Oral Complications of Head and Neck Cancer Therapy

Head and neck cancer (HNC) is among the 10 most common cancers worldwide. Oral and pharyngeal cancer is the 6^th most common cancer worldwide and the 7^th most common in Europe with estimated incidence and mortality rates of 3.1% and 2.8%, respectively, in Europe in 2018^[1,2,3].

A multifaceted approach is needed to treat HNC including surgery, radiotherapy (RT), chemotherapy (CT), targeted therapy (TT), immunotherapy (IT), or a combination of these treatments accordingly to the location, type, stage and former cancer treatments.

Even though current treatments are extremely advanced, there are still acute (developing during therapy) and chronic (developing months to years after therapy) HNC therapy complications (Table 1), which have a major impact on survivorship and quality of life (QoL)^[4], as well as economic consequences when managing oral complications^[5]. –

Oral complications due to RT are site specific, localized to the irradiated tissues, which tend to become permanent, therefore the patient is in a lifetime risk. Oral complications may include mucositis, pain, xerostomia, dysgeusia, infections, osteoradionecrosis, trismus and dental caries^[6].

Several complications might be mild with few symptoms, so the occurrence may be underestimated, as the oral cavity and oral symptoms may not be evaluated in the medical setting.

Severe oral complications can compromise cancer therapy. Treatment schedule modifications, dose reduction or discontinuation may be needed for the resolution of oral lesions, affecting patient's survival. Oral health care is mandatory before, during and after a cancer treatment^[14].

The impact of these complications is obvious in the 4 times higher suicide risk, in HNC survivors than in the general population and the approximately double rate of all cancer patients^[15].

This is a brief review of the oral complications due to the HNC therapy and their clinical implications.

Oral mucositis (OM) is an acute complication that affects the patients receiving RT (up to 80%), CT (up to 40%)^[16], TT (about 7%)^[17], IT (about 2%)^[10] or a combination of them (up to 100%)^[7,18,19] (Table 2).

There is a distinction between “oral mucositis” (describes the inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation) and “stomatitis” (refers to any inflammatory condition of oral tissue including oral mucositis)^[20,21] (Table 3).

Oral mucositis initially presents as erythema that progresses to painful mucosal ulcerations covered by pseudomembranes. It affects the nonkeratinized oral tissues, such as the buccal and labial mucosa, the lateral tongue, the soft palate and the floor of the mouth^[22,23] (Table 4). Ulcerations are associated with oral pain and odynophagia, which limit oral intake^[24]. Severe mucositis may also increase the possibility of systemic infections and aspiration pneumonia^[16].

Risk factors for the development of mucositis may be patient, treatment, or tumor related. Age, gender, comorbidities, genetic factors, use of tobacco and alcohol, preexisting periodontal diseases and oral microflora are patient related risk factors. Cumulative radiation dose, fraction size, radiated area size and overall treatment time are risk factors related to RT. Concurrent chemotherapy results in a higher incidence and severity of OM^[16]. Hyposalivation may exacerbate mucosal symptoms^[24].

Radiation induced OM is a locoregional complication, however, it can have systemic impact due to cytokine release. Oral mucositis begins at cumulative doses of around 15 Gy, presents as erythema of the oral mucosa after approximately 20 Gy and progresses to ulceration covered by pseudomembranes after approximately 30 Gy^[25]. OM can peak near the end of RT and usually resolves after 2–6 weeks of the completion of therapy, thought it may persist for 5–24 months^[26,27].

OM induced by CT develops within 1 week of drug administration and peaks within 2 weeks. When it is uncomplicated by infections, it usually heals within 2–4 weeks after the cessation of CT. Severity depends on the chemotherapeutic agent, the number of chemotherapy cycles and the patient's age and oral health. Oral mucositis may be induced by chemotherapeutics like anthracyclines, alkylating agents, platinum-based agents, vinca alkaloids and taxanes. Moreover, some chemotherapeutics like Methotrexate and Etoposide are secreted in saliva, which may increase mucosal toxicity^[16].

In HNC patients receiving chemoradiotherapy (CRT), OM may appear earlier in the treatment course, last longer, be more severe and extend beyond the RT fields^[23].

