Oral complications of cancer treatment arise in various forms and degrees of severity, depending on the individual and the

cancer treatment. Chemotherapy often impairs the function of bone marrow, suppressing the formation of white blood cells, red blood cells, and platelets (myelosuppression). Some cancer treatments are described as stomatotoxic because they have toxic effects on the oral tissues. The most common oral problems occurring after radiation and chemotherapy are mucositis (an inflammation of the mucous membranes in the mouth), infection, pain, and bleeding. Other possible complications might include dehydration and malnutrition, commonly brought on by difficulties in swallowing (dysphagia). Radiation therapy to the head and neck may injure the glands that produce saliva (xerostomia), or damage the muscles and joints of the jaw and neck (trismus). These treatments may also cause hypovascularization (reduction in blood vessels and blood supply) of the bones of the maxilla or mandible (the bones of the mouth). In addition, treatments may affect other forms of dental disease (caries, or soft tissue complications), or even cause bone death (osteonecrosis).

Oral complications common to both chemotherapy and radiation

y y y

Oral mucositis: inflammation and ulceration of the mucous membranes; can increase the risk for pain, oral and systemic infection, and nutritional compromise. Infection: viral, bacterial, and fungal; results from myelosuppression, xerostomia, and/or damage to the mucosa from chemotherapy or radiotherapy. Xerostomia/salivary gland dysfunction: dryness of the mouth due to thickened, reduced, or absent salivary flow; increases the risk of infection and compromises speaking, chewing, and swallowing. Persistent dry mouth increases the risk for dental caries.

y y y y y y y y

Functional disabilities: impaired ability to eat, taste, swallow, and speak because of mucositis, dry mouth, trismus, and infection. Taste alterations: changes in taste perception of foods, ranging from unpleasant to tasteless. Nutritional compromise: poor nutrition from eating difficulties caused by mucositis, dry mouth, dysphagia, and loss of taste. Abnormal dental development: altered tooth development, craniofacial growth, or skeletal development in children secondary to radiotherapy and/or high doses of chemotherapy before age 9. Neurotoxicity: persistent, deep aching and burning pain that mimics a toothache, but for which no dental or mucosal source can be found. This complication is a side effect of certain drugs. Bleeding: oral bleeding from the decreased platelets and clotting factors associated with the effects of therapy on bone marrow. Radiation caries: lifelong risk of rampant dental decay that may begin within 3 months of completing radiation treatment if changes in either the quality or quantity of saliva persist. Trismus: loss of elasticity of masticatory muscles that restricts normal ability to open the mouth.

Osteonecrosis: blood vessel compromise and necrosis of bone exposed to high-dose radiation therapy; results in decreased ability to heal if traumatized.

Who Has Oral Complications?

Risk for oral complications can be classified as :

y y

Lower risk: Patients receiving minimally myelosuppressive or nonmyelosuppressive chemotherapy. Higher risk: Patients receiving stomatotoxic chemotherapy resulting in prolonged myelosuppression, including patients undergoing hematopoietic stem cell transplantation; and patients undergoing head and neck radiation for oral, pharyngeal, and laryngeal cancer.

Points to remember

y y

High-dose radiation treatment carries a lifelong risk of xerostomia, dental caries, and osteonecrosis. Because of the risk of osteonecrosis, principally in the mandible, patients should avoid invasive surgical procedures, including extractions that involve irradiated bone. If an invasive procedure is required, use of antibiotics and hyperbaric oxygen therapy before and after surgery should be considered.

y y y y

Lifelong daily fluoride application, good nutrition, and conscientious oral hygiene are especially important for patients with salivary gland dysfunction. Dentures may need to be reconstructed if treatment altered oral tissues. Some people can never wear dentures again because of friable tissues and xerostomia. Dentists should closely monitor children who have received radiation to craniofacial and dental structures for abnormal growth and development. Dentists should be mindful about the recurrence of malignancies in patients with oral and head and neck cancers, and thoroughly examine all oral mucosal tissues at recall appointments.

Pathophysiology
The pathophysiology of mucositis can be divided into its 5 stages; including an initiation phase, a message generation phase, a signaling and amplification phase, an ulceration phase, and a healing phase. Different cytokines are responsible for the various stages. The initiation phase is caused by the production of free radicals caused by the chemo- or radio- therapy, which damages cell DNA. This causes the production of cell transcription factors such as NF- B, which upregulates inflammatory cytokines, marking the beginning of the ulceration phase. Main inflammatory cytokines involved are IL-1 and TNF-alpha. During the healing phase, epithelial cells are attracted to the site of the ulcer and begin the re-epithelialization of the ulcers.

Clinical manifestations

Severity depends on the quality of dental hygiene, the treatment schedule, the irradiated area and the amount of radiation given, as well as the age of the patient. Late effects can be characterized by thinning of the mucosa (the soft tissues of the oral cavity), and submucosal ulceration and necrosis. Oral mucositis is made worse by infection. The mouth can become infected, and the loss of soft tissues in the mouth can allow disease-causing organisms to enter the bloodstream. Once the mouth is affected by treatments, even the normal, good bacteria that exist as part of the natural flora of our mouth, can cause infections, as well as disease-causing organisms picked up from other sources. As the white blood cell count decreases as a result of treatments, the frequency and seriousness of infection increases. Patients who have low white blood cell counts over a long period of time, are at more risk of developing serious infections. Antibiotics used over a long period of time can change the number of normal, beneficial bacterial organisms in the mouth. Their decreased numbers may allow an excessive growth of fungi. Steroids given at the same time as treatments can also make the problem worse. Most oral infections in patients with solid tumors are caused by yeast and other fungi, while the rest are caused by viruses (such as herpes) and bacteria.

Cancer patients undergoing chemotherapy usually become symptomatic four to five days after beginning treatment, reaching a peak at around day 10, and then slowly improving over the course of a few weeks. Mucositis associated with radiotherapy usually appears at the end of the second week of treatment and may last for six to eight weeks. As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish white fibrin clot called a pseudomembrane. Peripheral erythema is usually present. Ulcers may range from 0.5 cm to greater than 4 cm. Severely painful. Pain is often described as a burning sensation accompanied by reddening.

Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth. Dysgeusia : An alteration in taste perception. It is a temporary condition that occurs because of effects on taste buds that are mostly located in the tongue. Sometimes, only partial recovery of taste occurs

Diagnosis
Red burn-like sores or ulcers throughout the mouth is enough to diagnose mucositis. Severity can be evaluated using several different assessment tools. 1. World Health Organization (WHO) Oral Toxicity score. 2. National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Oral Mucositis. While the NCI system has separate scores for appearance (erythema and ulceration) and function (pain and ability to eat solids, liquids, or nothing by mouth). WHO score combines both elements into a single score that grades the severity of the condition from 0 (no oral mucositis) to 4 (swallowing not possible such that patient needs supplementary nutrition). Another scale developed in 1999, the Oral Mucositis Assessment Scale (OMAS). The OMAS provides an objective assessment of oral mucositis based on assessment of the appearance and extent of redness and ulceration in various areas of the mouth. Treatment Oral hygiene patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse. Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid alcohol. Citrus fruits, alcohol, and foods that are hot are all known to aggravate mucositis lesions. Chlorhexidine gluconate and viscous Lidocain relief of pain.

Palifermin is a human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Caphosol is a mouth rinse which has been shown to prevent and treat oral mucositis caused by radiation and high dose chemotherapy. Sucking ice cubes is an effective method of relieving oral mucositis.

Complications
Sores or ulcerations can become infected by virus, bacteria or fungus. Pain and loss of taste perception makes it more difficult to eat, which leads to weight loss. Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may cause septicemia (especially in immunosuppressed patients).
Management of oral mucositis

As mucositis severity increases and topical pain management strategies become less effective, it becomes increasingly necessary to depend on systemic analgesics to manage oral radiation mucositis pain. Because there is generally no bleeding risk for head and neck radiation patients, analgesic treatment begins with nonsteroidal anti-inflammatory drugs (NSAIDs). As pain increases, NSAIDs are combined with opioids and patients can be made relatively comfortable. Systemic analgesics are given by the clock to achieve steady-state blood levels to provide adequate pain relief. Additionally, adjunctive medications are given to provide adjuvant analgesia and manage side effects of NSAIDs and opioids. Zinc supplementation used with radiation therapy may improve mucositis and dermatitis. The use of alcohol-free povidone-iodine mouthwash can reduce the severity and delay the onset of oral mucositis due to antineoplastic radiation therapy.
Radiation-induced mucositis depends on absorbed radiation dose, fractionation, delivery modality, and soft tissue status. The patient may feel a mucosal burning sensation 1-2 weeks after initiation of therapy; the mucosa may be edematous and leukoplakic or erythematous on clinical examination.

Bisphosphonate-associated osteonecrosis of the jaw

Bisphosphonate-associated osteonecrosis of the jaw, often abbreviated as BON, BON of the jaw or even BRONJ, is a recently discovered dental phenomenon that may lead to surgical complication in the form of impaired wound healing following oral or periodontal surgery or endodontic therapy.[1] There is presently no known prevention for bisphosphonate-associated osteonecrosis of the jaw.[2] For more general information, see Osteonecrosis of the jaw.

Contents
[show]
y

[edit] Definition
Osteonecrosis, or localized death of bone tissue, of the jaws is a rare potential complication in cancer patients receiving treatments including radiation, chemotherapy, or in patients with tumors or infectious embolic events. In 2003,[3][4] reports surfaced of the increased risk of osteonecrosis in patients receiving these therapies concomitantant with and an intravenous bisphosphonate.[5] Matrix metalloproteinase 2 may be a candidate gene for bisphosphonateassociated osteonecrosis of the jaws, since it is the only gene known to be associated with both bone abnormalities and atrial fibrillation, another side effect of bisphosphonates.[6] In response to the growing base of literature on this association, the United States Food and Drug Administration issued a broad drug class warning of this complication for all bisphosphonates in 2005.[7]

[edit] Pathogenesis and diagnosis

Although the methods of action are not yet completely understood, it is hypothesized that bisphosphonate-associated osteonecrosis of the jaw is related to a defect in jaw bone physiologic remodeling or wound healing. The strong inhibition of osteoclast function precipitated by bisphosphonate therapy can lead to inhibition of normal bone turnover. Because bisphosphonates are preferentially deposited in bone with high turnover rates, it is possible that the levels of bisphosphonate within the jaw are selectively elevated. To date, there has been no reported cases of bisphosphonate-associated complications within bones outside the craniofacial skeleton.[7] A diagnosis of bisphosphonate-associated osteonecrosis of the jaw relies on three criteria:[2]
1. the patient possesses an area of exposed bone in the jaw persisting for more than 8 weeks, 2. the patient must present with no history of radiation therapy to the head and neck, 3. the patient must be taking or have taken bisphosphonate medication.

