Radiotherapy and Its Consequences in Relation to Oral Squamous Cell Carcinoma—A Narrative Review

Simple Summary

Oral squamous cell carcinoma (SCC) mostly affects middle-aged or older adults, is more common in men, and can occur at any site in the mouth. It often has a poor prognosis. Radiotherapy is commonly used in the treatment of oral SCC, but it inevitably causes side effects that vary depending on the patient, the tumour, and the treatment approach. Common complications include oral mucositis, facial skin irritation, dry mouth, difficulty opening the mouth (trismus), and bone damage (osteoradionecrosis).

Abstract

Oral squamous cell carcinoma (SCC) is typically found in middle-aged or elderly individuals, is more common in men than women, can occur at any mucosal site, and is associated with a poor prognosis. The primary risk factors for oral SCC include the use of tobacco, betel nut, or areca nut, and excessive alcohol consumption. A comprehensive management plan for oral SCC typically involves a multidisciplinary team approach with surgery being the primary treatment approach, with or without radiotherapy. Radiotherapy is an essential component in the management of oral SCC, with its application guided by both tumour- and patient-related factors. It may be employed as a definitive, adjuvant, or palliative modality, depending on tumour stage, resectability, surgical margins, histopathological characteristics, as well as the patient’s overall health, financial considerations, and personal preferences. Effective radiotherapy for oral SCC inevitably leads to various tissue toxicities, which can vary among patients. These variations are primarily influenced by patient-specific characteristics, tumour-specific factors, and aspects related to the radiotherapy itself. Some of the complications resulting from ionizing radiation (IR) include oral mucositis, facial dermatitis, salivary gland dysfunction, trismus, and osteoradionecrosis, along with their management strategies.

1. Introduction

Oral squamous cell carcinoma (SCC) accounts for over 90% of all oral cancers and may affect all mucosal surfaces of the oral cavity, but most commonly the anterior ventral and lateral tongue, followed by the floor of the mouth, gingiva, and alveolar mucosa. Less frequently, it affects the buccal mucosa, labial mucosa, hard palate, and retromolar trigone [1,2,3,4]. The clinical course and biological behaviour of oral SCC vary by mucosal subsite, with tongue and floor-of-mouth cancers generally carrying a poorer prognosis than those at other locations. Oral SCC predominantly occurs in older males with histories of heavy tobacco and alcohol use [1,2,3,4], but other significant risk factors include betel nut chewing and lower socioeconomic and educational status [4,5,6]. In South Africa, a preference for traditional healers over conventional healthcare also contributes to delayed diagnosis and treatment [4].

Geographic and ethnic differences influence the prevalence of oral SCC, both in the general population and at specific oral sites, but it is evident that it arises through exposure to carcinogens, random genetic mutations, and impaired DNA repair mechanisms that affect proto-oncogenes and tumour suppressor genes [7,8]. Chronic inflammation, mechanical stress, and disruptions in the extracellular matrix (ECM) further contribute to carcinogenesis [9].

While high-risk HPV is causally associated with oropharyngeal SCC, there is insufficient evidence to establish its causative role in oral SCC [10,11]. HPV-positive oral SCC typically shows low DNA copy numbers and lacks oncogenic mRNA expression [7,12]. The role of electronic cigarettes in oral SCC pathogenesis remains unclear [13].

Oral SCC may present clinically as leukoplakia, erythroplakia, ulcerative lesions, or exophytic masses. Lesions often bleed easily when traumatized and may interfere with speech, chewing, and swallowing. Homogenous leukoplakia appears as flat, white plaques, while non-homogenous forms show nodular, verrucous, or mixed red and white features [5,7,14].

The five-year survival rate is around 50%, with poorer outcomes in black patients due to delayed diagnosis and healthcare access disparities [6]. Pain is common and worsens with disease progression, often resulting from nerve invasion, inflammation, and secondary infections [3]. Adverse events such as mucositis and xerostomia exacerbate pain and distress [15,16].

