Late Complications of Head and Neck Radiation
Salivary Gland Hypofunction and Xerostomia
Oral and dental management of the xerostomic patient
Management of xerostomia
Recommendations for future research directions
Current Clinical Trials
Late oral complications of radiation therapy are chiefly a result of chronic injury to vasculature, salivary glands, mucosa, connective tissue, and bone.[1-4] The types and severity of these changes are directly related to radiation dosimetry, including total dose, fraction size, and duration of treatment.Mucosal Lesions
Mucosal lesions include epithelial atrophy, reduced vascularization, and submucosal fibrosis. These changes lead to an atrophic, friable barrier. Fibrosis involving muscle, dermis, and the temporomandibular joint results in compromised oral function. Salivary tissue changes include loss of acinar cells, alteration in duct epithelium, fibrosis, and fatty degeneration. Compromised vascularization and remodeling capacity of bone leads to risk of osteonecrosis.Salivary Gland Hypofunction and Xerostomia
Ionizing radiation to salivary glands results in inflammatory and degenerative effects on salivary gland parenchyma, especially serous acinar cells. The early salivary gland tissue response to irradiation results in decreased salivary flow rates within the first week of treatment, and xerostomia (the subjective feeling of oral dryness) becomes apparent when doses exceed 10 Gy.
The degree of dysfunction is related to the radiation dose and volume of glandular tissue in the radiation field. Doses larger than 54 Gy are generally considered to induce irreversible dysfunction. Serous parotid glands may be more susceptible to radiation effects than are nonserous submandibular, sublingual, and minor salivary gland tissues. Management strategies described for late salivary gland complications are generally applicable to the acute complications in the head/neck radiation patient. (Refer to the Oral and dental management of the xerostomic patient section of this summary for more information.)
Salivary gland hypofunction (decreased salivary gland secretion) and xerostomia are among the most frequent and severe long-term side effects of radiation therapy to the head and neck region. The adverse effects will have a significant impact on a patient’s quality of life in a lifelong perspective after radiation treatment.
Xerostomia is caused by salivary gland hypofunction. Saliva is necessary for the normal execution of oral functions such as taste, swallowing, and speech. Unstimulated whole salivary flow rates lower than 0.1 mL per minute are considered pathologic low (normal salivary flow rate = 0.3–0.5 mL/min).
Late salivary tissue changes induced by radiation therapy include loss of acinar cells, alteration in duct epithelium, fibrosis, and fatty degeneration. The early response to irradiation resulting in markedly decreased salivary flow rates within the first week of treatment is followed by a further decline in saliva secretion and worsening of xerostomia after radiation therapy (1–3 months posttreatment), whereafter salivary secretion and xerostomia gradually recover over time (maximum recovery, 1–2 years posttherapy), depending on the total radiation dose to the gland tissue. Recovery of salivary gland function is usually incomplete, and the overall degree of dryness can range from mild to severe.
It should be noted that salivary gland hypofunction and xerostomia may also be sequelae of other radiation regimens, e.g., radioactive iodine treatment of thyroid cancer and preconditioning total body irradiation in hematopoietic stem cell transplantation for the treatment of hematologic malignancies—although to a much lesser severity.[7,8]
Symptoms and signs of salivary gland hypofunction include the following:
- Lip dryness/crusting.
- Fissures at lip commissures.
- Atrophy of dorsal tongue surface.
- Atrophic and fragile oral mucosa.
- Difficulties in speech, chewing, and swallowing.
- Difficulty in wearing dentures (edentulous patients).
- Oral burning sensation.
- Taste disturbances.
- Increased thirst.
- Sensitivity/pain in response to spicy foods and strong flavorings.
Salivary gland tissues that have been excluded from the radiation portal may become hyperplastic, partially compensating for the nonfunctional glands at other oral sites.