According to the updated 2009 BRONJ Position Paper published by the American Association of Oral and Maxillofacial Surgeons, both the potency of and the length of exposure to bisphosphonates are linked to the risk of developing bisphosphonate-associated osteonecrosis of the jaw.[8]

[edit] Bisphosphonates: intravenous vs. oral

Cases of BON have also been associated with the use of the following two intravenous and three oral bisphosphonates, respectively: Zometa (zoledronic acid) and Aredia (pamidronate) & Fosamax (alendronate), Actonel (risedronate) and Boniva (ibandronate).[9] [edit] Risk The overwhelming majority of BON diagnoses, however, were associated with intravenous administration of bisphosphonates (94%). Only the remaining 6% of cases arose in patients taking bisphosphonates orally.[2] Although the total United States prescriptions for oral bisphosphonates exceeded 30 million in 2006, less than 10% of BON cases were associated with patients taking oral bisphosphonate drugs.[10] Studies have estimated that BON occurs in roughly 20% of patients taking intravenous zoledronic acid for cancer therapy and in between 0-0.04% of patients taking orally administered bisphosphonates.[11] Head and neck radiation patients are a significant challenge relative to both intratherapy and posttherapy oral complications resulting from radiation therapy. Unlike the oral complications of chemotherapy that are of shorter duration and are significant for only a short period (a few weeks to 2 months) after the cessation of therapy, the oral complications of head and neck radiation are more predictable, often more severe, and can lead to permanent tissue changes that put the patient at risk for serious chronic complications.
Preradiation Evaluation and Disease Stabilization

Elimination of oral disease and implementation of oral care protocols designed to maintain maximum oral health must be a component of patient assessment and care prior to radiation therapy. During and after radiation therapy, oral management will be dictated by the specific needs of the patient, the specifics of the radiation therapy, and presence of chronic complications caused by radiation therapy. Ongoing oral assessment and treatment of complications are essential, because radiation to oral tissues typically renders patients at lifelong risk for oral complications. In addition, invasive oral procedures can cause additional sequelae. Dental care typically needs to be altered due to underlying chronic radiation-induced tissue damage. Patients should receive a comprehensive oral evaluation several weeks prior to initiation of highdose upper-mantle radiation. This timing provides an appropriate interval for tissue healing in the event invasive oral procedures, including dental extractions, dental scaling/polishing, and endodontic therapy, are necessary. The goal of this evaluation is to identify teeth at significant risk for infection and/or breakdown that would ultimately require aggressive or invasive dental treatment during or after the radiation that increase the risk of soft tissue necroses and osteonecroses. The likelihood of these lesions occurring postradiation increases over the patients lifetime as the risk of significant dental disease increases. This includes restorative, periodontal, and endodontic disease. Since xerostomia is an expected complication, it is especially important that preradiation dental care strategies to permanently reduce the impact of the complications of severe xerostomia and xerostomia decay are sought. In addition, three radiation-specific issues emerge:
1. 2. 3. Radiation injury is oral tissue-specific and is dependent on dosage and portals of therapy. Duration of radiation-induced oral mucositis typically extends for 6 to 8 weeks, versus the approximate 5 to 14 days observed in chemotherapy patients. The extended radiation treatment protocols are chiefly responsible for this difference. The primary cause of oral cancer is tobacco use; alcohol abuse further escalates risk. It is therefore critical that the head/neck cancer patient permanently cease tobacco use. (Refer to the PDQ summary on Smoking Cessation and Continued Risk in Cancer Patients for more information.)

y y y

Most patients with smoking-related cancer appear motivated to quit smoking at the time of cancer diagnosis. Continued smoking substantially increases the likelihood of recurrence or occurrence of a second cancer in survivors, particularly in those who previously received radiation therapy. A stepped-care approach to tobacco cessation is recommended, including direct physician advice to quit and provision of basic information to all patients at each contact during the first month of diagnosis, followed by more intensive pharmacologic treatment or counseling for those having difficulty quitting or remaining abstinent.

Oral Complications of Head and Neck Radiation

The oral complications of head and neck radiation can be divided into two groups based on the usual time of their occurrence: acute complications occurring during therapy or late complications occurring after radiation therapy has ended. Acute complications include oropharyngeal mucositis, sialadenitis and xerostomia, infections (primarily candidiasis), and taste dysfunction; occasionally tissue necrosis can be seen late during therapy, but this is relatively rare. Chronic complications include mucosal fibrosis and atrophy, xerostomia, xerostomia caries, infections (primarily candidiasis), tissue necrosis (soft tissue necrosis and osteonecrosis), taste dysfunction (dysgeusia/ageusia), muscular and cutaneous fibrosis,[1] and dysphagia.[2]
Early infections

Candidiasis is the most common clinical infection of the oropharynx in irradiated patients. Patients receiving head and neck radiation are frequently colonized with Candida, as demonstrated by an increase in quantitative counts and rates for clinical infection.[13] Candidiasis may exacerbate the symptoms of oropharyngeal mucositis. Treatment of oral candidiasis in the radiation patient has primarily utilized topical antifungals such as nystatin and clotrimazole. Compliance can be compromised secondary to oral mucositis, nausea, pain, and difficulty in dissolving nystatin pastilles and clotrimazole troches. Use of systemic antifungals including ketoconazole and fluconazole to treat oral candidiasis has proved effective and may have advantages over topical agents for patients experiencing mucositis. Bacterial infections may also occur early in the course of head/neck radiation and after appropriate diagnosis (i.e., culture and sensitivity tests) should be treated with antibiotics. Herpesvirus infections may also occur in patients who are seropositive prior to head and neck radiation.[14,15]
Taste dysfunction

As oral and pharyngeal mucosa are exposed to radiation, taste receptors become damaged and taste discrimination becomes increasingly compromised.[16,17] After several weeks of radiation, it is common for patients to complain of no sense of taste. It will generally take upwards of 6 to 8 weeks after the end of radiation therapy for taste receptors to recover and become functional. Zinc sulfate supplements (220 mg 2 or 3 times a day) have been reported to help with recovery of the sense of taste.[18-20]
Late reactions

Late oral complications of radiation therapy are chiefly a result of chronic injury to vasculature, salivary glands, mucosa, connective tissue, and bone.[21,22,18] Types and severity of these changes are directly related to radiation dosimetry, including total dose, fraction size, and

duration of treatment. Mucosal changes 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 for osteonecrosis.
Caries

Dental-caries risk 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 further information).[18] 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 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 not able 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. Due to 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.
Tissue necrosis

Necrosis and secondary infection of previously irradiated tissue is a serious complication for patients who have undergone radiation for head and neck tumors.[18] 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 is 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. As noted above, risk for necrosis is directly related to radiation dose and volume of tissue irradiated. The unilateral vascular supply to each half of the mandible results in osteonecrosis most frequently involving the mandible versus the maxilla. Presenting clinical features include pain, diminished or complete loss of sensation, fistula, and infection. Pathologic fracture can occur as the compromised bone is unable to appropriately undergo repair at the involved sites.

Risk for 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 risk for osteonecrosis for life, with an overall risk of approximately 15%. Ideally, osteonecrosis management centers on prevention that begins with comprehensive oral and dental care prior to radiation. 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 post radiation. Oral disease should be eliminated prior to cancer therapy. Dentition that exhibits poor prognosis and is within high-dose fields should be extracted prior to radiation therapy. Ideally, at least 7 to 14 days should be allowed for healing prior to initiation of radiation; some have suggested allowing up to 21 days. Surgical technique should be as atraumatic as possible and utilize primary wound closure. Patients who develop osteonecrosis should be comprehensively managed to include elimination of trauma, avoidance of removable dental prosthesis if the denture-bearing area is within the osteonecrotic field, assurance of adequate nutritional intake, and discontinuation of 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 sequestrae may be possible. Hyperbaric oxygen therapy (HBO) is recommended for management of osteonecrosis, 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 hyperbaric oxygen therapy are recommended. Unfortunately, HBO technology is not always accessible to patients who might otherwise benefit because of a lack of available units and the high price of care. Partial mandibulectomy may be necessary in severe cases of osteonecrosis. The mandible can be reconstructed to provide continuity for esthetics and function. A multidisciplinary cancer team including oncologists, oncology nurses, maxillofacial prosthodontists, general dentists, hygienists, and physical therapists is appropriate for management of these patients.
Mandibular dysfunction

Musculoskeletal syndromes may develop secondary to radiation 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 including mandibular stretching exercises as well as use of prosthetic aids designed to reduce severity of fibrosis. It is important that these approaches be instituted prior to trismus development. If clinically significant changes develop, several approaches including stabilization of occlusion, trigger point injection and other pain management strategies, muscle relaxants, and/or tricyclic medications can be considered.
Candidiasis is the most common oral infection during treatment for oral cancer, although other mycotic, bacterial, or viral infections are possible. Prophylactic or therapeutic topical and/or systemic antifungal agents are necessary to control candidiasis. Selection of an antifungal agent must consider the patient's degree of xerostomia and possible inability to dissolve a troche. Also of concern is the patient's level of oral hygiene and the risk associated with high levels of sucrose in topical preparations. The addition of chemotherapy to the treatment protocol may increase the severity of mucositis, xerostomia, and infection; it also increases the risk of bacterial and herpetic infections.

Because of the high probability of mucositis and infection, their potential severity, and their nutritional consequences, the radiation or chemotherapy patient needs comprehensive management protocols, particularly during periods of highest infection risk. Some cancer centers prescribe a cocktail preparation of antimicrobials, a steroid, a coating agent, and a topical anesthetic. However, the effectiveness of such preparations is empirically based and needs to be examined in a well-controlled clinical study. Salivary Gland Dysfunction Directing radiation therapy to the salivary glands or administering chemotherapeutic, antiemetic, or psychotropic drugs may alter salivary gland function. Chemotherapy does not typically cause chronic salivary gland changes; in contrast, high-dose ionizing radiation delivered to major glandular sites can cause permanent salivary gland dysfunction. The degree of oral dryness (xerostomia) will vary by the extent of salivary gland injury. These changes can exacerbate oral infection risk at various sites, including the mucosa and periodontium. Xerostomia may also affect mastication, speech, and the patient's overall quality of life. Unfortunately, there are few effective preventive or palliative interventions for xerostomia. Frequent oral rinses with water or saline and commercial saliva substitutes may be minimally helpful, as may salivary stimulants such as sugarless candies and gum. Currently, no saliva substitute exists that can (7-9) adequately replace the organic and biologic constituents of saliva. However, two studies that examined the effectiveness of oral pilocarpine as a sialogogue in irradiated patients with residual functional salivary gland tissue demonstrated its efficacy and safety; pilocarpine is now approved by the FDA for treating hyposalivation. However, the practitioner must be aware of its potential side effects and contraindications. Symptoms of dry mouth do not necessarily correlate with quantitative or qualitative changes in saliva. Some patients receiving highdose radiotherapy to major salivary glands may experience reduced saliva production but perceive an improvement in function over time after cessation of therapy. Despite improvement in symptoms, however, saliva production in these patients may continue to be (10,11) impaired, with reduced levels of antimicrobial proteins secreted. Thus, these patients will be at high risk for aggressive caries formation, demineralization, and periodontal disease for the balance of their lives. In addition, because mucous secretions from minor salivary glands are often unaffected, patients frequently complain of thick, ropey saliva. Comprehensive long-term preventive oral hygiene and dental follow-up are needed. (12,13) Dysgeusia Both chemotherapy and radiation therapy patients can experience disturbances in taste. Mechanisms for this sensory disturbance are often complex and range from direct molecular effects on acinar cell function to conditioned aversions to selected foods. Compositional and/or flow rate changes in saliva may also contribute to the symptom, although underlying mechanisms are not clearly established. Direct chemotherapy or radiotherapy injury to taste buds may produce partial (hypogeusia) or absolute (ageusia) taste loss. Taste buds may regenerate about 4 months after cessation of therapy, and normal taste function may resume. Given the complex interplay between physico-chemical and psychologic alterations, however, this recovery may not occur. Patients should be counseled as to realistic outcomes and give ongoing dietary consultation as well as programs to resolve food (14) aversions that may have emerged during cancer therapy. High-dose zinc supplementation has helped some patients. Nutritional Complications Radiation, chemotherapy, or surgery can impair nutrition through a variety of mechanisms. 15 Maintenance of appropriate levels of nutritional support is essential; indeed, many cancer patients are underweight at diagnosis and lose weight during therapy. Nutritional complications stem from altered taste sensations, ageusia, anorexia, food aversion, pain, xerostomia, and dysphagia. Inadequate intake of calories leads to weight loss, weakness, and (16) malaise. Tumor factors responsible for anorexia include direct tumor utilization of metabolites. Release by the tumor of chemical moieties that produce protein loss and negative nitrogen balance has also been hypothesized to contribute to cachexia. Finally, nutritional complications may be caused by lack of access to appropriate reconstructive techniques and rehabilitation, leaving the patient without complete masticatory restoration. Dental Caries and Periodontal Disease Patients receiving adjuvant chemotherapy for management of disseminated oral cancer are not typically at high risk for chemotherapy-induced progressive compromise of the dentition and periodontium. However, the compliance of such patients with oral hygiene protocols and nutrition guidelines may be deficient. Such limitations can produce extensive oral disease patterns. Patients whose major and minor salivary glands have been exposed to therapeutic doses of ionizing radiation are at significant risk for progression of oral infections and demineralization, even if routine oral management strategies are utilized. Several covariates, including salivary function, nutrition, medications, parafunctional habits, tobacco habits, and compliance with comprehensive oral