Treatment options for oral SCC include surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, or a combination of these approaches. Surgery is the preferred option when feasible; however, advanced-stage disease often necessitates a multimodal treatment strategy [6,17,18]. Treatment decisions are influenced by factors such as the tumour-node-metastasis (TNM) staging system, histopathological characteristics, and patient-related factors, including age, overall health, financial situation, lifestyle, and expected functional and cosmetic outcomes [5,6,11,19].

Radiotherapy and chemoradiotherapy are commonly recommended for patients with unresectable oral SCC, those who are either unwilling or unable to undergo surgery, or as adjuvant treatment for advanced-stage disease. These modalities are also used when histopathological features suggest a high risk of local or regional recurrence, as salvage treatment for persistent disease, or as a palliative option [2,11,19,20,21]. The treatment approach is developed through a shared decision-making process between the oncologist, surgeon, and the patient [8].

Postoperative radiotherapy (PORT), with or without chemotherapy (PORCT), is indicated when there is an increased risk of locoregional recurrence or metastasis [21]. High-risk clinical factors for PORT include advanced T3-T4 disease, positive (<1 mm) or close (1 to ≤5 mm) surgical margins at the primary site; and pathological risk factors include microscopic disease at the margins of the resection, extracapsular extension of nodal disease in the neck, tumour size pT3 and pT4 (UICC/AJCC TNM 8th ed), depth of invasion above 4 mm, perineural invasion, and lymphovascular invasion [11,22].

Oral SCC subsites may be classified as “lateralized” or “non-lateralized,” as these differ in their risk of contralateral neck recurrence. Lateralized subsites comprise the buccal mucosa, upper and lower alveolar mucosa, retromolar trigone, lateral tongue border, and lateral floor of the mouth. In carcinomas of these subsites—provided there is at least a 10 mm clearance from the oral cavity midline and no involvement of the anterior third/tip of the tongue or the anterior floor of the mouth—the risk of contralateral neck recurrence is low. Consequently, elective treatment of a clinically N0 contralateral neck is generally unjustified. By contrast, non-lateralized subsites—comprising the lower and upper alveolar mucosa, floor of the mouth, hard palate, and tongue within one centimeter of the midline—are associated with a relatively high risk of contralateral neck recurrence, justifying elective management of a clinically N0 contralateral neck [11].

The total treatment package time (TPT) for oral SCC is defined as the interval from initial surgery to the completion of all adjuvant therapy. For optimal loco-regional control and survival outcomes, PORT should commence within five weeks—and no later than seven weeks—after surgery [11,21,22], unless delayed by postoperative complications. Evidence suggests that adherence to TPT guidelines exerts a greater positive impact on loco-regional recurrence and overall survival than radiation dose alone [11].

The objective of this narrative review is to provide a balanced overview of radiotherapy and its biological consequences in the context of oral SCC. The information for this article was gathered through a literature search of the PubMed and Medline databases, along with an analysis of references from relevant articles considered pertinent. The key search terms included oral SCC, PORT, POCRT, irradiation dose, treatment package time (TPT), IR-induced complications, IR-induced oral mucositis, IR-induced dermatitis, IR-induced salivary gland dysfunction, IR-induced trismus, and osteoradionecrosis. Only articles published in English were included. No other strict inclusion or exclusion criteria were applied.

The primary limitation of this article lies in the fact that it is neither a meta-analysis nor a systematic review and, therefore, does not employ rigorous data collection or transparent analytical methods. As a result, the work may be subject to potential biases, including selection and confirmation bias, which could limit the ability to draw definitive conclusions with strong clinical impact. Nevertheless, this narrative review offers a broad, integrative perspective on radiotherapy in the context of oral squamous cell carcinoma and IR-induced oral complications and may serve as a valuable resource for clinicians and researchers with an interest in this field.

2. General Aspects of Oral SCC-Related Radiotherapy

Radiotherapy for oral SCC uses high-energy ionizing radiation (IR) to induce cancer cell death either through direct DNA damage or immunogenic cell death via cytotoxic T cells [23]. IR dose, fractionation, and sequencing determine the radiotherapy protocol, which may be definitive, adjuvant, neoadjuvant, or palliative. Radiotherapy alone is insufficient for curing advanced SCC. Combination with immune checkpoint inhibitors may enhance outcomes [24,25,26].