Targeted therapies like agents targeting the EGFR inhibitors amplify OM^[28]. Cetuximab as monotherapy has been found to induce OM in 7% of the patients^[7,17,29], while a higher incidence of severe mucositis is observed when combined with RT^[30] or CRT^[28,31], resulting in extension to sites beyond the sites that receive high-dose of RT with broad involvement of the oral mucosa including the labial mucosa^[8,32,33].

Administration of PD-1 inhibitors can sporadically induce nonspecific oral mucosal inflammation. OM is reported in patients receiving Nivolumab^[34,35] or Pembrolizumab^[36].

There is a profound clinical impact of OM; OM is associated with increased oral pain, dietary modifications, feeding tube placement, gastrostomy, dehydration, weight loss^[24], fatigue, anorexia, and reduced performance status, frequent hospitalization and breaks in treatment. Ulcerations may persist for several months beyond expected healing, causing prolonged symptomatology^[27]. Furthermore, OM is associated with diminished QoL and significant health and economic outcomes with increased resource requirements and healthcare costs^[5,37].

Oral pain is one of the most prevalent, debilitating and feared consequence. Pain results to increased use of feeding tubes and opioid medication, increased cases of hospitalization and treatment breaks, even increases medical costs^[1,2,37]. Chewing, swallowing, speaking, and other oral functions trigger pain constantly. During RT for HNC, OM induced pain generally starts at cumulative doses of around 30 Gy, peaks at about 50 Gy and persists for 2–4 weeks since the completion of RT^[1,3]. Cramet et al^[38]. studied HNC survivors at 1 to 20 years after diagnosis. Among survivors, 45.1% reported pain and 11.5% reported severe pain. Mucositis pain interferes with daily activities in approximately one-third of patients, affecting mood in half of them^[16]..

Pain may also develop from treatment induced polyneuropathy^[10] following CT, hormonal therapy, TT, IT and RT^[7,8]. Platinum agents, Fluorouracil (5FU) and Taxanes are chemotherapeutic agents that could produce pain. Targeted therapy may cause neurotoxicity and mucosal (aphthous like) ulcerations resulting pain, while immunotherapy could result in pain by stimulating immune-inflammatory processes^[7,10,23,39]. Patients receiving RT for HNC may develop mucosal atrophy and telangiectasias and may experience chronic mucosal pain and sensitivity; it sometimes is described as a burning or a scalded sensation that may represent neuropathy^[16,40]. HNC therapy-induced pain can be nociceptive and/or neuropathic (Table 3). Nociceptive pain is commonly induced by the damaged tissues in the oral cavity. Persistent unrelieved nociceptive pain induced by OM ulcers as well as the actual therapy-related neuron damage can exacerbate the dysfunction in the nervous system, producing neuropathic pain (NP)^[40].

Osteoradionecrosis and medication related osteonecrosis of the jaw may also cause pain; pain and swelling are included in the clinical presentation^[6].

Moreover, OM in HNC patients treated with RT/CRT is often complicated by candidiasis and herpetic infection, thus altering pain characteristics; candidiasis is often associated with a burning sensation of the mouth^[41], while herpetic infection was observed to aggravate radiation-induced ulcerative OM and exacerbate pain, as it is associated with painful ulcerations in the oral cavity^[42].

Xerostomia and the consequent lack of lubrication of the oral mucosa increase the mucosal friction during oral functions, making it vulnerable to greater trauma and pain^[43].

Xerostomia is defined as the subjective sensation of oral dryness; it may be secondary to salivary gland disfunction or hypofunction with changes in quantity and/or quality of saliva^[16,49]. The term “dry mouth” is also used to indicate either xerostomia or hyposalivation or both (Table 3). Xerostomia is a frequent and debilitating acute complication, which in many cases develops into a chronic condition. Xerostomia may increase the risk of secondary oral infection (e.g., candidiasis), pain, dental and periodontal disease, mucosal trauma, taste disfunction, dysphagia and speech difficulty^[16,24,50].

Salivary glands are sensitive to RT. Doses greater than 30 Gy can cause permanent damage and xerostomia^[16,50]. RT causes xerostomia due to direct damage to salivary acini and ducts and indirect damage to epithelial and connective tissue elements of the gland like blood vessels and nerves. The serous acini are initially more sensitive to RT. This often results in decreased saliva volume and increased viscosity. However, during RT, mucinous acini may become similarly impaired^[16,19,51].