care protocols that include remineralizing solutions and fluoride use, collectively interact and produce either a stable or regressive oral disease profile. These diseases are caused by infecting pathogens, with consequences that include hard or soft oral tissue destruction, pain and bleeding, and systemic sequelae consistent with infection progression. Osteoradionecrosis Ionizing radiation can lead to osteoradionecrosis (ORN), a complication that results from compromised vascularity following surgery or from radiation-induced hypovascularity, as well as from cytotoxic effects on bone-forming cells and tissue, hypocellularity, and hypoxia of affected (17-21) bone. The risk of ORN increases over time following completion of radiation dosing and is present through the lifespan. Complications associated with ORN include intractable pain, drug dependency, pathologic fractures, oral and cutaneous fistulas, and loss of large areas of bone and soft tissue. (22) The incidence of ORN is quite variable and depends mostly on the aggressiveness of radiation (17) therapy; reported incidence ranges from 2% to 40%. Although trauma (e.g., dental extraction or scaling, denture irritation, periodontal disease) can initiate ORN, the etiologies of many cases are not identified. Managed unsuccessfully, ORN can have serious consequences, including progressive pain, trismus, and, eventually, loss of major segments of the jaw bone. Ideal management of ORN calls for eliminating potentially riskful foci of oral disease prior to instituting radiation therapy. This approach requires a multidisciplinary team, which conducts comprehensive treatment planning well in advance of the cancer therapy. (See Table 2 for a list of evaluation and management issues.) Intact teeth can be preserved under certain conditions, such as when the patient is highly motivated toward maintaining ideal oral health and receiving comprehensive dental care. Conversely, compromised teeth in the poorly compliant patient should be extracted at least 10 days prior to radiation. However, the patient's disease state may change the timing of (23) extraction. Realistic clinical judgment combined with comprehensive management is the best tool for preventing osteoradionecrosis. Table 2: Evaluation and Management Issues Prior to Surgery and Radiotherapy extraoral head and neck exam complete intraoral exam proposed surgical defects radiographic evaluation oral hygiene previous dental or oral hygiene compliance status of dentition and periodontium Management of ORN with antibiotics and surgical debridement is not always successful. Courses of hyperbaric oxygen to facilitate healing of compromised bone may be helpful when combined with appropriate surgery and antibiotics. However, because this treatment is expensive and offered by only a limited number of facilities, many patients will not be able to take advantage of it. Trismus Alterations Ionizing radiation can also cause obliterative endoarteritis with associated tissue ischemia and fibrosis. This process can contribute to development of trismus if the masticatory muscles are within the portals of radiation. As treatment of trismus can be very difficult, preventive management with jaw exercises using tongue blades and other devices is recommended when signs of this disorder occur. Psychosocial Impact Functional and aesthetic changes may profoundly affect a patient's psychic and social status. The clinician should give these factors serious consideration in pre-treatment consultation and post operative rehabilitation. Failure to do so may have critical consequences for the patient's later quality of life in socioeconomic areas as well as in personal relationships and lifestyles. (24) B. Emerging Trends A number of emerging trends in the management of head and neck cancer may directly affect complications of therapy by altering treatment approaches in ways that will selectively protect normally functioning tissues. To assure effetive use of new approaches, organizations such as the American Cancer Society (ACS) have for years promulgated the principle of multidisciplinary care for the cancer patient, including those with head and neck malignancies (see the discussion of treatment and the multidisciplinary tumor board concept in Chapter VI). temporomandibular dysfunction parafunctional habits baseline salivary flow diet and medication analysis tobacco and alcohol habits psychosocial impact of treatment

C. Opportunities and Barriers to Progress There are several approaches to improving the management of patients with oral cancer, including professional and public education, increased multidisciplinary management, and applied and laboratory-based research. However, the current situation is not promising because of:

y y y y

limited attention in medical, dental, dental hygiene, and nursing curricula to the oral complications of cancer therapy limited patient education about the need to comply with preventive or therapeutic oral interventions declining availability of both public and private research funding lack of trained basic and applied research directed specifically at management of oral complications.

Currently, there is a great need to develop tools to assess and prevent oral mucositis. Over the past 5 years, the standard for oral mucosa assessment tools has changed from a simplified, global scale to a more complex scale that assesses changes in multiple qualities of oral status that collectively contribute to mucositis severity. Future research must be directed to developing instruments that: (1) eliminate subjectivity in assessing and classifying oral complications; (2) measure oral toxicities with high degrees of specificity and sensitivity relative to the pathologic process under investigation; (3) take little time and are cost-effective to administer; and (4) can be tolerated by the patient with severe mucositis. Such instruments are essential to assess whether new technologies can reduce the severity of radiation- or chemotherapy-induced mucositis. At present, clinical studies are needed to develop mechanisms for increasing patient compliance with recommended long-term care and preventive measures. The effect that cultural, sociologic, and psychologic factors have on compliance also needs investigation (see Chapter IX). Current deficits in professional knowledge frequently stem from a failure to understand that communication between the medical and dental teams is essential. Although some cancer centers have integrated medical, nursing, dental, and dental hygiene management of the patient, a number of university-based and most community-based oncology programs have not done so. Yet, the complex management of the oral cancer patient mandates multidisciplinary care; unless the relevant professional groups communicate successfully, patient care may suffer. More research on managing the patient with mucositis and xerostomia is also needed. Protocols to manage mucositis should be tested in clinical studies. Additional research is also needed on slow release techniques for the drug oral pilocarpine that might minimize its side effects while maximizing its therapeutic effect. Long-term studies are also needed to evaluate reconstructive techniques, including their effect on dental function, to prevent nutritional complications and ensure full rehabilitation (see Chapter VIII). Finally, outcome assessments are necessary to evaluate the impact of treatment and non-treatment on long-term results and quality of life. Information from these assessments will be useful in allocating research dollars and establishing protocols for care. Eating and swallowing issues - dysphagia

You are here: Home > Treatment > Complications of treatment > Eating and swallowing issues - dysphagia Difficulty eating and swallowing fooddysphagiacan have a significant impact on a patient's life after radiation treatment and surgery. Consuming enough nutrition is critical to a your ability to recover from surgery and tolerate life saving treatments. Recognizing this disorder early allows you and your doctor to implement an effective treatment plan. In the long term, patients may experience some permanent eating and swallowing disability as a result of treatment, but in many cases this can be treated or compensated for. Oropharyngeal dysphagia is a swallowing problem that happens before food reaches the esophagus and may result from neuromuscular disease or obstructions. Patients experience difficulty starting a swallow, food goes down the wrong pipe, or there is choking and coughing. This may result in poor nutrition or dehydration, aspiration (accidentally sucking food into the lungs during swallowing, which can lead to pneumonia and chronic lung disease) or embarrassment in social situations that involve eating... http://www.mayoclinic.org/swallowing-problems/index.html The following information is heavily drawn from an original CE course written by Joy E. Gaziano, MA, CCC-SLP. For the original version of the article click here