The irradiation field typically includes surrounding tissue to account for subclinical disease and technical inaccuracies, increasing the risk of tissue toxicity [18], and consequently out-of-field bystander effects, mediated by signals from irradiated cells, can damage nearby non-irradiated tissues [27,28]. These effects, along with IR-induced release of cytokines, growth factors, and reactive oxygen species, contribute to facial tissue fibrosis and functional impairments [29,30], mucositis, xerostomia, dysphagia, and dysgeusia or ageusia [31,32].

Radiotherapy outcomes and toxicity vary due to patient-specific factors (age, health, genetic polymorphisms), tumour-specific factors (site, TNM stage, bone invasion), and radiation parameters (dose, volume, concurrent therapies). Poor oral hygiene, active infections, tobacco and alcohol use, and inadequate dental plaque control increase toxicity risk [32,33,34,35].

Patients with advanced oral SCC often experience psychological, social, and physical challenges, necessitating multidisciplinary support [32]. Radiotherapy side effects are classified as early (e.g., mucositis, dermatitis, dysphagia) or late (e.g., fibrosis, xerostomia, osteoradionecrosis) [36,37,38,39]. Older patients are generally at increased risk of IR-related physical and emotional adverse reactions due to age-related physiological changes, comorbidities, and polypharmacy [40].

The National Comprehensive Cancer Network (NCCN)’s Clinical Practice Guidelines (Version 4, 2025) recommend definitive radiotherapy doses of 66–70 Gy for high-risk areas, and 45–63 Gy for intermediate-to-low-risk areas, depending on the fractionation strategy. Hyperfractionated and concomitant boost regimens are also used. Postoperative radiotherapy (PORT) is advised for patients with high-risk histological features, with doses of 60–66 Gy for high-risk and 45–63 Gy for lower-risk sites, ideally starting within six weeks post-surgery [41].

For advanced disease where curative treatment is not feasible due to poor performance status or extensive metastatic spread, palliative radiotherapy should be considered, primarily to alleviate pain and to reduce locoregional symptoms while minimizing toxicity. As there are no standardized palliative radiotherapy regimens, treatments should be individualized. Suggested regimens include 50 Gy/20 fractions, 37.5 Gy/15 fractions, or 30 Gy/5–10 fractions with adjusted schedules [41].

The balance between tumour control and tolerable toxicity is critical. Individualized approaches, based on comprehensive evaluation of personal risk factors and clinical features, may allow for more aggressive yet effective treatment strategies [29,42,43].

3. Some General Guidelines Minimising IR-Induced Oral Toxicities

Before commencement of radiotherapy, patients should undergo a comprehensive oral health examination and assessment. A proactive oral healthcare program should be put in place, which includes the extraction of unrestorable teeth, treatment of dental caries, tooth-related inflammatory lesions, periodontal disease, oral mucosal inflammatory conditions, and salivary gland dysfunctions [34]. Additionally, patient education plays a crucial role. Patients must be educated on maintaining excellent oral hygiene, adopting healthy lifestyle behaviors, and following a suitable nutritional diet. They should also be informed about the early signs and symptoms of oral mucositis and taught how to monitor their oral mucosal color, dryness, and surface integrity [35,38,44]. Implementing these measures is essential for controlling some of the IR-induced biological and clinical side effects that may affect the mouth.

Unless urgent, routine oral health procedures should be completed 2–4 weeks before the initiation of radiotherapy to allow sufficient time for tissue healing [45]. Alternatively, such procedures can be carried out three months after treatment. Invasive surgical procedures should ideally be conducted 30 days before radiotherapy or at least 6 months after completion of treatment. Furthermore, the surgical placement of osseointegrated implants for dental rehabilitation should be postponed for at least 12 months following radiotherapy. All invasive procedures must be performed under prophylactic antibiotic coverage to reduce the risk of infection [34].