Salivary gland hypofunction also alters the mechanical cleansing ability and the buffer capacity of the mouth, thereby contributing to a high risk of accelerated dental caries (cavities) and periodontal disease. Also, the progression of dental caries is accelerated by the reduction in antimicrobial proteins normally contained in saliva.
In summary, salivary gland hypofunction produces the following changes in the mouth that collectively cause patient discomfort and increased risk of oral lesions:
- Increase in salivary viscosity, with resultant impaired lubrication of oral tissues.
- Decrease in flushing/clearance of acid production after sugar exposure, resulting in demineralization of the teeth and leading to dental decay.
- Compromise of buffering capacity and salivary pH, with increased risk for dental caries and erosion.
- Increase in pathogenicity of oral flora.
- Accumulated bacterial plaque levels caused by patient difficulty in maintaining oral hygiene (caused by soreness of oral mucosa and/or muscular fibrosis/trismus).
Patients who experience salivary gland hypofunction and xerostomia must maintain excellent oral hygiene to minimize the risk of oral lesions. Periodontal disease can be accelerated and caries can become rampant unless preventive measures are instituted. Multiple preventive strategies should be considered.Oral hygiene protocol
Perform systematic oral hygiene at least 4 times per day (after meals and at bedtime):
- Brush teeth (if soreness of oral mucosa and trismus are present, use small ultrasoft toothbrush).
- Use a fluoridated toothpaste when brushing.
- Floss once daily.
- Apply a prescription-strength fluoride gel at bedtime to prevent caries.
- Rinse with a solution of salt and baking soda 4 to 6 times a day (½ tsp salt and ½ tsp baking soda in 1 c warm water) to clean and lubricate the oral tissues and to buffer the oral environment.
- Sip water frequently to rinse the mouth and alleviate mouth dryness.
- Avoid foods and liquids with a high sugar content. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.)
[Note: Prescription-strength fluorides should be used because nonprescription fluoride preparations are inadequate for moderate to high risk of dental caries. If drinking water does not contain enough fluoride to prevent dental decay, oral fluoride (e.g., drops or vitamins) should be provided.]
Use of topical fluoride has demonstrable benefit in minimizing caries formation. During radiation treatment, it has been recommended that mouth guards be filled with topical 1% sodium fluoride gel and placed over the upper and lower teeth. The appliances should remain in place for 5 minutes, after which the patient should not eat or drink for 30 minutes.
- Fluoride and calcium/phosphates.
- Topical high-concentration fluorides.
- Children: topical and systemic.
- Adults: topical.
Prevention of salivary gland hypofunction and xerostomia
To prevent or reduce the extent of salivary gland hypofunction and xerostomia, parotid-sparing intensity-modulated radiation therapy (IMRT) is recommended as a standard approach in head and neck cancer (HNC), if oncologically feasible. In addition, treatment should focus on approaches to further reduce the radiation dose to the submandibular and minor salivary glands, as these glands are the major contributors to moistening of oral tissues.
Another preventive strategy to reduce radiation-induced salivary gland hypofunction and xerostomia is surgical transfer of one submandibular gland to the submental space not included in the radiation portal in selected oropharyngeal and hypopharyngeal/laryngeal cancer patients.;[Level of evidence: I]
Amifostine is an organic thiophosphate approved for the protection of normal tissues against the harmful effects of radiation or chemotherapy, including reduction of acute or late xerostomia in patients with HNC. Studies have reported varying degrees of effectiveness.[12,13][Level of evidence: I] One randomized prospective study reported that intravenous amifostine administered during head and neck radiation therapy reduces the severity and duration of xerostomia 2 years after amifostine treatment, without apparent compromise of locoregional tumor control rates, progression-free survival, or overall patient survival.[Level of evidence: I] The intravenous administration of amifostine may cause severe adverse effects such as hypotension, vomiting, nausea, and allergic reaction. These adverse effects might be reduced by subcutaneous administration of amifostine. The possible risk of tumor protection by amifostine remains a clinical concern.Alleviation of xerostomia
Treatment of salivary gland hypofunction and xerostomia induced by radiation therapy is primarily symptomatic. Alleviation of xerostomia includes frequent sipping or spraying of the oral cavity with water, the use of saliva substitutes, or stimulation of saliva production from intact salivary glandular tissues by taste/mastication, pharmacological sialogogues, or acupuncture.