Evaluation and Management of Oropharyngeal Dysphagia in Head and Neck Cancer Introduction Dysphagia, derived from the Greek phagein, meaning "to eat," is a common symptom of head and neck cancer and can be an unfortunate sequelae of its treatment. Dysphagia is any disruption in the swallowing process during bolus transport from the oral cavity to the stomach. In head and neck cancer patients, dysphagia may be caused by surgical ablation of muscular, September/October 2002, Vol. 9, No. 5 Cancer Control 401 bony, cartilaginous, or nervous structures or may be attributable to the effects of antineoplastic agents including radiation and/or chemotherapy. The severity of the swallowing deficit is dependent on the size and location of the lesion, the degree and extent of surgical resection, the nature of reconstruction, or the side effects of medical treatments. Evaluation and treatment of swallowing disorders present unique challenges to the speech pathologist working with the head and neck cancer population. Successful management requires interdisciplinary collaboration, accurate diagnostic workup, effective therapeutic strategies, and consideration for unique patient characteristics. Normal Swallowing Function Swallowing is a complex series of sequential neuromuscular events that are integrated into a smooth and continuous process. To appreciate the potentially devastating effects of oral cancer on swallowing, it is helpful to understand normal anatomy and physiology. Generally, the process is divided into three stages: oral, pharyngeal, and esophageal. The oral phase is completely voluntary and involves the entry of food into the oral cavity and preparation for swallowing; this includes mixing with saliva, mastication, and formation into a cohesive bolus in preparation for the swallow. It requires coordination of the lips, tongue, teeth, mandible, and soft palate. The pharyngeal phase is initiated as the tongue propels the bolus posteriorly and the base of tongue contacts the posterior pharyngeal wall, eliciting a reflexive action that begins a complex series of events. The soft palate elevates to prevent nasal reflux. The pharyngeal constrictor musculature contracts to push the bolus through the pharynx. The epiglottis inverts to cover the larynx and prevent aspiration of contents into the airway. The vocal folds adduct to further prevent aspiration. The hyolaryngeal complex moves anteriorly and superiorly, which, in combination with the pressure generated by a bolus, provides anterior traction and intrabolus pressure to open the cricopharyngeus. The esophageal phase is completely involuntary and consists of peristaltic waves that propel the bolus to the stomach. Total swallow time from oral cavity to stomach is no more than 20 seconds. Cranial nerve function is often interrupted in surgical resection of head and neck tumors. Swallowing deficits may result when any one or more of five cranial nerves are affected. The trigeminal nerve (CN V) controls general sensation to the face and motor supply to the muscles of mastication. The facial nerve (CN VII) controls taste to the anterior two thirds of the tongue and motor function to the lips. The glossopharyngeal nerve (CN IX) provides general sensation to the posterior third of the tongue and motor function to the pharyngeal constrictors. The vagus nerve (CN X) provides general sensation to the larynx and motor function to the soft palate, pharynx, larynx, and esophagus. The hypoglossal nerve (CN XII) controls motor supply to the intrinsic and extrinsic muscles of the tongue. Evaluation of Dysphagia in Head and Neck Cancer A comprehensive evaluation of dysphagia should include several medical disciplines including the surgeon, medical oncologist, radiation oncologist, speech pathologist, radiologist, and dietitian. While each has a role to play, it is usually the speech pathologist who conducts a clinical or instrumental assessment of swallowing function and makes recommendations for therapeutic intervention. A thorough examination begins with a clinical swallow assessment that includes a detailed history of subjective complaints and medical status, pertinent clinical observations, and a physical examination. Swallowing trials can be initiated with a range of food textures. An oromotor examination assesses the function of the oral structures for swallowing. Blue dye testing can be utilized with patients who are tracheostomized to accurately determine the relative risk of aspiration. Cervical auscultation uses a stethoscope on the larynx to detect the sounds of swallowing and respiration. The goals of a clinical assessment are screening for the presence of dysphagia, contributing information as to the possible etiology of the impairment, determining the relative risk of aspiration, ascertaining the need for non-oral nutrition, and recommending additional assessment procedures. Several instrumental assessments of swallowing exist to provide objective information about swallowing function and safety. The most widely used procedure is a video fluoroscopic assessment of swallowing. It is performed in the radiology department by a radiologist and speech pathologist. Benefits include the ability to view the complex interaction of the phases of swallowing, describe the anatomy changes and dynamics of the swallow, identify the etiology of aspiration, and assess the benefit of treatment strategies during the study. The modified barium swallow is thought to be the "gold standard" for assessment of swallowing. However, the fiberoptic endoscopic evaluation of swallowing (FEES) is a useful tool in the assessment of swallowing in the head and neck cancer patient. It consists of passing a thin, flexible endoscope into the pharynx and observing the act of swallowing. It provides excellent visualization of post surgical or post radiation anatomical changes. It can also be used as biofeedback to retrain swallowing function. Scintigraphy, manofluorography, and ultrasound, have all been used as methods of assessment. However they are generally used as an adjunct to modified barium swallow or FEES rather than an alternative. Instrumental assessment of swallowing in the head and neck cancer population provides useful information about both the structure and function of the swallowing mechanism. Patients with oral cavity lesions generally demonstrate swallowing symptoms specific to

bolus preparation, containment, and posterior movement to the pharynx. Oral phase deficits that can be identified using the modified barium swallow include insufficient lip seal, impaired mastication, poor bolus control, oral stasis, premature leakage of foods to the pharynx, and structural abnormalities. Tumors located in the oropharynx and/or pharynx may demonstrate a delayed or absent swallow response, reduced pharyngeal contraction, reduced epiglottic inversion, decreased laryngeal elevation, or diminished or uncoordinated cricopharyngeal sphincter relaxation (Fig 1). Laryngeal penetration or tracheal aspiration may occur as a result of the aforementioned deficits. Swallowing evaluation using FEES provides information regarding the structure and functions of the pharyngeal phase of swallowing. It offers optimal visualization of the tumor, reconstructed anatomy, and associated treatments, as well as their effects on swallowing. FEES also allows assessment of palatal function in patients with palatal resections and assists the maxillofacial prosthodontist in developing palatal obturators. It also permits inspection of secretion management, a known indicator of swallowing safety. Effects of Radiation on Swallowing External-beam radiation has both early and late side effects that can impact swallowing function. Early effects include xerostomia (dry mouth), erythema superficial ulceration, bleeding, pain, and mucositis, which is a painful swelling of the mucous membranes lining the digestive tract . These usually result in oral pain that may cause only minimal diet alterations, require prescription of pain medications, or necessitate reliance on non-oral nutrition. Hypopharyngeal stricture (a narrowing of the pharyngeal structure as a side effect of the radiation) may require dilation or surgery (Fig 3). Xerostomia is a side effect of treatment that persists for years and may worsen over time. Late radiation effects may include osteoradionecrosis (a condition where irradiated bone and surrounding tissues lose their reserve reparative capacity and start to degenerate ), trismus (lockjaw), reduced capillary flow, altered oral flora, dental caries, and altered taste sensation. The late effect of reduced blood supply to the muscle can result in fibrosis, reduced muscle size, and the need for replacement with collagen. This can dramatically affect swallowing years after treatment with a fixation of the hyolaryngeal complex, reduced tongue range of motion, reduced glottic closure, and cricopharyngeal relaxation, resulting in potential for aspiration. Specific swallowing exercises have been shown to reduce these effects and improve prognosis for oral intake. These include jaw range of motion, tongue base range of motion exercises, and effortful swallow exercises, tongue holding maneuver, Mendelsohn maneuver, and super supraglottic swallow. Patients are encouraged to practice these exercises daily during and after treatment since effects of chemoradiation can occur long after treatment completion. As new delivery methods of radiation therapy are developed, such as shielding and intensity modulation, the negative effects of treatment should be reduced. The speech pathologist, as part of the interdisciplinary team, should provide patient education about strategies to reduce the effects of radiation on swallowing. These strategies may include optimal oral hygiene, avoidance of alcohol and tobacco, decreased caffeine consumption, adequate hydration, avoidance of irritating food tastes or textures, and use of artificial saliva or saliva replacement medication. If dental caries are present, dental interventions such as full mouth extractions are considered prior to radiation therapy. Otherwise, daily mouth care, use of topical fluoride, and avoidance of foods that induce dental pain are recommended. In cases of severe osteoradionecrosis, patients are usually converted to a puree diet, liquid nutritional supplements are encouraged, and tube feeding may be required. Effects of Chemotherapy on Swallowing Chemotherapeutic agents for head and neck cancer can also cause side effects that impact swallowing and nutrition. They can cause nausea, vomiting, neutropenia, generalized weakness, and fatigue. Anorexia and weight loss are common. Mucositis may cause sufficient pain to require non-oral supplementation. The incidence rate of mucositis has been reported to be approximately 40% for chemotherapy patients; however, it approximates 100% in patients receiving chemoradiation. Symptomatically, mucositis manifests itself in odynophagia (pain) during mastication and swallowing, oral bleeding, dysphagia, dehydration, heartburn, vomiting, nausea, and sensitivity to salty, spicy, and hot/cold foods. Stomatitis refers to chemotherapy-related oral cavity ulcers that result in eating difficulty. The cytotoxic agents most commonly associated with oral, pharyngeal, and esophageal symptoms of dysphagia are the antimetabolites such as methotrexate and fluorouracil. The radiosensitizer chemotherapies, designed to heighten the effects of radiation therapy, also heighten the side effects of the radiation mucositis. Considerable attention has been given to both prophylactic and treatment measures to counteract the adverse side effects of these medications. Prophylactic measures begin with an increased emphasis on improved oral hygiene. Oral cryotherapy, the therapeutic administration of cold, is a prophylactic measure for oral inflammation. Cryotherapy can be provided in the form of ice chips just prior to chemotherapy and for 30 minutes after drug administration. A marked decrease in the incidence of stomatitis has been noted in patients utilizing cryotherapy. Therapeutic measures to control mucositis and stomatitis include the use of anesthetics, analgesics, anti-inflammatory agents, antimicrobial therapy, and coating agents. Anesthetics are usually used in tandem with mouthwashes or rinses. An oral suspension of diphenhydramine, lidocaine, and an antacid (Maalox) called "magic mouthwash" can be prescribed, which is swished and swallowed for symptom management. Effects of Surgical Resection Oral Cavity

Cancers in the oral cavity can cause a range of predictable but complex swallowing problems. The location, size, and extent of the tumor as well as the surgical reconstruction procedure can significantly affect the functional outcome. Groher proposed that the removal of less than 50% of a structure involved with swallowing will not interfere or seriously impact swallowing function. However, Sessions et al showed that the size of the lesion excised was less a prognostic indicator than the area excised and that resultant dysphagia could be predicted in cases of base of tongue and arytenoid cartilage resections. Another complication that may affect swallowing function is the loss of sensation that accompanies the interruption of nerve function with surgery. The use of nonsensate flap closures may interfere with the normal sensation needed to guide the bolus through the oropharynx for efficient swallowing. Additionally, tissue flaps have no motor function resulting in the loss of propulsive force. They also may obstruct bolus passage if they are large and bulky. Studies show that resections of up to one third of the tongue result in only transitory swallowing problems. Optimal function is achieved when lesions of the anterior tongue are treated with composite resection and when neural control and some tongue movement are preserved. If tongue tethering to the floor of mouth or hypoglossal nerve involvement occurs, the swallowing deficits will be more severe. They may consist of problems with chewing, controlling food in the mouth, and initiating a swallow. Patients undergoing total glossectomy can regain functional swallowing. However, if glossectomy is combined with anterior mandible resection, recovery is poorer because the patient cannot adequately elevate the larynx, which impacts cricopharyngeal opening. Outcome studies show that patients with oral tongue resections that are uncomplicated by involvement of other structures can regain oral nutrition 1 month post-healing. However, a significant percentage of patients must undergo more extensive resections to achieve adequate cancer control. If the tumor is located in the posterior oral cavity including the base of tongue, soft palate, retromolar trigone or tonsillar fossa, surgical excision usually will cause more severe dysphagia. The tongue base plays a critical role in initiating the swallow, propelling the bolus through the pharynx, and efficient pharyngeal peristalsis. Any procedure that minimizes the tongue base to posterior pharyngeal wall contact can result in reduced pressure generation causing pharyngeal stasis post-swallow, delayed initiation of the swallow resulting in aspiration before the swallow, or reduced hyolaryngeal elevation causing pharyngeal stasis and post-swallow aspiration. Resections of the tongue and hard palate result in loss of pressure needed to propel the bolus into the pharynx. Combined resection of the soft palate and tonsillar pillars may impact bolus transport through the oral cavity and pharynx causing nasopharyngeal reflux and pharyngeal stasis. Patients undergoing glossectomy and submental resections have reduced tongue propulsion and lip sensation. Sacrifice of the hyomandibular constrictors reduces the protective tilting action of the larynx with potential for significant aspiration. Total glossectomy with bilateral neck dissections has a poor swallowing outcome unless the superior laryngeal nerve, hyoid bone, and epiglottis remain intact. Pharynx Resection of cancer in the pharynx, including the pharyngeal wall, valleculae, or pyriform sinus, can result in significant dysphagia. The peristaltic contraction begins superiorly and courses inferiorly. Any disruption of the muscular contraction may cause food to coat the pharynx. The larger the pharyngeal resection, the greater the pharyngeal residue. Additionally, surgery that affects the lateral pharynx may cause fixation of the larynx so that it cannot elevate during swallowing. If this occurs, epiglottic inversion is compromised and laryngeal penetration or tracheal aspiration can occur. Scar tissue in the pharynx can also reduce laryngeal elevation. Larynx The laryngeal complex serves two critical functions during swallowing. First, the larynx elevates and moves anteriorly under the tongue base to move it from the path of the bolus and to assist in cricopharyngeal sphincter opening. Second, it protects the airway from aspiration by closing at three levels -- the epiglottis, false vocal folds, and true vocal folds. Any surgery that compromises this closure, especially of the true vocal folds, will likely result in aspiration during the swallow. Supraglottic laryngectomy can interfere with laryngeal elevation and sometimes vocal fold adduction. If a laryngeal suspension procedure is performed during reconstruction, laryngeal elevation is improved and swallowing is safety enhanced. If a supraglottic laryngectomy procedure encompasses more that the traditional procedure and includes portions of the hyoid bone, base of tongue, aryepiglottic folds, or false vocal folds, prognosis for swallowing recovery is diminished. Patients undergoing vertical hemilaryngectomy generally display reduced laryngeal closure due to the loss of one half of the larynx. If the procedure is limited to a unilateral true and false focal fold, then swallowing recovery is possible with a combination of increased effort during laryngeal adduction and compensatory head posturing. If the hemilaryngectomy extends to the opposite vocal fold, then swallowing recovery is prolonged and may require an exercise program to improve adduction or an augmentation or medialization procedure. Patients undergoing total laryngectomy have few swallowing problems following surgery due to the permanent separation of the trachea and esophagus. However, occasionally the laryngectomee may have problems propelling the bolus through the oral cavity and pharynx as a result of the loss of hyoid bone, which is the anchor for the tongue. Increased pressure in the pharyngoesophagus following laryngectomy requires the tongue to move with greater force. Stricture at the anastomosis may cause narrowing and reduced bolus flow through the pharynx. Pseudoepiglottis, a postsurgical fold of tissue from the pharynx at the level of the base of tongue, may serve as a mechanical barrier to efficient bolus flow and trap food in its pocket. Swallowing and Postoperative Radiation