Moderate xerostomia is reported in less than 7.5% of patients receiving PD1 inhibitors^[10]; 6%–6.5% of patients treated with Nivolumab and 4%–7.2% of patients treated with Pembrolizumab^[7].

Antiemetics administered for the management of nausea and vomiting due to CT may also cause xerostomia^[52]. The antiemetics reported to cause xerostomia are 5-HT3 receptor antagonists^[53], dopamine antagonists^[54], cannabinoids^[55], benzodiazepines^[56], NK1 receptor antagonists^[57] and the atypical antipsychotic Olanzapine^[58]. Olanzapine is reported to induce mostly xerostomia; however, one animal study reported dual secretory effects: xerostomia and sialorrhea^[58].

Xerostomia is reported as a lifelong morbidity having important effects on oral health and QoL; it resolves completely in only 20%–30% of patients, 1 year after the completion of RT^[48].

Dysgeusia is frequently underreported and overlooked and is impacting patients’ QoL as it can lead to malnutrition and weight loss^[23,48]. In HNC patients under treatment, there are several taste function changes including taste alteration, loss of taste, hypersensitivity, or hyposensitivity^[48]; they usually are all reported under the term dysgeusia (Table 3).

In patients receiving RT alone, the incidence of dysgeusia is 16–100%, depending on the study. Radiotherapy has a direct cytotoxic and antiproliferative effect on the epithelium of the tongue and on the gustatory nerves^[48]. Taste impairs during the first week of treatment, becomes worse during the second week, reaching the greatest impairment during the third or fourth week of treatment. Improvement can be found between the end of the 1^st and the 2^nd month post RT and normal or near-normal levels of taste can be observed within 1 year after RT; however, changes may persist up to 7 years post RT or even indefinitely^[16,23].

Chemotherapy and targeted therapeutic agents may affect taste by direct taste receptor stimulation due to secretion in saliva or via gingival crevice fluid (patients frequently describe a metallic or chemical taste when chemotherapy is delivered), and taste change may persist after drug clearance due to damage to the taste buds^[16,48]. Patients treated with 5-FU, Taxanes, Cyclophosphamide, Doxorubicin and Cisplatin may develop taste changes, including ageusia or hypogeusia^[60].

Moderate dysgeusia has been noted in less than 4% of PD1 inhibitors treated patients^[7].

Hyposalivation may reduce taste due to limited delivery of tastants to the receptors.

Damage to the cranial nerves and oral, dental, and oropharyngeal pathology may affect taste function changes, mediated by the trigeminal nerve, correlated with touch and temperature sensation. Moreover, smell mediated by the olfactory nerve may alter taste perception^[16,48].

Dysgeusia is highly reported among patients with reduced dietary intake and weight loss and when associated with oral mucositis and xerostomia, affected patients’ appetite^[24].

During ulcerative OM, patients are more prone to infections because the oral microbial flora is altered and the oral cleansing property of saliva is diminished by reduced salivary flow; odontogenic, periodontal and dormant viral infections usually become reactivated. Ulcers can be colonized by Candida species, Herpes virus, and bacteria. Differential diagnosis of OM, candidiasis and herpetic infection is important, as candidiasis and herpetic infection superimposed on mucositis can aggravate the mucosal condition and exacerbate pain, consequently causing—in clinical practice—a reduction of the patient compliance to the therapy. The differentiation of candidal pseudomembranes and the herpetic ulcers covered by the fibrinous exudate from the pseudomembranes and the ulcers of the ulcerative phase of mucositis, in case of concurrent development, is at times difficult yet mandatory (Table 4).