It has been reported that up to 60% of patients receiving radiotherapy for head and neck cancer may experience dysphagia, and up to 75% may experience taste alterations [46]. Both taste alteration and dysphagia are driven by direct IR-induced harmful biological effects on the taste buds and oral and oropharyngeal soft tissues, respectively. Indirectly, they are also caused by IR-induced salivary gland damage, leading to adverse quantitative and qualitative changes in salivary flow and oral microbial flora. This can promote subclinical and clinical soft tissue infections and inflammatory reactions, further negatively impacting taste sensation and swallowing [33]. Additionally, fatigue manifested as physical tiredness, emotional exhaustion, mental weariness and/or lack of mental energy, and nausea/vomiting are common IR-induced toxicities to the head and neck region [47].

4. IR-Induced Oral Mucositis

Oral mucositis is an IR-induced complex and debilitating condition characterized by erythematous, atrophic, erosive, or ulcerative painful lesions that often become secondarily infected. The pain associated with mucositis impairs physiological functions, including sleep, speech, eating, and swallowing, leading to inadequate nutritional intake and weight loss. This also results in psychosocial dysfunction and a reduced quality of life [48]. Patients with severe oral mucositis are at risk of septicemia and may require hospitalization to manage life-threatening infections, dehydration, nutritional deficiencies, and pain. In some cases, severe oral mucositis may require the de-escalation or interruption of the radiotherapy program, which can negatively impact the anti-cancer treatment outcome [38,44].

Several systems have been used to grade the severity of oral mucositis, including the Radiation Therapy Oncology Group (RTOG) system, the World Health Organization (WHO) system, the National Cancer Institute Common Toxicity Criteria (NCI-CTC), and the Western Consortium for Cancer Nursing Research (WCCNR) system [38,44,49].

Table 1. Grading scale for oral mucositis.

Grade	I	II	III	IV
Radiation therapy oncology group (RTOG)	Erythema	Patchy reactions (<1.5 cm, non-contagious)	Confluent mucositis (>1.5 cm, confluent)	Ulceration, necrosis, bleeding

Source: Adapted from Niscola et al., 2007 [50].

describes the RTOG scale [50].

Oral mucositis occurs in up to 90% of patients who receive radiotherapy (with concurrent cancer chemotherapy) for oral SCC [38,44,49], and it affects the non-keratinized mucosa more frequently than the keratinized oral mucosa [48]. The incidence and severity of IR-induced mucositis are directly related to the characteristics of the IR employed, such as the cumulative dose, fractionation, and duration, as well as to the adjunct anti-cancer chemotherapeutic agents used. Patient-related risk factors include older age, female gender, genetic predisposition, xerostomia, tobacco smoking, alcohol consumption, poor oral hygiene, increased dento–gingival bacterial load, and low neutrophil counts [38,44,49,51].

IR-induced oral mucositis typically begins 2 to 5 days after the initiation of the radiotherapy program, with the lesions peaking 7 to 14 days later [48,52]. Initially, the lesions appear erythematous, progressing to painful erosions and ulcers as the condition worsens [44]. Oral mucositis is generally self-limited, persisting throughout the duration of the treatment, and usually resolves within 4 to 6 weeks following the completion of radiotherapy [51,52,53].

The evolution of IR-induced oral mucositis is driven by the release of inflammatory cytokines, chemokines, growth factors, reactive oxygen species, and other inflammatory mediators into the local microenvironment. These mediators are released by injured endothelial, connective tissue, and epithelial cells, as well as by locally recruited immunoinflammatory cells [44,49,53]. This complex interaction between direct cellular damage and the inflammatory response contributes to the progression and severity of oral mucositis during radiotherapy.

Since there are no evidence-based standard treatment guidelines for oral mucositis, the management is primarily symptomatic and palliative. Common treatments include cryotherapy, low-energy laser therapy, and the use of mouthwashes such as anti-inflammatory, antibacterial, saline, or sodium bicarbonate solutions. Other options include topical analgesic agents, adhesive protective agents, topical or systemic antibiotics, and systemic analgesics [38,44,51]. While these treatments can sometimes provide relief, their effectiveness is often unpredictable [48,53].