While the extent, type, and location of the surgical resection play a major role in determining swallowing outcomes, the effects of postoperative radiation also may impact swallowing rehabilitation. Irradiated patients have significantly reduced oral and pharyngeal functions including longer oral transit times, increased pharyngeal residue, and reduced cricopharyngeal opening times. Impaired function may be the result of radiation effects such as edema, fibrosis, and reduced salivary flow. Delayed healing and fistula development are more common in radiated tissue. Goals of Swallowing Rehabilitation There are several goals in swallowing rehabilitation. The primary goals are to prevent malnutrition and dehydration and reduce the risk of aspiration. Re-establishment of safe and efficient oral intake, prevention of dysphagia prior to medical treatment, and patient education regarding the specifics of their disorder are also important goals of intervention. Pretreatment counseling is beneficial in addressing the possibility that dysphagia may develop during or after the completion of the planned treatment. Poorly prepared patients may become frustrated when attempting to feed and thus may fail to ingest enough to maintain adequate nutrition and hydration. Individuals can be given strategies, recommendations, or exercises prophylactically to reduce the chances of developing a problem. Researchers are currently investigating the benefits of pre radiation exercise. Treatment for post surgical cases usually begins once the surgeon indicates the patient has healed sufficiently, usually 5 to 10 days post surgery. Patients on chemoradiation protocols may receive swallowing therapy during treatment, but often the development of mucositis results in oral pain and prohibits exercise or significant oral intake until after it is resolved. Swallowing therapy can be initiated years after cancer treatment, since the effects of chemoradiation can occur long after treatment is completed. Treatment Strategies for Dysphagia For those patients who have undergone surgical resection or organ preservation protocols for head and neck cancer and who are unable to resume functional swallowing, several treatment options are available. Treatment strategies should be introduced during the video fluoroscopic evaluation to determine the effectiveness of the strategy prior to implementation. Several categories of interventions exist including postural changes, sensory procedures, maneuvers, diet changes, physiologic exercise, and orofacial prosthetics. Used alone or in combination, these options can be extremely successful in returning a patient to safe and efficient oral intake. Postural strategies are simple techniques designed to alter the bolus flow. A chin down posture improves base of tongue contact to the posterior pharyngeal wall, opens the vallecular space, and puts the larynx in a more protected position. Head rotation to the damaged side closes off a weakened pharynx and allows bolus passage down the intact contralateral side. Head tilt to the intact side provides gravity assist in bolus flow through the oral cavity and pharynx. A side lying position may be useful in a delayed swallow or with poor airway protection as it slows the flow of the bolus through the pharynx. Combinations of these strategies can be used with an additive effect. Sensory procedures provide altered sensory feedback or sensory enhancement during swallowing. Alterations in bolus volume, taste, and temperature can be used to affect changes in swallowing physiology. For example, cold and added pressure (thermaltactile stimulation) have been shown to increase the speed of initiation of the swallow response. Added pressure on the tongue by a utensil also increases sensory feedback. Since chewing sends sensory information to the pharynx, a soft masticated diet should be utilized when possible. Finally, the sensory motor integration achieved during self-feeding helps to normalize swallow patterns. Therefore, patients should feed themselves whenever possible. Extensive data exist regarding the efficacy of swallowing maneuvers in the head and neck population. They are designed to alter the physiology of the swallow. The supraglottic swallow maneuver closes the vocal folds before and during the swallow. The effortful swallow improves tongue base retraction and pressure generation. The Mendelsohn maneuver enhances and prolongs laryngeal elevation and anterior movement to improve laryngeal elevation and extent and duration of cricopharyngeal opening. The tongueholding maneuver improves the tongue base to posterior pharyngeal wall contact and exercises the glossopharyngeal muscle. Dry or repeated swallows reduce pharyngeal residues. Diet alterations and food presentation strategies also can be use therapeutically to improve efficiency and safety of swallowing. Thickening liquids may slow the rate of bolus flow through the pharynx for patients with a delayed swallow. A puree diet can be used if surgical resection or trismus prevents chewing. Foods prepared with sauces and gravies may be useful for a xerostomic patient. Alternating solids and liquids can reduce pharyngeal stasis. Liquids can be presented by cup, straw, spoon, or syringe, depending on specific patient needs. Chopsticks or an iced teaspoon can place foods in the posterior oral cavity. A glossectomy spoon is specially designed to push food into the pharynx, bypassing the oral phase of swallow. Food placement on the surgically unaffected side can increase efficiency and safety as well. All of these dietary changes can be used in combination with postural alterations and swallow maneuvers at mealtime. Range of motion exercises for the jaw, lips, oral tongue, tongue base, upper airway closure, and laryngeal elevation are useful for head and neck cancer patients who have structural or tissue damage. Resistance exercises are used for strengthening musculature. Exercises can be enhanced with new technology and devices. The Therabite (Therabite Corp, West Chester, Penn) improves jaw range of motion in patients with trismus (Fig 4). The Swallowing Workstation (Kay Elemetrics Corp, Pine Brook, NJ) provides biofeedback for a range of treatment applications (Fig 5). Surface electromyography (EMG) biofeedback provides visual and auditory feedback for added motivation and success during therapy. Surface EMG combined with respiratory tracing can provide

feedback on the coordination between respiration and swallowing. Video endoscopy can be used to view vocal fold closure associated with swallowing. Intraoral tongue array sensors provide visual biofeedback during tongue-strengthening exercises.

Figure 4. The Therabite rehabilitation system improves jaw range of motion in patients with trismus. Copyright Therabite Corp, West Chester, Pa. Reprinted with permission.

Oral prosthetics can offer structural support and compensation to oropharyngeal structures that were lost or altered post surgery. Palatal lowering prostheses recontour or lower the palate to allow the remaining portion of the resected tongue to contact the palate when swallowing. Obturators can fill a palatal defect, preventing food leakage into the nasal cavity and establishing more normal intraoral pressure. Use of these devices can significantly reduce oral residue. The speech pathologist collaborates with the maxillofacial prosthodontist to provide feedback on the configuration, use, and benefits of the prosthesis. Nutritional Issues Nutritional changes related to dysphagia are another concern for patients with head and neck cancer. The side effects of treatment can contribute to malnutrition and dehydration in head and neck cancer patients. Cancer patients have the highest incidence of protein calorie malnutrition of all hospitalized patients. Approximately one third of patients with advanced head and neck cancers are severely malnourished and another third of them experience mild malnutrition. The degree of malnutrition is related to the patient's nutritional status before tumor development, to the characteristics of the tumor, and to the cancer treatment itself. Aggressive cancer treatments may worsen the severity of nutritional status. In severe cases, interruption or discontinuation of cancer treatment may be required. Head and neck surgery can have a negative effect on nutritional status due to loss of swallowing function and cosmetic deformities. Alterations in taste and smell may affect enjoyment and motivation to eat. The increased time required to consume a meal with a structural alteration may reduce the amount of oral intake. Diet modifications, such as a liquid-only diet, may result in reduced caloric intake. The physical effort of swallowing or the accompanying pain may also render patients unwilling or unable to meet the nutritional requirements for optimal healing. Radiation therapy can also have a deleterious effect on nutritional status. Used as a primary intervention or as an adjunct or palliation, radiation can cause xerostomia, stomatitis, mucositis, dysgeusia, dysosmia, and odynophagia. Pain from mucosal ulcerations can lead to reduced intake. Many patients develop food aversions or loss of taste sensation due to radiation-induced damage to the taste buds. Xerostomia, caused by damage to the salivary glands, may become progressively worse during and after treatment. It can be a factor in poor nutrition as a result of reduced tolerance to various food textures, temperatures, and acidities. The thick, ropey secretions that may result often interfere with adequate intake. Chemotherapeutic agents can negatively impact nutritional intake primarily as a result of its effects on the lining of the oral cavity, oropharynx, and esophagus, causing mucositis and odynophagia. Contributing to cachexia and malnutrition are the side effects of nausea and vomiting. Cisplatin, a chemotherapeutic agent frequently used in head and neck cancer management, has a high emetic potential. Diarrhea, constipation, and malabsorption also may occur. These side effects generally subside shortly after