Patients with HNC under RT are at high risk of developing rampant decays, the “Radiation caries”, due to direct enamel and dentin modifications and indirect effect of xerostomia, with accelerated decalcification of mineralized tissues^[48]. When the teeth are in the irradiation field, irradiation causes decreased circulation through pulp, secondary fibrosis, and degeneration of the odontoblast processes. The effect of irradiation on tooth structure is dose dependent. Doses under 30 Gy cause minimal damage, doses 30–60 Gy increase the risk of tooth damage two to three times, while in doses over 60 Gy, there is a tenfold increase of tooth deterioration possibility^[19]. Dental demineralization is thought to be mediated through the decreased buffering capacity of the saliva, the shift to cariogenic bacteria of the oral flora (Streptococcus mutans and Lactobacillus species), and the dietary changes^[16]. After RT, salivary viscosity is increased and salivary pH becomes cariogenic, decreasing from 7.0 to 5.0, making minerals of enamel and dentin dissolve easily^[19]. A correlation between CT-induced vomiting and dental erosion has been also reported^[67]. Demineralization may progress to teeth fractures and consequent extractions and osteoradionecrosis of the jaw (ORN)^[16].

Radiation caries has a quick progress, affect the cervical margins and the smooth tooth surfaces where caries is unusual in nonradiated patients; the affected teeth become discolored and demineralized, with erosions in the cervical region, which makes them fracture easily. The lesions are painless and may develop within 3 months of the completion of radiotherapy^[19,48].

The prevalence in patients receiving chemoradiation ranges from 14%–21%^[48].

Fibrosis is a late effect from HNC RT. Trismus is a result of high-dose RT exposure to the temporomandibular joint (TMJ) region and of masticatory muscles’ fibrosis with a tendency to be a persistent and chronic condition^[16,48]. Trismus also occurs following head and neck surgery in combination with RT or CRT^[68]. Radiotherapy is a repetitive injury, where widespread fibrosis is observed due to excess production of fibroblasts and extracellular matrix^[48], and therefore, it can affect tongue function and swallowing, depending on the affected muscles, lingual or pharyngeal constructive muscles. There is a cut of a maximum mouth opening below 35 mm, where trismus is defined^[69]. At this point, functional abnormalities of the maxillofacial structures are present. The incidence of trismus in HNC patients varies between 5% and 45% depending on the study^[23,68]. Galitis et al^[68]. reported a 37.5% of patients with trismus at the end of radiotherapy, while the reduction of mouth opening was seen in all the patients and the mean mouth opening reached the levels of trismus. Oral mucositis, with its subepithelial changes, may facilitate the development of fibrosis, with a subsequent limited mouth opening. Fibrosis may also affect the salivary glands by substitution of the gland parenchyma with fibrous tissue^[48].

Osteoradionecrosis (ORN) of the jaw is an RT-induced complication, which causes significant morbidity to the patients. Definition includes irradiated bone, which becomes devitalized and exposed in the oral cavity, persisting without healing for 3 months and without tumor recurrence^[48,70]. It may occur in approximately 5% of patients receiving a total radiation dose of 50 Gy or more, most commonly in the mandible^[16]. Diabetes, collagen and vascular disease, tobacco and/or alcohol abuse and poor nutrition may increase the risk of ORN^[70]. It is not yet clear whether radiation schedules by 3-dimensional conformal radiotherapy (3D-CRT) and intensity modified radiotherapy (IMRT) affect the risk of developing ORN; the main risk factor is the total radiation dose delivered^[71]. Bone radiation (50 Gy or more) may lead to hypovascularity and osteocytes apoptosis, which causes infection, poor wound healing and bone necrosis. Most of the ORN cases occur after local trauma or dental extraction. Up to 50% of cases follow dental extractions. Spontaneous ORN is reported in almost 35% of all cases^[71]. Thus, pre-radiation oral evaluation and dental management is crucial. Patient may complain of oral pain and swelling. Clinically, ORN may present with tooth mobility, exposed necrotic bone, fistula formation, or pathologic fracture or with a combination of these. Radiographically, ORN presents as poorly defined radiolucencies with areas of radiopacity^[16].

