factors, can cause acute side effects that affect the oral cavity, including altered taste and injury to the oral mucosa. This can lead to complications such as mucositis, xerostomia (dry mouth), pain, dysphagia (difficulty swallowing) and trismus (restricted mouth opening). These side effects can significantly impair a patient’s ability to maintain adequate nutrition, often resulting in rapid weight loss and decreased body mass index (BMI).[1] Poor oral intake and compromised nutritional status may hinder the effectiveness of treatment, lower the quality of life and potentially necessitate treatment interruptions. Early identification of patients at risk of malnutrition is thus critical to preserving treatment continuity and patient well-being.

Radiation can also cause chromosomal damage and interfere with the mitotic processes of cells by directly interacting with DNA. Furthermore, it may generate reactive oxygen species (ROS) – such as superoxide, hydrogen peroxide and hydroxyl radicals – through interactions with water or oxygen molecules. These ROS further contribute to cellular injury and DNA damage.[2] The oropharyngeal mucosa comprises non-keratinised squamous epithelial cells, endothelial tissue and connective tissue. Stem cells located in the basal layer of the endothelium continuously regenerate the mucosal lining by differentiating into mature epithelial cells.[3] Oral mucositis occurs due to a combination of factors, including epithelial thinning, damage to stem cells, reduced proliferation of transit cells and impaired regeneration. Patients undergoing cancer therapy may develop painful red or ulcerative lesions in the mouth, which can interfere with eating, reduce quality of life and increase the risk of both local and systemic infections.[4]

In a typical course of treatment, patients with HNC receive 2 Gy of radiation per day, 5 days a week over 5–7 weeks. Most will experience some form of oral mucositis, which tends to worsen as the radiation dose increases. Severe mucosal damage typically manifests at cumulative doses between 50 and 60 Gy. Hyperfractionated regimens – where radiation is administered twice daily – are associated with more intense mucositis.[5] The addition of cytotoxic chemotherapy further compounds mucosal damage by inhibiting the repair of irradiated tissues through suppression of cell division. When radiation therapy is combined with chemotherapy, severe mucositis can develop in 60% to 100% of patients.[5,6]

MATERIALS AND METHODS

Our institute carried out a prospective pilot study after obtaining approval from the institutional ethics committee (MCRI/2025/1/0012, dated January 11, 2025). The study included 50 consecutive patients diagnosed with oral cancer and its subsites, all confirmed as having squamous cell carcinoma histologically and treated between February 2024 and July 2024. These patients received adjuvant radiotherapy or chemoradiation between 3 and 6 weeks following tumour resection.

Oral health and hygiene were evaluated on days 1, 15 and 30 of radiation treatment, as well as 1 month after completing therapy. The study focused on assessing the severity of oral mucositis, weight loss, dietary habits and oral infections linked to inadequate oral hygiene. Patients who developed mucositis were encouraged to increase their food intake to help maintain body weight and BMI. For individuals unable to consume food orally, Ryle’s tube or percutaneous endoscopic gastrostomy (PEG) feeding was recommended. Emphasis was placed on ensuring sufficient caloric intake and hydration throughout the treatment period. Both weight loss and mucositis severity were closely monitored, as these factors are known to significantly affect treatment outcomes and overall quality of life. This research aimed to explore the interplay between mucositis and nutritional status. Mucositis severity was graded using the Radiation Therapy Oncology Group (RTOG) classification scale, which ranges from grade 0–4.

RESULTS

The study analysed data from 50 patients, with carcinoma of the tongue being the most frequently diagnosed condition, representing 34.0% (17 patients). This was followed by carcinoma of the left buccal mucosa in 28.0% (14 patients), and carcinoma of the right buccal mucosa in 20.0% (10 patients). Carcinoma of the alveolus accounted for 10.0% (five patients), whereas carcinoma of the palate was the least common at 6.0% (three patients). Despite the predominance of tongue cancer, the sample was relatively well-balanced across different subsites [Table 1]. Regarding radiation therapy techniques, the most commonly used modality was 30 fractions of image-guided radiation therapy (IGRT) at 60 Gy, administered in 30% of cases (15 patients). This was followed by 30# three-dimensional conformal radiation therapy (3D CRT)-60 Gy in 24% (12 patients) and 30# intensity-modulated radiation therapy (IMRT)-60 Gy in 20% (10 patients). TOMOTHERAPY-60 Gy, utilising helical delivery, was used in 12% (six patients). Less commonly employed were 33# IMRT-66 Gy (8%, four patients), 33# IGRT-66 Gy (4%, two patients), and 33# 3D CRT-66 Gy, used in just 2% (one patient). These figures suggest a preference for advanced radiotherapy methods like IGRT, IMRT and 3D CRT, with most patients receiving a 60 Gy dose [Table 2].

Table 1.

Distribution of patients based on their diagnoses

BM: Buccal mucosa, CA: Carcinoma

Table 2.