treatment has been completed. However, without nutritional intervention, the effects of the undernourishment can be long-lasting. Combined chemoradiation can put patients at even higher nutritional risk due to the combined toxicities of the two modalities and their effects on swallowing. Although nutritional support does not directly improve survival rates, proper nutrition and hydration can improve tolerance to cancer treatments and functional outcomes. Patients also experience fewer complications and express a greater sense of well-being. Fewer rehospitalizations occur with those patients who receive early nutritional interventions and supplemental nutritional support. Interdisciplinary interventions by the dietician and speech pathologist can help to ensure that adequate nutrition is achieved by either oral or non-oral routes. Psychosocial Issues Dysphagia resulting from head and neck cancer has psychosocial implications. Patients are often unprepared for the emotions they encounter when mealtime consumption is significantly altered. The inability to participate in mealtimes and dining out as they are accustomed to can be isolating. Increased mealtimes, limited food choices, special food preparation methods, and untidy consumption contribute to avoidance of social food consumption. Family relationships can be altered when substantial lifestyle modifications are encountered. Patients may become dependent on the medical providers and family members for basic care and emotional support. After cancer recovery, patients may experience distress related to return to work and the alterations in the feeding process. Use of tube feeding, diet modifications, adaptive equipment, or rehabilitative strategies for safe and adequate intake can call attention to themselves and thus become a source of anxiety. The financial impact of dysphagia is evident in the cost of non-oral tube feeding supplementation. If patients cannot return to oral intake, the financial burden of lifelong tube feeding formula can be significant. Patients are often uninsured or under insured. Special meal preparation, equipment, and meal supplements can also contribute to added financial burden. Self-esteem can be affected when normal facial appearance or communication ability is altered by surgery. Altered facial appearance also can lead to social isolation and psychological distress. Pain and fear of disease progression or recurrence can result in physical and psychological symptoms that require interventions from psychosocial and pain management team members. Withdrawal from tobacco and alcohol throughout the treatment process also requires special interventions from the appropriate disciplines. Substance withdrawal can result in behaviors such as anxiety, irritability, and decreased cognition that can affect the success of the swallowing interventions provided by the speech pathologist. Pretreatment counseling by all team members including the speech pathologist should focus on identifying a patient's unique learning needs, cultural preferences, coping skills, support systems, and financial situation. In addition, information on substance abuse history, cognition, and communication skills will provide an understanding of the patient's ability to participate in the rehabilitation process. Compliance with treatment recommendations is also enhanced when cultural and religious practices are identified and incorporated into the plan of care. Various religions have specific regulations regarding food and food preparation. Patients of varying cultures have food preferences, cooking styles, and customs unique to that ethnic group. Pretreatment counseling about the anticipated swallowing deficits and functional outcomes should be provided. All team members play a critical role in preparing the patient and family for the head and neck cancer intervention. Post treatment psychosocial and behavioral interventions by the speech pathologist include treatment of the swallowing disorder and any resulting communication impairment. Education and support about altered body image, lifestyle changes, nutrition, and community resources are provided in close collaboration with the physician, nurse, dietician, social worker, physical therapist, pharmacist, psychiatric professional, and other pertinent team members. Participation in support groups encourages improved coping, socialization, and physical recovery. Conclusions Evaluation and management of swallowing disorders in head and neck cancer patients present unique challenges to the rehabilitation team. Evaluation of the patient must take into account not only the structure and function of the swallowing mechanism, but also the side effects that the chosen medical interventions will impose. Assessment of unique patient characteristics, including medical history, nutritional status, cultural preferences, coping style, support systems, and communication and cognitive abilities, is crucial in developing a treatment plan that will enhance functional outcomes. Treatment should be designed to improve the safety of oral intake, normalize nutritional status, reduce the complications of the cancer treatment, and enhance the quality of life. Accurate identification and efficient management of swallowing disorders are best accomplished in an interdisciplinary team environment. Radiation issues

One way in which radiation therapy kills cancer cells, is by shrinking blood vessels in the affected area. Fast growing tumor cells require more oxygen and nutrients than normal cells, and they are "oxygen starved" to death. Additionally, both radiation therapy to the head and neck and chemotherapy drugs affect the ability of cells to divide, an efficient manner in which to kill cancer cells. This however, also makes it difficult for tissues in the mouth to repair themselves in the treated sites. Therefore, people being treated with radiation therapy for head and neck tumors, frequently have side effects associated with the radiation itself, or with the decreased blood flow. The mucus membranes, or soft tissues inside our mouth and throat, are tender to this lifesaving treatment; salivary glands are especially sensitive as well. The damage to these tissues and glands depends on the amount and kind of radiation used, the total dose, and the size of the area irradiated. Damage caused by radiation therapy affects the tissues for the rest of the patient's life. These hard and soft tissues are more easily damaged after treatment has been completed, and normal methods of cell repair do not work as well once cells have been exposed to radiation. It is of extreme importance that the patient's dentist is aware and educated in the issues regarding radiation therapy. The special dental considerations surrounding posttreatment care last forever. Chemotherapy issues Chemotherapy kills cancer cells by taxing some aspects of their life cycles more than it taxes the life cycle of most normal cells. However normal cells in the body can be susceptible to the stress of chemotherapy. When the white blood cell count is lowest, oral tissues are most prone to damage. The mouth is able to recover only when the white blood cell count returns to normal. The lips, tongue, floor of the mouth, inside of the cheeks, and soft palate (the upper back of the mouth) are more affected by chemotherapy drugs than are the hard palate (the upper front of the mouth) and the gingiva surrounding the teeth. Some chemotherapy drugs are more likely to cause problems in the mouth, especially when they are given in high doses, in repeating schedules, or when given simultaneously with radiation therapy. Spicy foods, abrasive foods, and alcohol should be avoided so as not to aggravate the sore tissues, and water should be consumed in high volume to maintain the moistness of tissues and the body's fluid balance. During and shortly after chemotherapy, an oncologist should be consulted before any dental care is performed. With white blood counts and clotting factors at low levels, dental treatment should be postponed until after a blood test confirms a return to normal levels. Chemotherapy can also lead to neurotoxicity, a persistent, deep pain that mimics a toothache, but that has no dental or mucosal source. Surgical issues Patients who undergo a surgical solution to the removal of their cancer may have unique problems related to the oral structures which are now missing. While necessary in some cases, surgery can be deforming. Reconstructive surgery may be employed during the primary surgery or afterwards as a secondary procedure. Alterations to the structures of the oral cavity and face result in complications which frequently require prosthetic reconstruction after completion of the healing process. Read more information on reconstruction and rehabilitation. The use of dental and facial implants may be employed in achieving the final solution.

The success rates of these osteointegrated implants, is well substantiated. Implants to replace teeth and to hold maxillofacial prosthesis, have been placed successfully even in irradiated tissues, though with lower success rates.

One of the more common fungal infections is Candidiasis, which colonizes the damaged mucosa. Mucosal healing should be complete within three to six weeks after radiation therapy, and mucositis should begin to resolve at the same time. Radioprotectors may also be employed to reduce the negative biological effects of radiation therapy, and they may prove useful in reducing tissue toxicity. A dentist or oncologist may prescribe viscous topical anesthetics such as lidocaine to reduce discomfort, or a "Miracle Mix" (a tissue coating agent and numbing agent) to aid in oral comfort, if the symptoms are especially bad. While an uncomfortable aspect of treatment, mucositis will heal by itself shortly after treatment is completed. Xerostomia (dry mouth) changes the ability of the mouth to neutralize acid, clean the teeth and gums, and protect the mouth from infection. Saliva is needed for taste, swallowing, and speech. Xerostomia is the thickening of, or reduction in volume of saliva. Symptoms include dryness, a sore or burning feeling (especially on the tongue), cracked lips, cuts or cracks at the corners of the mouth, changes in the surface of the tongue, and difficulty wearing dentures. An extremely dry mouth will also impair proper speaking, and the swallowing of foods. Saliva contains important protective enzymes which aid in the prevention of tooth decay and periodontal disease. To protect against tooth decay during and after treatments, patients with xerostomia should apply fluoride to the teeth daily to protect them. Besides a reduction in salivary volume, treatments can cause saliva to become thick, stringy, and annoying to the patient. Once saliva is thickened or reduced in volume, minerals can be lost from the teeth

(demineralization), and needed minerals (calcium, phosphorus) are not redeposited on the teeth. Plaque becomes heavy and thick, and the acids produced after eating sugary foods can cause additional mineral loss. All this contributes to dental decay. It is essential that once salivary function begins to diminish that attention to oral hygiene must be increased. It is not uncommon for post treatment individuals to visit their dental hygienist at rates far more frequently than what is recommended for the general public. Quarterly for cleanings would not be too often, and some patients go even more frequently because even with the most diligent program at home they are unable to prevent the accumulation of plaque and calculus on the teeth. Xerostomia is typically not reversible, and the chronic effects may persist for months or years, with recovery depending on the area radiated, the total dose, and the individual patient. Obviously when the salivary glands are directly in the field of radiation, the condition is unavoidable. New developments in the manner in which radiation is delivered such as IMRT treatments, More about IMRT and radio-protective drugs such as Amifostine may reduce the effects of radiation induced xerostomia. Synthetic saliva solutions and saliva substitute lubricants are helpful in many patients with dry mouth, and some favorable reports have been published. Oral Balance, an over-the-counter gel, also available as a liquid which can be carried easily in the pocket, is a good example. In some patients in whom the salivary complaint is related to the "thickness" (excess mucous-type secretions), guaifenesin (Organidin NR) as a liquid or tablet may help as a mucolytic agent (200-400 mg, 3 to 4 times daily). There are a variety of over the counter products that contain this active ingredient - read labels. During the treatment phase of these moisture changes in the mouth the thickening of saliva and mucous production can be problematic. OTC products such as Mucinex which contain the same active ingredient, may be helpful in this area. Demineralization Demineralization of the teeth and the breakdown of tooth structure can also occur as a result of treatment. This is not necessarily the result of the teeth being in the direct field of radiation therapy. Demineralization may also result when the parotid and/or submandibular/sublingual salivary glands are included in the field of radiation, and are damaged. A diminished supply of saliva, or a change in the quality of saliva, particularly of the resting flow from the submandibular/sublingual glands, deprives the oral cavity of the protective components of saliva, and the calcium and phosphate ions necessary to maintain the hydroxyapatite content of tooth enamel and dentin. Demineralization may contribute to dental caries, or hypersensitive teeth. Scrupulous hygiene must be maintained indefinitely; daily topical fluoride applications are effective as a means of combating the tendency of oral cancer patients to develop dental caries which can be a by-product of demineralization. Loss of taste With radiation therapy, a loss of taste (dysgeusia) may also occur due to damage of the taste bud cells. These cells occur primarily in the tongue papilla and are very sensitive to radiation. These cells usually are capable of repopulating within four months following treatment, but some permanent impairment may remain. There are essentially four tastes; sweet, sour, bitter, and salty. Patients are unique, and different tastes will return at different rates after treatment, and in different amounts. The degree to which taste returns is highly variable and varies from patient to patient. Xerostomia and mucositis also contribute to dysgeusia. Speech and swallowing Complications from treatment also have a profound effect on speech and swallowing. The two go hand in hand, as the same coordinated movement of the structures in the mouth and throat that is essential for the production of intelligible speech, are also necessary for a person to swallow normally. The effects of a cancer on speech and swallowing depend on the location and size of the growth. Both speech and swallowing may also be compromised by surgical interventions, and to a lesser extent by radiation treatments. A sore or lump on the lips, for example, may restrict movement, resulting in unclear production of labial sounds, and the patient's ability to hold food in their mouth while eating may also be reduced. A lesion on the tongue may affect the intelligibility of some lingual sounds, and limit the ability to move food around the mouth or push food back toward the throat during swallowing. A growth on the roof of the mouth (soft palate) or in the throat may change the nasal quality of the voice. The size of the cancerous growth does play a role in how speech and swallowing abilities are affected. After surgery there are other important factors which determine the extent of complications such as; the amount of tissue removed, the removal of portions of speech and swallowing related anatomy such as the tongue, the availability and frequency of speech/swallowing therapy post-treatment, and the motivation of the patient. Reconstructive surgery and the use of prosthetic devices have become very sophisticated, and current techniques have been shown to restore oral functioning to near normal levels. Frequently, evaluation and treatment by a speech-language pathologist is essential to restore speech intelligibility and swallowing skills. Speech-language specialists are integral parts of the hospital-based cancer team and perform both pre and post surgical assessments, as well as post treatment therapy. Trismus This is essentially the inability to open the mouth properly. Trismus is another complication that may develop after radiation treatment. Trismus occurs as a result of fibrotic changes to the muscles of mastication and the temporomandibular joint capsule, when they are included in the radiation field. The full extent of trismus usually becomes evident three to six months after the end of radiation treatment. The patient's limited ability to open the mouth properly, combined with impaired salivary production, may interfere with the ability to maintain adequate oral hygiene, speech, and the ability to sustain adequate nutrition. Stretching exercises are important during the treatment process to minimize post treatment trismus.