Maintaining good oral hygiene is critical in managing oral mucositis and minimizing dentogingival plaque accumulation. This can be achieved through periodic professional scaling and polishing, as well as personal oral care practices such as gentle tooth brushing with an ultra-soft toothbrush and fluoride toothpaste. Additionally, frequent mouth rinsing with saline or sodium bicarbonate solution can help. When oral mucositis progresses to high-grade severity, causing intense pain and interfering with sleep and daily oral functions, systemic pain control, nutritional support, and treatment to prevent or manage secondary infections are necessary [38,44,49,51].

IR-induced injury to the oral mucosal membrane barrier, changes in salivary composition and flow, and the dysregulation of local immune-inflammatory responses create an environment that promotes microbial growth, particularly by gram-negative bacteria and Candida albicans. These secondary infections can exacerbate local inflammation and worsen the symptoms of established mucositis, making the condition more difficult to manage [44].

Severe oral mucositis can be treated with a combination of local and systemic interventions. For pain relief, swish-and-spit solutions such as 2% viscous lidocaine or opioid-based mouthwashes (e.g., 2% morphine) can be used. Anti-inflammatory agents such as corticosteroids and benzydamine hydrochloride, as well as antimicrobial treatments such as chlorhexidine gluconate, can help manage inflammation and prevent secondary infections. If Candida albicans is present, antifungal agents such as daktarin gel, amphotericin B, or nystatin are necessary [38,44,49,51].

Systemic analgesics such as morphine derivatives to manage severe pain and systemic corticosteroids to reduce harmful immuno-inflammatory responses may be indicated. Salicylic acid derivatives should be avoided due to the increased risk of bleeding. In addition to pharmacological treatment, maintaining a well-balanced nutritional diet and avoiding rough, spicy foods, alcohol, and tobacco use are essential for managing IR-induced oral mucositis effectively [38,44,49].

The pathogenesis of IR-induced oral mucositis is multifactorial and complex. Ionizing radiation primarily targets the rapidly proliferating transient-amplifying epithelial cells as well as non-dividing mature epithelial cells, leading to epithelial atrophy and erosion. Additionally, radiation damages the subepithelial connective tissue, disrupting the endothelial vasculature and interfering with cell–cell and cell–extracellular matrix (ECM) interactions. These processes, combined with the IR-induced local immuno-inflammatory reaction, result in ulceration, pain, and dysphagia, which are characteristic symptoms of oral mucositis. Moreover, the use of anti-cancer chemotherapeutic agents may create a neutropenic environment, which can facilitate the development of neutropenic ulcers and increase the risk of super-infections. These infections exacerbate the tissue damage, dysfunction, and pain, further complicating the condition [54,55]. The non-keratinized epithelium of areas of the soft palate, buccal mucosa, and tongue, which have a high rate of cellular proliferation (high turnover rate), is more susceptible to the harmful effects of IR compared to the keratinized epithelium of the hard palate and gingiva. The latter tissues have a lower rate of cellular proliferation, making them less prone to damage by IR [56,57].

After the completion of radiotherapy, the undifferentiated, slow-cycling, self-renewing epithelial stem cells in the basal cell layer that survived the radiation-induced damage will play a key role in restoring the integrity of the injured epithelium. At the margins of the mucositis, these epithelial stem cells divide and give rise to transient-amplifying daughter cells, which then undergo maturation, driving the healing process. This epithelial healing occurs alongside the repair of the underlying connective tissue, ultimately leading to the complete regeneration of the affected area [48].