Medication related osteonecrosis of the jaw (MRONJ) is a complication related mainly with the exposure to drugs with antiresorptive effects for osseous metastases or myeloma. However, there are reported cases associating MRONJ with agents that have no antiresorptive properties, such as TT, IT (Nivolumab) and administration of cytotoxic CT (concomitant administration of Gemcitabine, Vinorelbine and Doxorubicin)^[12,34]. MRONJ is an underdiagnosed complication, with nonspecific symptoms in early stages. In most cases, a diagnosis of MRONJ requires exposed bone, or bone that can be probed through a fistula (intraoral or extraoral), persisted for more than 8 weeks, without history of radiation therapy to the jaw or obvious metastatic disease^[72]. The 8-week period may be appropriate in cases of post-extraction sockets, but this observation time may not be needed when there is a clear diagnosis. In addition, there are reports of nonexposed forms of MRONJ, which should also be included in the differential diagnosis^[73]. Local dental and/or periodontal infections are reported preceding to the appearance of necrotic bone in patients receiving antiresorptive therapies^[74]. The radiographic findings of sclerosis or absence of the lamina dura of the involved teeth as well as periapical radiolucency and periodontal ligament widening may be indicative of early MRONJ presence^[6,75]. MRONJ related to non-antiresorptive drugs has an earlier onset time and may have better prognosis since there is greater likelihood of healing and shorter healing time compared to bone targeting agents related osteonecrosis of the jaw^[12].

Immune checkpoint inhibitors are monoclonal antibodies that modulate the effects of immune checkpoints; Programmed Cell Death protein 1 (PD-1) is a co-inhibitory signal responsible for immune suppression. Anti-PD1 inhibitors due to their mechanisms of action, are associated with autoimmune-like/inflammatory side effects, with collateral damage to normal organ systems and tissues, including the skin, gastrointestinal, hepatic, pulmonary, mucocutaneous, and endocrine system^[11,77]. The most common cutaneous adverse events include lichenoid reactions, eczema, vitiligo, and pruritus. Cases of lichenoid oral mucosal lesions and oral lichen planus are observed in patients treated with Nivolumab or Pembrolizumab^[7,78,79]. Lesions can be spotted to the dorsal and lateral side of the tongue, lips, hard palate, the buccal mucosa or gingivae or on all of these, as whitish papules, reticular or linear, confluent in places, sometimes with erythema^[7,80] (Table 4). These toxicities require prompt recognition and intervention.

In patients receiving anti-PD1 therapy, with preexisting autoimmune disease, there has been reported a flare of their underlying autoimmune condition^[81] suggesting a potentially higher risk of side effects^[13].

Agents targeting the EGFR, like the monoclonal antibody Cetuximab, also represent an important strategy in cancer management. Cetuximab, is used for HNC treatment in combination with RT or CRT. The therapeutic inhibition of EGFR is associated with cutaneous or mucosal toxicities in most of the patients; EGFR has a key role in homeostasis of the epidermal and epithelial cells. Saraswat et al^[17]. reported aphthous-like lesions observed in about 7.8% of the patients treated with Cetuximab^[17].

They are painful, single or multiple, well circumscribed round or ovoid superficial lesions, having a gray central area surrounded by erythematous halo, involving the non-keratinized oral mucosa (Table 4). They appear shortly after starting treatment with rapid onset and gradual disappearance^[7,9,84].

Systematic examination of oral cavity is recommended as part of patients’ monitoring.

Clinicians should be alert to the potential for increased toxicity with escalating dose or treatment duration when therapy demonstrates gastrointestinal mucosal toxicity. Systematic assessment of the oral cavity following treatment permits early identification of lesions^[85]. Oral hygiene and other supportive and palliative care measures are important to minimize the severity of the lesions^[86].

After cancer therapy, routine systematic oral hygiene is also important for reducing incidence and severity of oral sequelae, for restoring functional and esthetic impairments and for removing the remaining foci of infection^[87]. Patients should be followed up every month for the first 3 months, every 3 months for the first year and every 6 months from there on^[88].

Treatment-related oral complications require increased awareness and recognition to promote prevention and appropriate intervention in order to limit dose modifications and preserve patients’ QoL. It is noteworthy that treatment-related oral changes can be underreported when relying upon patient's report who may be hesitant to report them, as patients are afraid of a therapy adjustment. Treatment-related toxicities are also associated with high costs; patients often visit the emergency departments, are hospitalized, and are in need of supportive agents for pain management and palliation. It is important to be aware of these complications so that appropriate measures can be properly implemented; multidisciplinary health care teams must be integrated and effectively communicating in order to provide the best patient care. Experienced oral health care professionals should be included. Further research into the epidemiology, pathobiology, and analysis of HNC-related toxicities would help in minimizing acute and late effects of therapy.