More on Trismus Osteoradionecrosis Perhaps the most severe side effect of radiation therapy is osteoradionecrosis (ORN), or bone death. This condition occurs in three to ten percent of patients. Osteoradionecrosis develops as irradiation diminishes the bone's ability to withstand trauma and avoid infection, and it can be facilitated by poor nutrition and hygiene. This process may be spontaneous or result from trauma, leading to non-healing soft tissue and bone lesions, followed by bone necrosis. The non-healing bone may become secondarily infected. All patients who are to receive chemo-radiation therapy should have unsalvageable teeth removed, periodontal health maximized, and fluoride therapy instituted prior to treatment. Osteoradionecrosis is an extremely serious complication for patients requiring tooth extraction after radiation therapy, and the risk does not appear to diminish with time (for the rest of his/her life the patient should never allow a dentist to extract a tooth after radiation therapy without consulting a radiation oncologist). The ability of the bony tissues to heal is compromised by hypovascularization.

Essentially, the radiation destroys some of the very small blood vessels within the bone. These blood vessels carry both nutrients and oxygen to the living bone. A reduction in these vessels correlates to a reduction in the bone's ability to heal itself. All patients who require extraction of teeth in a previously irradiated field should be considered at risk of developing osteoradionecrosis. The traumatic fracture of a maxillary bone or the mandible post treatment in an accident can also result in severe consequences. Such a problem when complicated by ORN, can cause massive destruction of the jawbones. Treatment for ORN may include hyperbaric oxygen treatments in which the bone is subjected to saturation with oxygen in a pressure chamber, not unlike those used to treat divers for the bends. More about hyperbaric treatments When the severity of these post treatment ORN complications is considered, aggressive dental treatments such as extractions before radiation therapy become understandable. More about ORN here Nutritional problems All of these factors, in addition to the nausea and vomiting that can follow treatment, have an effect on the patient's nutrition, and can lead to eating deficiencies. The inability to maintain adequate nutritional health is a particularly common problem for persons with oral cancer, and it is a major cause of morbidity and mortality. A healthy diet is of the utmost importance when undergoing therapy. Anorexia is the most common symptom that may occur early in the disease process, or later as the tumor grows and metastasizes. Cachexia is a clinical wasting syndrome evidenced by weakness and a marked and progressive loss of body fat and muscle tissues. Anorexia and cachexia frequently occur together, but cachexia may occur in individuals who are ingesting adequate calories and protein but experience malabsorption of the nutrients. During and after treatment, there may be less enjoyment in eating and drinking, or embarrassment or isolation in social situations. Sometimes the patient simply may not want to eat, but it is very important to maintain a nutritious diet, particularly when undergoing treatment. It is integral to health and the recovery process. For patients who lose a significant amount of weight during treatments or have compromised eating abilities afterwards, the use of a feeding tube must be considered.

Oral mucositis can be complicated by infection in the immunocompromised patient. Specific organisms may play a role in upregulating proinflammatory cytokines via bacterial metabolic products such as liposaccharides. Also, oral organisms can disseminate systemically in the setting of ulcerative oral mucositis and profound, prolonged neutropenia.[2-8] Both indigenous oral flora and hospital-acquired pathogens have been associated with bacteremias and systemic infection. As the absolute neutrophil count falls below 1,000/mm3, incidence and severity of infection rises.[9] Patients with prolonged neutropenia are at higher risk for development of serious infectious complications.[10,11] Compromised salivary function can elevate risk for infection of oral origin. Other oral sites, including the dentition, periapices, and periodontium, can also become acutely infected during myelosuppression secondary to high-dose chemotherapy.[12-15] Dental management prior to initiation of the cytoreductive therapy can substantially reduce the risk of acute infectious flares.[16-19]
Bacterial Infection

Changes in infection profiles in myelosuppressed cancer patients have occurred over the past 3 decades. This evolving epidemiology has been caused by multiple factors, including use of prophylactic and therapeutic antimicrobial regimens, as well as decreased depth and duration of myelosuppression via growth factor therapy.[20] Gram-positive organisms, including viridans streptococci and enterococci species, are currently associated with systemic infection of oral origin. In addition, gram-negative pathogens including Pseudomonas aeruginosa, Neisseria species, and Escherichia coli remain of concern. Myeloablated cancer patients with chronic periodontal disease may develop acute periodontal infections with associated systemic sequelae.[12,4,13-15] Extensive ulceration of sulcular epithelium associated with periodontal disease is not directly observable, yet may represent a source for disseminated infection by a wide variety of organisms. Inflammatory signs may be masked due to the underlying myelosuppression. Thus, neutropenic mouthcare protocols that reduce microbial colonization of the dentition and periodontium are important during myelosuppression. Topical therapy may include the following:
y y y
Oral rinses with 0.12% chlorhexidine digluconate. Irrigation with effervescent (peroxide) agents which may affect anaerobic bacteria colonizing the periodontal pocket. Gentle mechanical plaque removal, including dental brushing and flossing.

Pulpal/periapical infections of dental origin can complicate the course of the chemotherapy patient.[16] These lesions should be eliminated prior to initiation of chemotherapy. Prechemotherapy endodontic therapy should be completed at least 10 days prior to initiation of chemotherapy. Teeth with poor prognoses should be extracted, utilizing the 10-day window as a guide. Specific management guidelines are delineated in the NIH Consensus Conference statement.[16,17] Ill-fitting removable prosthetic appliances can traumatize oral mucosa and increase risk of microbial invasion into deeper tissues. Denture soaking cups can readily become colonized with a variety of pathogens, including P. aeruginosa, E. coli, Enterobacter species, Staphylococcus aureus, Klebsiella species, and Candida albicans. Dentures should be evaluated prior to chemotherapy and adjusted as necessary to reduce risk for trauma. Denture cleansing solutions

should be changed daily. In general, dentures should not be worn when the patient has ulcerative mucositis and is neutropenic (e.g., <500 ANC/mm3).
Fungal Infection
Candidiasis

Candidiasis is typically caused by opportunistic overgrowth of C. albicans.[21,22] A number of variables contribute to its clinical expression, including myelosuppression, mucosal injury, and salivary compromise.[4] In addition, antibiotics used during prolonged neutropenia and/or concurrent steroid therapy typically alter oral flora, thereby creating a favorable environment for fungal overgrowth. Final diagnosis must be based on the collective relevant features of the history, risk factor analysis, and physical examination. Protocols utilizing topical oral antifungal agents appear to have variable efficacy in preventing or treating fungal infection in immunocompromised patients.[23,21,24-29] Several studies have demonstrated the inability of nystatin suspension to effectively reduce incidence of either oropharyngeal or systemic infections caused by Candida in immunocompromised patients receiving chemotherapy or radiation; however, the practice continues in many centers. In contrast, clotrimazole troches and amphotericin oral solutions or tablets may have some efficacy in reducing colonization and treating oropharyngeal infections in cancer patients who are immunocompromised. There is increasing evidence that prophylactic systemic azole antifungals can effectively reduce overall oral fungal colonization levels and reduce the risk of oral candidiasis, with fluconazole being the agent of choice.[27] Patients with superficial candidiasis should be instructed to:
y y y
Clean the oral cavity prior to administering topical antifungal medication; irrigation and mechanical plaque removal may be necessary prior to drug dosing. Remove dentures while medication is being applied to the oral tissues. Disinfect oral tissues in addition to dental prostheses.

Use a suspension instead of a troche if xerostomia is present (if a troche is preferred, the patient should rinse or drink water prior to dosing). Persistent or locally invasive fungal infection, especially when risk for systemic dissemination exists, should be treated with appropriate systemic agents. Although topical antifungal prophylaxis and treatment may clear superficial oropharyngeal infections, topical agents are generally not well absorbed and are ineffective against more deeply invasive fungal infections. Systemic agents are thus indicated for treating all except superficial fungal infections in the oral cavity. Therapeutic doses of fluconazole and itraconazole have been reported to produce effective responses in marrow transplant patients. Systemic candidal infections represent considerable risk to the myelosuppressed patient; treatment efficacy is limited and triazole-resistant organisms may emerge. Amphotericin B is often the drug of choice for treatment of systemic candidiasis.
Noncandidal fungal infections

An increasing number of different fungal organisms are being associated with oral infection in immunocompromised cancer patients in recent years, and includes infection by species of Aspergillus, Mucormycosis, and Rhizopus.[4] The clinical presentation is not pathognomonic;

lesions may appear similar to other oral toxicities. Microbiologic documentation is essential. Systemic therapy must be instituted promptly due to high risk for morbidity and mortality.
Viral Infections
Herpes virus

Herpes group viral infections, including those caused by oral lesions, can cause a variety of diseases that range from mild to serious conditions in patients receiving cancer therapy.[30-38] The severity and impact of these lesions, as well as systemic sequelae are directly related to the degree of immunocompromization of the patient. Comorbid oral conditions such as mucositis or graft-versus-host disease, can dramatically increase the severity of oral lesions and significantly increase the difficulty of diagnosis. In most instances, herpes simplex virus (HSV), varicellazoster virus (VZV), and Epstein-Barr virus (EBV) infections result from reactivation of latent virus, while cytomegalovirus (CMV) infections can result from either reactivation of a latent virus, or via a newly acquired virus. The viral infections can cause oral mucosal lesions. With the recognition of the increased risk of HSV and VZV reactivation in seropositive patients who are expected to become profoundly immunosuppressed during cancer therapy, prophylaxis with antiviral medications has proven to drastically reduce the incidence of disease. This primarily includes patients receiving high-dose chemotherapy and undergoing hematopoietic stem cell transplantation. Early diagnosis and prompt therapy remain hallmarks of management. As with other infections, risk for systemic dissemination and morbidity/mortality increases with degree and duration of immunocompromise. The infections can be fatal, depending on degree of immunosuppression. Current studies appear to indicate that patients receiving head and neck radiation are not at increased risk of HSV reactivation specifically related to therapy, although occasional instances of simultaneous oral HSV lesions occurring during therapy have been reported.
Herpes simplex virus