Saliva substitutes or artificial saliva preparations (e.g., oral rinses or gels containing hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyglycerylmethacrylate, mucin, or xanthan gum) are palliative agents that relieve the discomfort of xerostomia by temporarily wetting the oral mucosa.
Sugar-free lozenges, acidic candies, or chewing gum may produce transitory relief from xerostomia by stimulating residual capacity of salivary gland tissue (acidic products can result in demineralization of the teeth and may not be recommended in dentate patients).
Pilocarpine is the only drug approved by the U.S. Food and Drug Administration for use as a sialogogue (5-mg tablets of pilocarpine hydrochloride) for radiation xerostomia. Treatment is initiated at 5 mg by mouth 3 times a day; the dose is then titrated to achieve optimal clinical response and minimize adverse effects. Some patients may experience increased benefit at higher daily doses; however, incidence of adverse effects increases proportionally with dose. The patient’s evening dose may be increased to 10 mg within 1 week after starting pilocarpine. Subsequently, morning and afternoon doses may also be increased to a maximum 10 mg per dose (30 mg/d). Patient tolerance is confirmed by allowing 7 days between increments.
The most common adverse effect at clinically useful doses of pilocarpine is hyperhidrosis (excessive sweating); its incidence and severity are proportional to dosage. Also reported, typically at doses higher than 5 mg 3 times a day, are the following:
- Increased lacrimation.
- Bladder pressure (urinary urgency and frequency).
It has been suggested that pilocarpine given during radiation therapy may reduce salivary gland impairment and xerostomia both during and after treatment. However, in a randomized study of 249 patients with HNC, the concomitant use of pilocarpine during radiation did not have a positive impact on quality of life or patient assessment of salivary function, despite the maintenance of salivary flow.[Level of evidence: I] It has been indicated that the efficacy of pilocarpine depends on the radiation dose distributed to the parotid glands during treatment, i.e., in patients in whom the mean parotid dose exceeds 40 Gy, pilocarpine may spare parotid gland function and reduce xerostomia—particularly significant after 12 months.[Level of evidence: I]
Cevimeline (30 mg 3 times a day) also appears anecdotally to have efficacy in managing radiation-induced xerostomia.;[Level of evidence: I] Although cevimeline is approved for use only in the management of Sjögren syndrome, appropriate clinical trials are under way, and its efficacy should be established soon. While cevimeline has greater selective affinity for M3 muscarinic receptors than pilocarpine, whether this can prove advantageous for treating radiation xerostomia remains unclear.
Acupuncture appears to offer an intervention for the treatment of radiation-induced xerostomia in patients with a residual functional capacity of the salivary glands and is a treatment modality without serious adverse effects.[21-23] Further randomized controlled clinical trials, including sham acupuncture, are warranted.
Intraoral electrical stimulation devices delivering a low-intensity electrical current to the oral mucosa—thus stimulating salivary gland secretion by innervating afferent neurons of the salivary reflex and efferent neurons (e.g., the lingual nerve)—is under development and has been tested, with promising initial results in the palliation of xerostomia.; Special considerations appear to be indicated when electrostimulation devices are used in head and neck radiation patients.[Level of evidence: I] Further studies are needed.Caries
The risk of dental caries increases secondary to a number of factors, including shifts to a cariogenic flora, reduced concentrations of salivary antimicrobial proteins, and loss of mineralizing components. (Refer to the Conditions Affected By Both Chemotherapy and Head/Neck Radiation section for more information.) As reported in a systematic review, the overall count of decayed, missing, or filled teeth (DMFT) in patients who were post–antineoplastic therapy was 9.19 (standard deviation [SD], 7.98; n = 457). The DMFT for patients who were post–radiation therapy was 17.01 (SD, 9.14; n = 157), which was much higher than that in patients who were postchemotherapy (DMFT, 4.5).