Distribution of various radiation types among the patients

IGRT: Image guided radiotherapy, Gy: Gray, 3DCRT: 3-Dimensional conformal radiotherapy, IMRT: Intensity modulated radiotherapy

Among the 21 patients who received concurrent chemotherapy, the most frequent regimen was five cycles of cisplatin (5# CISPLATIN), used in 42.9% (nine patients), followed by six cycles (6# CISPLATIN) in 38.1% (eight patients). Less common regimens included three cycles of cisplatin (3# CISPLATIN) and four cycles of docetaxel (4# DOCETAXEL), each given to 4.8% (one patient). Overall, cisplatin was the primary chemotherapeutic agent used, administered in varying dosages [Table 3]. Radiation therapy resulted in a significant reduction in patient weight. The average pre-treatment weight was 68.48 kg (standard deviation [SD] =11.77), whereas the post-treatment average dropped to 60.65 kg (SD = 11.78). The standard error of the mean was 1.68 before and 1.70 after treatment. The mean weight loss of 7.96 kg was statistically significant (t = 9.403, P < 0.001), indicating that RT had a considerable impact on body weight [Table 4]. The severity of radiation-induced mucositis varied amongst patients. Grade 2 mucositis was the most frequently observed, affecting 32% (16 patients). Grades 1 and 3 each affected 24% of patients (12 cases each), whereas Grade 4 occurred in 8% (4 cases). Notably, 12% (6 patients) did not develop mucositis [Table 5].

Table 3.

Distribution of concurrent chemotherapy with radiation therapy among the patients

Table 4.

Comparison of weight before and after radiation therapy

RT: Radiotherapy

Table 5.

Distribution of radiation-induced mucositis in the patient population

Statistical analysis revealed a strong association between mucositis severity and weight loss, with an F-statistic of 137.463 and a P < 0.001. The mean weight loss increased consistently with mucositis grade: Patients with no mucositis lost just 0.50 kg; Grade one patients lost an average of 3.33 kg; Grade 2, 7.38 kg; Grade 3, 12.42 kg; and Grade 4, a substantial 22.00 kg. The variability in weight loss was also greater with more severe mucositis, particularly in Grade 4 (SD = 4.32), underlining the clinical burden of severe mucositis on nutritional status [Table 6]. Further analysis of the relationship between mucositis grade and percentage weight loss showed that six patients with no or mild mucositis lost <5% of their body weight. In the Grade 1 group, five patients lost under 5%, while seven experienced 5%–10% weight loss. Among those with Grade 2 mucositis, five lost 5%–10%, nine lost 10%–15%, and two lost 15%–20%. For Grade 3, four patients lost 10%–15%, five lost 15%–20% and three lost more than 20%. In the Grade 4 group, two patients experienced 15%–20% weight loss, and two lost over 20%. This clearly shows an upwards trend in weight loss severity as mucositis progresses [Table 7].

Table 6.

Mean weight loss according to the severity of mucositis

Table 7.

Relationship between weight loss percentage and mucositis

For the 16 patients experiencing severe mucositis, Ryle’s tube or PEG feeding was recommended. Eight of them opted for tube-based nutritional support. During follow-up, the patients who received nutritional interventions via Ryle’s tube or PEG, along with a carefully managed diet, showed a reduction in both mucositis severity and weight loss 1 month after completing therapy.

DISCUSSION

All patients in this study underwent various advanced radiation therapy techniques, each selected based on specific mechanisms aimed at optimising treatment effectiveness. IGRT uses real-time imaging to precisely deliver 60 Gy across 30 sessions, targeting tumours accurately while minimising damage to surrounding healthy tissues. IMRT allows modulation of radiation intensity, improving focus on the tumour and sparing adjacent organs. 3D-CRT shapes radiation beams to conform to the tumour’s geometry, reducing harm to normal tissues. Tomotherapy, which combines helical computed tomography imaging and radiation, offers precise targeting and delivery, enhancing treatment accuracy and safety. These state-of-the-art radiation methods contribute to improved efficacy and patient outcomes.

To evaluate mucositis severity, the RTOG classification was applied, a standardised grading system based on clinical signs and mucosal injury:

• Grade 0: No visible mucosal changes

• Grade 1: Mild pain not requiring analgesics

• Grade 2: Patchy mucositis with possible blood-tinged discharge, <1.5 cm in size, and non-contiguous; may require mild pain relief

• Grade 3: Large (>1.5 cm), continuous mucositis with intense pain needing narcotics

• Grade 4: Presence of necrosis or deep ulcers, with or without bleeding.