5. Salivary Gland Dysfunction

IR-induced damage to the major salivary glands (parotid, submandibular, sublingual) leads to significant alterations in the volume, composition, consistency, and pH of the saliva. The saliva becomes more viscous and acidic, and the flow of saliva is reduced, compromising its lubricating and antimicrobial properties. These changes may result in several complications, including dry mouth (xerostomia), a burning sensation in the mouth, an increased susceptibility to oral candidiasis and dental caries, as well as difficulty and discomfort while eating and speaking. Additionally, taste impairment is commonly experienced [33,34,46,58].

Salivary gland dysfunction, including xerostomia, is a common side effect of radiotherapy for head and neck cancer, affecting up to 80% of patients [33,59]. The reduction in salivary flow typically begins within the first week of radiotherapy and can persist for months. Some recovery of salivary gland function may occur, but it may take 12 to 18 months post-radiotherapy. Unfortunately, xerostomia often becomes a persistent and irreversible complication of radiotherapy to the head and neck [33,46].

Treatment options for xerostomia are primarily symptomatic, and include saliva substitutes that replicate natural saliva, and are available in various forms such as solutions, sprays, gels, and lozenges, and homeopathic remedies such as olive oil and aloe vera gel. Alongside the use of these agents, maintaining a rigorous oral hygiene routine is crucial to minimizing the damaging impact of xerostomia on oral tissues. This involves both professional measures, such as scaling and polishing, and personal care practices, including tooth and interdental brushing. Additionally, regular fluoride applications and mouth rinsing with chlorhexidine mouthwash help prevent dental caries, gingivitis, and periodontitis, which are common complications in patients with reduced saliva flow [33,46,58].

In cases where IR-induced salivary gland damage is not complete and some functional activity remains, stimulating salivary production from the residual active glandular tissue may still be possible. This can be achieved by mechanical manipulation of the major salivary glands and by sucking on acidic sugarless candies or chewing gum containing xylitol, which can promote saliva flow. Systemic administration of sialagogic agents, such as pilocarpine or cevimeline, which are muscarinic-cholinergic agents, may also stimulate salivary secretion. However, these systemic medications may come with significant side effects, so they should be used cautiously [33,34,46,58].

6. IR-Induced Dermatitis

IR-induced facial dermatitis, like other radiation-related skin reactions, is typically classified into early (acute) and late (chronic) stages. The severity of these reactions is often greater in areas of the skin that are more exposed to sunlight, likely because the combination of ultraviolet radiation (UVR) from the sun and radiotherapy-related IR can amplify the skin damage. While melanin in the skin helps absorb UVR and provides some degree of protection against sunlight-induced damage, it does not seem to offer the same level of protection against IR-induced dermatitis. Even individuals with darker skin, who have higher melanin content, do not appear to be protected from these radiation-induced skin reactions [47].

Early radiotherapy dermatitis is primarily caused by IR-induced oxidative stress and the acute inflammatory response that follows. Clinically, this condition is characterized by symptoms such as pain, erythema, edema, localized heat, melanin hyperpigmentation, and ulcerations [39,47,60,61]. The severity of dermatitis can range from mild erythema to necrosis. It usually begins with faint erythema and dry desquamation (peeling of the skin), followed by more noticeable erythema and patchy moist desquamation. In severe cases, it can progress to blister formation, tissue necrosis, and ulcerations [62]

Table 2. Classification of acute radiation dermatitis (according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 3) [62].

Grade	1	2	3	4
Common terminology criteria for adverse events (CTCAE)	Faint erythema or dry desquamation	Moderate to brisk erythema or patchy dry desquamation, mostly confined to skin folds and creases; moderate erythema	Moist desquamation other than skin folds; pitting oedema, bleeding from minor trauma or abrasion	Skin necrosis or ulceration of full-thickness dermis; may have spontaneous bleeding from the affected area

.

Early radiation dermatitis typically develops within days or a few weeks after the initiation of the radiotherapy program. It is often painful and, in general, resolves gradually over 2–3 weeks post-treatment [39]. This condition affects up to 90% of patients undergoing radiotherapy, and high-grade reactions may require interruption of the radiotherapy regimen, which could negatively impact cancer treatment outcomes [47].