Treatment strategies must be directed to each component of the caries process. Optimal oral hygiene must be maintained. Xerostomia should be managed whenever possible via salivary substitutes or replacements. Caries resistance can be enhanced with the use of topical fluorides and/or remineralizing agents. Efficacy of topical products may be enhanced by increased contact time on the teeth by application using vinyl carriers. Patients unable to effectively comply with use of fluoride trays should be instructed to use brush-on gels and rinses.
Increased colonization with Streptococcus mutans and Lactobacillus species increases caries risk. Culture data can be useful in defining level of risk in relation to colonization patterns. Topical fluorides or chlorhexidine rinses may lead to reduced levels of S. mutans but not Lactobacilli. Because of adverse drug interactions, fluoride and chlorhexidine dosing should be separated by several hours.
Remineralizing agents, which are high in calcium phosphate and fluoride, have demonstrated salutary in vitro and clinical effects. The intervention may be enhanced by delivering the drug via customized vinyl carriers. This approach extends the contact time of active drug with tooth structure, which leads to increased uptake into enamel.
- Fluoride: The use of fluoride products reduces caries activity in patients who are post–radiation therapy. The type of fluoride gel or fluoride delivery system used did not significantly influence caries activity.
- Chlorhexidine: The use of chlorhexidine rinse reduces plaque scores and oral streptococcus mutans scores. This reduction was not seen with lactobacillus counts.
- Dental restorative materials: There is evidence suggesting that conventional glass ionomer restorations performed more poorly than did resin-modified glass ionomer, composite resin, and amalgam restorations in patients who had been treated with radiation therapy.
Risk of osteoradionecrosis (ORN) is directly related to radiation dose and volume of tissue irradiated. The unilateral vascular supply to each half of the mandible results in postradiation ORN most frequently involving the mandible, compared with the maxilla. Presenting clinical features include:
- Diminished or complete loss of sensation.
Pathologic fracture can occur because the compromised bone is unable to appropriately undergo repair at the involved sites. Risk of tissue necrosis is in part related to trauma or oral infection; however, idiopathic cases can also occur. Patients who have received high-dose radiation to the head and neck are at lifelong risk for ORN, with an overall risk of approximately 15%.
Ideally, postradiation management or ORN is based on prevention that begins with comprehensive oral and dental care before radiation therapy begins. The dentition, periodontium, periapices, and mucosa should be thoroughly examined to identify oral disease, which could lead to serious odontogenic, periodontal, or mucosal infections that could necessitate surgical therapy postradiation. Oral disease should be eliminated pretreatment. Dentition that exhibits poor prognosis and is within high-dose fields should be extracted before radiation therapy begins. Ideally, at least 7 to 14 days should be allowed for healing before initiation of radiation; some have suggested allowing up to 21 days. Surgical technique should be as atraumatic as possible and use primary wound closure.
Patients who develop ORN should be comprehensively managed to:
- Eliminate trauma.
- Avoid removable dental prosthesis if the denture-bearing area is within the osteonecrotic field.
- Ensure adequate nutritional intake.
- Discontinue tobacco and alcohol use.
Topical antibiotics (e.g., tetracycline) or antiseptics (e.g., chlorhexidine) may contribute to wound resolution. Wherever possible, coverage of the exposed bone with mucosa should be achieved. Analgesics for pain control are often effective. Local resection of bone sequestra may be possible.