Nutritional status plays a crucial role in the prognosis of HNC patients. Tumour site, disease stage, and treatment modalities such as radiation or chemoradiation can significantly impact outcomes. Post-treatment weight loss and appetite loss (anorexia) are common and serve as poor prognostic indicators. Radiotherapy and chemotherapy lead to the destruction of epithelial, endothelial, and fibroblast cells, which activate genes involved in cellular stress responses, particularly nuclear factor-kappa B and nuclear factor erythroid 2 pathways.[7,8] Activated immune cells, especially macrophages, secrete pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-1β, interferon gamma and tumour necrosis factor alpha (TNF-α), which are linked to anorexia and contribute to weight loss.[9] The destruction of basal epithelial cells by radiation/chemotherapy generates free radicals and inflammatory mediators, worsening mucosal damage. These changes, along with shifts in oral microbiota, promote ulcers and infections that further increase cytokine levels.[10]

Radiation also lowers salivary pH and glycoprotein content, impairing the protective functions of saliva, including its antimicrobial properties.[11] This reduction in salivary flow and composition compromises oral defence mechanisms, aggravating mucositis and reducing appetite, leading to poor calorie intake and further weight loss.[12] Damaged mucosal tissues, due to weakened local immunity, become more vulnerable to fungal (e.g., Candida albicans), bacterial and viral infections, which can escalate into systemic infections, especially in immunocompromised individuals.[13,14]

Symptoms such as anorexia, xerostomia, dysphagia, taste alterations, surgical changes, chemotherapy toxicity, cancer cachexia and mucositis contribute to post-radiotherapy nutritional deficiencies. Mucositis-related oral pain and taste changes hinder chewing and swallowing, reducing oral intake. The consequent decline in calorie and protein consumption impairs tissue regeneration, further intensifying mucositis.[15] According to our findings, unmanaged early mucositis can lead to nutrient depletion, initiating a vicious cycle of inflammation, appetite suppression, weight loss and worsening mucositis [Figure 1].

Figure 1.

The vicious cycle of radiation-induced mucositis leading to weight loss

Patients with oral mucositis benefit from soft or liquid diets, and those with severe symptoms may require gastrostomy tube feeding. Given the role of Gram-negative bacteria in mucositis, selective decontamination has been explored using agents such as polymyxin E, tobramycin and amphotericin B lozenges. Antibiotics such as ciprofloxacin or ampicillin, in combination with clotrimazole and sucralfate, have shown mucositis-reducing potential.[16] Maintaining good oral hygiene is essential. Studies confirm that regular care – including flossing, soft-bristle brushing, and using non-medicated rinses (e.g., saline or sodium bicarbonate) – significantly lowers mucositis incidence. Education for both patients and caregivers is strongly advised.[17]

Sucralfate, a cytoprotective agent for gastrointestinal ulcers, forms a protective barrier over ulcerated mucosa. Kaolin, pectin and diphenhydramine (a local anaesthetic and antihistamine) help manage discomfort.[18] Growth factors such as palifermin (a keratinocyte growth factor) and velafermin (fibroblast growth factor-20) are being studied for their ability to enhance epithelial healing and reduce severe mucositis in oncology patients.[19,20] Topical agents like benzydamine hydrochloride help reduce inflammation and pain by inhibiting cytokines like TNF-α. The International Society of Oral Oncology (ISOO) recommends benzydamine mouthwash for patients undergoing moderate-dose radiation. Saforis, a glutamine-rich oral suspension, supports epithelial cell health and protects against mucositis by reducing cytokine activity and cell death.[20,21]

Beta carotene (a Vitamin A derivative) may reduce mucositis when supplemented.[22] Low-dose intramuscular immunoglobulins have been shown to lessen both the severity and duration of radiation-induced mucositis. Regular infection monitoring and timely use of antifungals (e.g., clotrimazole and fluconazole) are crucial, especially since fluconazole may outperform nystatin but often requires longer or higher dosing in resistant cases.[23] Low-level laser therapy has demonstrated effectiveness in reducing inflammation and ROS, easing mucositis symptoms.[24]

Ghrelin, a 28-amino acid peptide primarily produced in the stomach, plays a key role in appetite regulation, energy balance, and anti-inflammatory responses. It also inhibits pro-inflammatory cytokines like IL-1α, IL-1β and TNF-α, potentially alleviating mucositis-related symptoms, weight loss and anorexia.[25,26] Methylene blue, known for its analgesic, antioxidant and anti-inflammatory effects, can be used as a mouth rinse to treat mucositis. It works by desensitising nociceptors, blocking N-methyl-D-aspartate receptors and inhibiting nitric oxide pathways, thereby reducing pain and inflammation.[27] Hyperbaric oxygen therapy (HBOT) – involving 100% oxygen at 1.5 ATA – enhances oxygen delivery to hypoxic tissues, promoting wound healing, reducing inflammation and restoring damaged tissues. HBOT also has bactericidal effects and is effective in mitigating symptoms such as oral pain, dry mouth, chewing difficulty and mucositis.[28]

CONCLUSION

Patients with HNC who undergo radiotherapy (RT) frequently experience oral mucositis. It is essential for clinicians to have a thorough understanding of the underlying mechanisms of RT-induced mucositis. Findings from this study highlight that timely and appropriate interventions can help delay the onset of mucositis, minimise weight loss and prevent interruptions in treatment. Current guidelines emphasise the importance of meticulous treatment planning, comprehensive supportive care, consistent oral hygiene, appropriate pain management, early consideration of feeding tube placement and therapeutic exercises to lessen both the severity and duration of mucositis. In summary, effectively managing oral mucositis – particularly through proactive weight management – is crucial for enhancing treatment outcomes and maintaining continuity of care in HNC patients receiving radiotherapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.