Late (chronic) radiation dermatitis manifests three or more months post-radiotherapy and is characterized by clinical features such as xerosis, hyperkeratosis, telangiectasia, fibrosis, dyspigmentation, and itchiness. Some of these features may be irreversible [39]. The affected skin becomes more prone to secondary immunoinflammatory conditions such as eczema, contact dermatitis, and other allergic skin reactions. Additionally, the skin may become more sensitive to direct sunlight exposure [39].

A rare but serious late complication of IR is the development of non-melanoma skin cancers (NMSC), such as basal cell carcinoma (BCC) and cutaneous SCC, often in areas previously irradiated and affected by chronic dermatitis [45]. These secondary skin cancers can exhibit aggressive biological behavior with poor prognosis. Consequently, persistent non-healing ulcers in irradiated areas should be biopsied to rule out malignancy [62].

Maintaining proper skin hygiene is crucial to minimizing the development of early acute IR-induced skin reactions and moderating the adverse effects of chronic radiation dermatitis. This approach can also facilitate healing. The skin in the irradiation field should be washed with lukewarm water and mild soaps containing gentle, calming ingredients that help keep the affected skin hydrated. Additionally, applying lipid-free hydrophilic moisturizers and low-potency corticosteroids has been shown to help minimise some of the post-radiotherapy skin reactions [61,62].

For skin affected by IR-induced dry desquamation, treatment with hydrophilic moisturizers is recommended. To address pruritus, irritation, and itchiness, low-to-mild potency topical corticosteroids ought to be considered. In cases of moist desquamation, either hydrogel or hydrocolloid dressings should be applied. These dressings maintain a wet environment over the damaged, de-epithelialized skin, which helps improve patient comfort, reduce the risk of secondary infection, and promote healing [61,62,63]. If non-healing ulcers or full-thickness skin necrosis develop, the radiotherapy program should be interrupted, and the patient should be referred to a multidisciplinary medical team of radiation oncologists, dermatologists, wound specialists, and dedicated nurses. Radiotherapy can only be resumed once healing has been achieved [62,63].

7. Trismus

Trismus refers to restricted mouth opening of ≤35 mm, and in the context of oral SCC, may be brought about by multiple factors. These include direct tumour invasion into the masticatory muscles, tumour-related inflammation, radiation-induced fibrosis affecting the temporo–mandibular joint (TMJ) and/or masticatory muscles, as well as post-surgical scarring. Trismus can significantly impair daily functions such as eating, speaking, kissing, and maintaining good oral hygiene, and it can have a profound negative impact on mental well-being and quality of life [16,32,36,60].

Trismus is a late complication of radiotherapy, often reaching its peak between 12 to 18 months after treatment [60]. Its reported incidence ranges from 25% to 42% [32]. Several factors influence the occurrence of IR-induced trismus, including the type of pre-radiotherapy surgery performed, whether there was any pre-existing hypomobility, the size of the irradiated field, the specific oral subsite irradiated, and the type of chemotherapy used. These variables can contribute to the wide range of incidence and prevalence rates reported in the literature [34,45].

The management of post-radiotherapy trismus lacks standardized treatment guidelines, leading to an empirical approach. Common strategies include mechanical therapies such as exercises to improve jaw mobility, guided manipulation of mandibular movements, and massages of the temporo–mandibular joint (TMJ) and masticatory muscles to reduce stiffness. Pharmacotherapy, including muscle relaxants, analgesics, and anti-inflammatory agents, is often used to alleviate pain and inflammation. Acupuncture is also utilized for pain management and muscle relaxation. In more severe or refractory cases, surgery may be considered to release fibrosis and restore jaw function [34]. The treatment approach is tailored to the severity of trismus and the specific needs of the patient.

The prevalence of pre-radiotherapy trismus in patients with oral SCC ranges between 35% [32] and 55% [36], which may impact the accuracy of the reported incidence and prevalence of post-radiotherapy trismus. This is because it is not always possible to distinguish between pre- and post-radiotherapy trismus.