Hyperbaric oxygen therapy (HBO) is recommended for management of ORN, although it has not been universally accepted. HBO has been reported to increase oxygenation of irradiated tissue, promote angiogenesis, and enhance osteoblast repopulation and fibroblast function. HBO is usually prescribed as 20 to 30 dives at 100% oxygen and 2 to 2.5 atmospheres of pressure. If surgery is needed, ten dives of postsurgical HBO are recommended. Unfortunately, HBO technology is not always accessible to patients who might otherwise benefit because of lack of available units and the high price of care.
A systematic review regarding treatment-dependent frequency, current management strategies, and future studies has been published. A total of 43 articles published between 1990 and 2008 were reviewed. The weighted prevalence for ORN included the following:
- Conventional radiation therapy, 7.4%.
- IMRT, 5.1%.
- Chemoradiation therapy, 6.8%.
- Brachytherapy, 5.3%.
HBO may contribute a role in management of ORN. However, no clear recommendations for the prevention or treatment of ORN could be established on the basis of the literature reviewed. The review concluded that new cancer treatment modalities such as IMRT and concomitant chemoradiation therapy have had minimal effect on prevalence of ORN. No studies have systematically addressed the impact of ORN on either quality of life or cost of care. Research addressing these collective issues is needed.
Partial mandibulectomy may be necessary in severe cases of ORN. The mandible can be reconstructed to provide continuity for esthetics and function. A multidisciplinary cancer team that includes oncologists, oncology nurses, maxillofacial prosthodontists, general dentists, hygienists, and physical therapists is appropriate for management of these patients.Tissue Necrosis
Necrosis and secondary infection of previously irradiated tissue is a serious complication for patients who have undergone radiation therapy for head and neck tumors. Acute effects typically involve oral mucosa. Chronic changes involving bone and mucosa are a result of the process of vascular inflammation and scarring that in turn result in hypovascular, hypocellular, and hypoxic changes. Infection secondary to tissue injury and osteonecrosis confounds the process.
Soft tissue necrosis can involve any mucosal surface in the mouth, though nonkeratinized surfaces appear to be at moderately higher risk. Trauma and injury are often associated with nonhealing soft tissue necrotic lesions, though spontaneous lesions are also reported. Soft tissue necrosis begins as an ulcerative break in the mucosal surface and can spread in diameter and depth. Pain will generally become more prominent as soft tissue necrosis becomes worse. Secondary infection is a risk.Mandibular Dysfunction
Musculoskeletal syndromes may develop secondary to radiation therapy and surgery. Lesions include soft tissue fibrosis, surgically induced mandibular discontinuity, and parafunctional habits associated with emotional stress caused by cancer and its treatment. Patients can be instructed in physical therapy interventions such as mandibular stretching exercises and the use of prosthetic aids designed to reduce the severity of fibrosis. It is important that these approaches be instituted before trismus develops. If clinically significant changes develop, several approaches can be considered, including the following:
- Stabilization of occlusion.
- Use of trigger-point injection and other pain management strategies.
- Use of muscle relaxants.
- Use of tricyclic medications.
Trismus has been associated with significant morbidity post–radiation therapy, with significant health implications, including reduced nutrition due to impaired mastication, difficulty in speaking, and compromised oral hygiene. Limitations in jaw opening have been reported in 6% to 86% of patients who received radiation to the temporomandibular joint and/or masseter/pterygoid muscles, with frequency and severity that are somewhat unpredictable.
The loss of function and range of mandibular motion from radiation therapy appears to be related to fibrosis in and damage to the muscles of mastication. Studies have demonstrated that an abnormal proliferation of fibroblasts is an important initial event in these reactions. Additionally, there may be scar tissue from radiation therapy or surgery, nerve damage, or a combination of these factors. Regardless of the immediate cause, mandibular hypomobility will ultimately result in degeneration of both muscle and temporomandibular joint.
Radiation therapy involving the temporomandibular joint, the pterygoid muscles, or the masseter muscle is most likely to result in trismus. Tumors related to this type of radiation can appear in the following locations:
- Oral cavity.