8. Osteoradionecrosis of the Jaw

Osteoradionecrosis of the jaw is an uncommon late complication of oral SCC-related radiotherapy, typically occurring 1–3 years post-treatment. The mandible is more commonly affected than the maxilla due to its more limited blood supply, whereas the maxilla is richly vascularized [45,60,64,65,66]. Clinical manifestations of osteoradionecrosis include pain, swelling, ulceration, and necrosis of the local oral mucosa, along with suppuration, orofacial fistula, exposed necrotic bone, trismus, dysgusia, dysphagia, and difficulties with chewing and speech [34,45].

The reported incidence of osteoradionecrosis with the use of two-dimensional conformal radiotherapy (2D-CRT) and three-dimensional conformal radiotherapy (3D-CRT) ranges from 13% to over 20%. However, with the advancement of modern intensity-modulated radiotherapy (IMRT), the incidence has significantly dropped to between 0% and 8% [64,67,68]. IR-induced damage to the bone vasculature and cellular network leads to hypovascularity, hypocellularity, and a hypoxic microenvironment, which in turn impairs bone turnover, functionality, and healing. This can ultimately cause necrosis and predispose the area to secondary infection [34,64,69]. Mild osteoradionecrosis is typically treated with frequent oral rinsing using saline and antimicrobial solutions, systemic antibiotics, local debridement, and removal of superficial necrotic bone. In more severe cases, radical resection with microvascular reconstruction and soft tissue grafts may be required, along with the use of hyperbaric oxygen [45,65,69].

There is a clear positive association between pre-radiotherapy carious and periodontally compromised teeth and the subsequent development of post-radiotherapy osteoradionecrosis [65,67]. As a result, it is recommended to extract all unrestorable carious teeth and those with unsavable periodontal compromise, as well as to treat any existing periodontal diseases or other soft tissue inflammatory conditions before radiotherapy. Establishing an effective oral hygiene and dento–gingival plaque control regimen is crucial to minimize the risk of developing oral soft tissue inflammatory or infective conditions, such as gingivitis, periodontitis, mucositis, and candidiasis, which can predispose one to osteoradionecrosis [65]. Additionally, cessation of tobacco smoking is vital, as it interferes with tissue healing and can exacerbate complications [70]. Importantly, extracting teeth without clinical or radiological pathology does not reduce the risk of IR-induced osteoradionecrosis [21].

9. Conclusions

Treatment options for oral squamous cell carcinoma (SCC) include surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, or a combination of these approaches. Surgery is the preferred option when feasible; however, advanced-stage disease often necessitates a multimodal treatment strategy. Treatment decisions are influenced by factors such as the tumour-node-metastasis (TNM) staging system, histopathological characteristics, and patient-related factors, including age, overall health, financial situation, lifestyle, and expected functional and cosmetic outcomes.

Radiotherapy and/or chemoradiotherapy are commonly recommended for patients with unresectable oral squamous cell carcinoma (SCC), those who are either unwilling or unable to undergo surgery, or as adjuvant treatment for advanced-stage disease. These modalities are also used when histopathological features suggest a high risk of locoregional recurrence, as salvage treatment for persistent disease, or as a palliative option. The treatment approach is developed through a shared decision-making process between the oncologist, surgeon, and the patient.

The tissue response to radiotherapy is a complex and dynamic process, characterized by reciprocal interactions among patient-specific, tumour-specific, and radiotherapy-related factors. Patient-specific factors include age, sex, health status, and genetic variations in genes related to DNA repair and free radical scavenging. Tumour-specific factors encompass clinical and pathological TNM staging, as well as the specific oral subsite affected. Radiotherapy-related factors include the ionizing radiation (IR) dose, technique used, volume of irradiated tissue, and the potential use of adjunct chemotherapeutic or immunotherapeutic agents. These factors collectively influence the extent and severity of IR-induced toxicity.

Future research should aim to identify factors that may enhance tumour radiosensitivity, promote immunogenic cell death, mitigate IR-induced pathological tissue responses and toxicities, and ultimately improve clinical judgment and decision-making in routine radiation oncology practice.