- Base of tongue.
- Salivary gland.
- Maxilla or mandible.
The prevalence of trismus increases with increasing doses of radiation, and levels in excess of 60 Gy are more likely to cause trismus. Patients who have been previously irradiated and who are being treated for a recurrence appear to be at higher risk of trismus than those who are receiving their first treatment.[32,33] This suggests that the effects of radiation are cumulative, even over many years. Radiation-induced trismus may begin toward the end of radiation therapy or at any time during the subsequent 24 months. Limitations in opening the mouth often increase slowly over several weeks or months. The condition may worsen over time or remain the same, or the symptoms may reduce over time, even in the absence of treatment.
Limited mouth opening frequently results in reduced nutritional status. These patients may experience significant weight loss and nutritional deficits. It is generally accepted that weight loss of more than 10% of initial body weight is considered significant. This is of particular importance at a time when the patient is recovering from surgery, chemotherapy, and/or radiation therapy. Additionally, it lowers the ability for social eating and thereby increases the risk of social isolation and decrease in quality of life in patients with HNC.
Finally, limited mouth opening can result in compromised oral hygiene. Patients who have undergone radiation therapy involving the salivary glands must maintain excellent oral hygiene to prevent dental caries. Deficits in oral hygiene can aggravate mucosal and dental problems, with the subsequent risk of mandibular ORN. Also, dental work and other professional oral care measures such as surgery can be made more difficult, which might even result in compromised oncologic follow-up.
The weighted prevalence of trismus with conventional radiation is estimated to be 25%, but 5% with IMRT only. Trismus prevalence in studies of chemoradiation is approximately 30%.Prevention strategies
Early treatment of trismus has the potential to prevent or minimize many of the consequences of this condition. If the clinical examination reveals the presence of limited mouth opening, and diagnosis determines the condition to be trismus, treatment should begin as soon as is practical. As restriction becomes more severe and likely irreversible, the need for treatment becomes more urgent.
Over the years, clinicians have attempted to prevent or treat trismus with a wide array of appliances. These devices include the following:
- Cages that fit over the head.
- Heavy springs that fit between the teeth.
- Screws that are placed between the central incisors.
- Hydraulic bulbs placed between the teeth.
These devices range widely in cost. Some devices, such as continuous passive motion devices, must be custom made for each patient; others are rented on a daily or weekly basis, at rates of up to several hundred dollars per week. The least expensive option is the use of tongue depressors, which has been used for many years to mobilize the jaw. A search of the literature, however, failed to reveal any studies that demonstrated significant improvement in treating trismus with tongue depressors.Curative approach
Some therapeutic interventions seem to show some efficacy in decreasing the intensity of cancer treatment–related trismus (e.g., pentoxifylline,[36,37] Botulinum toxin, exercise using the Therabite device, and the Dynasplint Trismus System ). However, this proposed efficacy must be confirmed by randomized controlled studies, which are lacking in this area.Recommendations for future research directions
Radiation oncology textbooks often fail to mention trismus as a sequela of radiation therapy for HNC patients, contributing to a lack of recognition of the prevalence and significance of this condition. There has been an ongoing attempt by the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer to develop LENT (late effects in normal tissue) morbidity scales. The National Cancer Institute consensus conferences introduced the SOMA (subjective, objective, management, analysis) classification for late toxicity. However, both scales are focused on major organ and dermatological injuries, and trismus is not addressed. This should be corrected in future revisions of these scales.
Considering the high prevalence of trismus in published studies and the deficits in quality of life associated with trismus, increased efforts for patient education, prevention, and early treatment options are warranted. Larger prospective trials that include the prevention and treatment of trismus are needed to improve management and to confirm the benefit of IMRT in the reduction of radiation-induced trismus and the quality-of-life and economic impact of this common oral sequela of radiation.Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about xerostomia that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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