Oral herpetic lesions can range from routine herpes labialis to severe stomatitis causing large painful ulcerations throughout the mouth. The severity of lesions dramatically increases with increasing degrees of immunosuppression. The incidence of recurrent oral HSV lesions in myelosuppressed cancer patients has been considerably reduced with the use of prophylactic acyclovir and more recently, valacyclovir regimens.[39-41] Additionally, the severity and duration of actual HSV lesions have been reduced by antiviral therapies. Breakthrough infections are uncommon but can occur. While true resistance to antivirals occurs, clinical infection in the face of antiviral therapy is more likely due to insufficient dosing or compromised gastrointestinal absorption of oral acyclovir. The introduction of valacyclovir appears to have reduced the incidence of breakthrough oral HSV infections. Topical therapy alone is generally not efficacious in the immunocompromised patient. In patients not receiving antiviral prophylaxis, oral lesions typically emerge concurrent with chemotherapy or chemoradiotherapy during the period of most significant immunosuppression (white blood cell nadir). Typically, in hematopoietic stem cell transplant patients this represents the period a few days prior to transplant through day 35 posttransplant. The risk of HSV reactivation remains higher than normal until immune reconstitution occurs. Similar patterns of risk are noted in patients receiving high-dose (immunosuppressive) chemotherapy. Recurrentoral

HSV infections occurring simultaneously with cancer therapy-induced oral mucositis can result in the development of extensive, confluent mucosal ulcerations clinically similar to primary herpetic stomatitis. As such, HSV stomatitis can be confused with cancer therapy-induced ulcerative mucositis. Viral cultures from lesions in HSV seropositive patients are essential to accurate diagnoses. Assays that produce more rapid results, including direct immunofluorescence, shell vial testing, and specific immunoassay for HSV antigen and/or biopsy, may also be useful.
Varicella-zoster virus

This infection classically distributes via dermatomes, although the clinical manifestations can be altered in immunocompromised patients and multiple dermatomes or more widespread distribution of lesions can be seen. For patients receiving high-dose chemotherapy, orofacial VZV lesions are typically observed several weeks after cessation of chemotherapy. This is in contrast to HSV, which often occurs within 2 to 3 weeks after chemotherapy is discontinued. For reasons that are not entirely clear, the period of increased risk for reactivation of VZV essentially extends from approximately 3 to 12 months posttransplant, with allogeneic transplant recipients being at highest risk. Acyclovir, valacyclovir, and famciclovir are currently the primary drugs used for treatment.[42]
Cytomegalovirus

Oral lesions associated with CMV have been documented in immunocompromised patients, including those who have undergone marrow transplantation.[4,33,34] Appearance is not pathognomonic and is characterized by multiple mild to moderate ulcerations with irregular margins. The lesions initially present during early periods of marrow regeneration (e.g., 3 weeks after chemotherapy is discontinued) and are characterized by nonspecific pseudomembranous fibrin exudate-covered ulcerations with a granulomatous-appearing base. Surface swab cultures may yield false-negative results, perhaps due to viral propensity for infecting endothelial cells and fibroblasts with resulting low levels of free virus. Shell vial cultures can enhance identification of CMV, but CMV-specific immunohistochemical staining of biopsy specimens remains the gold standard. Ganciclovir is currently the treatment of choice for acute CMV infection. Improved prophylactic measures have reduced the incidence of both primary and recurrent CMV infections.[43,44]
Epstein-Barr virus

EBV is linked with tumor development.[45] In addition, oral hairy leukoplakia has been attributed to EBV infection in immunocompromised patients, including those with AIDS and renal transplant. The lesion does not appear to be clinically significant in chemotherapy recipients, however. In contrast, hematopoietic stem cell transplant patients who are immunocompromised for a prolonged period may be at risk for development of EBV-related lymphomas of the head and neck region, especially when T-celldepleted grafts are used for allogeneic transplant. As such, risk for EBV infection typically emerges months after cessation of myeloablative therapy used for transplant conditioning.

EBV has been associated with nasopharyngeal carcinomas.[46] After treatment (surgical and/or radiation therapy) anti-EBV antibody titers are often noted to decrease; subsequent increase in titers can be associated with recurrence.
Nonherpes group virus infections

Infections caused by nonherpes viruses are more common in immunocompromised patients, with the risk of infection apparently increasing with the depth and duration of immunosuppression. Oral lesions caused by adenovirus and oral human papilloma virus (HPV) have been described. Often, patients with increased cutaneous HPV lesions will demonstrate oral lesions. These lesions can present as hyperkeratotic verrucoid lesions or as flat acuminata-like lesions. Restoration of immune function will often result in a digression and possibly, disappearance of the oral mucosal lesions. Laser surgery or cryotherapy are typically utilized to remove oral HPV lesions when medically or cosmetically necessitated; intralesional injections of interferon alfa may prove effective for recurrent lesions.
Hyposalivation predisposes to dental caries, periodontal diseases, mucosal infection, mucosal trauma (e.g. denture irritation), reduced denture retention, altered speech and taste, and inability to take certain foods by mouth.. Basic Oral Care Excellent oral hygiene should be promoted to reduce the oral bacterial load and decrease the risk of caries and periodontal diseases. There is some evidence that good oral hygiene is associated with less severe OM. However, there is no universally recommended oral care protocol.2628 In addition, trauma to the oral tissues should be avoided.29 Oral Mucositis Bland oral rinses are commonly recommended; however, evidence of effectiveness in reducing OM is lacking.30 A study comparing saline and hydrogen peroxide rinses during H&N RT found no differences in OM, although oral sensitivity was greater in those using peroxide.31 The literature supports using ice chips (cryotherapy) for short halflife stomatotoxic chemotherapy delivered by bolus injection.32 Coating agents have been used as vehicles and as topicals to cover damaged mucosa. These include sucralfate, kaopectate, milk of magnesia, amphojel, hydroxypropyl methylcellulose film-forming agents, and Gelclair.33 Sucralfate, an aluminum salt of sucrose octasulfate, is a cytoprotectant that has been studied in OM associated with chemotherapy, radiation, and HCT. It is thought to adhere to ulcer bases, thus creating a surface barrier in the gastrointestinal tract. In addition, sucralfate may have some antibacterial activity and may accelerate wound healing.While less severe OM has been reported in some trials,numerous others have found no benefit.3437 Another hypothesized benefit of sucralfate use is reduced mucosal adherence of potentially pathogenic oral organisms in patients with OM, but no proof of this effect on infectious outcomes has been reported.34 Anti-microbial therapy has long been considered as an OM intervention.A reduction in the bacterial load on the surface of ulcerative lesions would seem of benefit in assuring that secondary infection does not interrupt ulcer

healing. However, there are no consistent data to support the use of antimicrobials as a primary mucositis therapy. Chlorhexidine rinses have been subject to a number of clinical trials for prevention of OM.While the potential value of chlorhexidine for controlling chemotherapyassociated OM was reported in some studies,38,39 this finding has not been universal. Chlorhexidine has been shown to have no effect on radiation OM.40 The benefits of rinsing with chlorhexidine are control of dental plaque levels and reducing gingivitis, caries risk, and oropharyngeal candidiasis, rather than prevention of OM. The acceptance of chlorhexidine oral rinses in patients with OM is limited because the alcohol and flavoring agents generally used in these rinses can be painful, although aqueous solutions may be better accepted. Studies evaluating the potential of a non-absorbable anti-microbial lozenge combining polymixin, tobramycin, and amphotericin B (PTA) to prevent or ameliorate OM report mixed results. Although a large single-center study using PTA reported a reduction in radiation-induced OM in the lozenge arm,41 another double-blind multi-center study on PTA found no effect.42 Other randomized single-center studies on PTA and H&N RT or chemotherapy-induced OM also reported negative or modest results.4345 Isegenan is an anti-microbial peptide that has been reported to ameliorate chemotherapy-induced OM in a phase II study;46 a larger multi-center phase III study on H&N RT patients failed to show reduction of OM.47 A prospective study on povidoneiodine rinses in patients treated with chemoradiotherapy for head and neck cancer reported reduced severity and duration of OM.48 Growth factors and cytokines have pluripotential effects.Time of administration, dose, concentration, and duration of contact in the oral environment may affect the outcome. A number of studies have examined the potential benefit of the hematopoietic growth factors to prevent OM, but have shown inconsistent results. A placebo-controlled trial on topical granulocyte colony stimulating factor (G-CSF) in patients receiving chemotherapy for non-Hodgkins lymphoma reported a trend to less severe OM.49 Several preliminary studies have assessed granulocyte-macrophage colony stimulating factor (GM-CSF) mouth rinses on oral mucositis, and less severe or reduced duration of OM was seen in several trials.50,51 However, a double-blind, placebo-controlled study of GM-CSF mouth rinse conducted in
45

patients receiving chemotherapy showed no reduction in mucositis.52

Epidermal growth factor (EGF) may represent a marker of mucosal damage and has the potential to promote resolution of radiation-induced OM.A preliminary study in head and neck cancer patients showed increase of OM in patients with higher levels of EGF in saliva.53 However, in a larger study, higher EGF salivary levels were associated with less severe OM.54 A double-blind trial of EGF mouth wash in patients treated with chemotherapy showed no differences in the healing of established ulcers, but a delay in onset and reduced severity was seen in recurrent ulceration, suggesting that topical EGF may protect the mucosa.55 Transforming growth factor beta 3 (TGF-3), which reduces epithelial cell proliferation, reduced the incidence, severity and duration of mucositis when given after chemotherapy in animal studies.56 Clinical trials with this agent suffered from dosing concerns and results were mixed.57,58 Interleukin (IL)-11 demonstrated efficacy in reducing both experimental and clinical OM.59 IL-11 was shown to modulate gene expression responsible for tumor necrosis factor alpha (TNF-a) in irradiated mucosa.60 Similarly, benzydamine HCl has anti-TNF-a capacity. This nonsteroidal anti-inflammatory agent has been shown to reduce the severity of OM during radiation therapy and to reduce oral pain.61,62 Benzydamine is available in many countries and is currently in phase III trial in the

US.Amifostine is a thiol compound shown in animal studies to protect a variety of tissues when administered prior to irradiation. Systemic amifostine is indicated for salivary gland protection during radiation therapy and it may reduce OM. Pre-clinical studies showed reduction of radiation-induced OM after local application of amifostine, whereas a recent study on nonsmall- cell lung cancer patients failed to show clinically detectable reduction of OM.63 Glutamine has been demonstrated to have an effect upon mucosal maintenance and protection. Oral glutamine may reduce the duration and severity of radiation-induced OM64 in patients receiving intensive chemotherapy and HCT,65,66 although Okuna et al.67 reported no alleviation of OM induced by 5-fluoroucil (5-FU) in a phase III study.A new formulation designed to increase cellular uptake of glutamine has been reported recently to result in OM prophylaxis in patients receiving chemotherapy for breast cancer.68
A phase III study of oral chamomile mouthwash was conducted in 164 patients receiving 5-FU chemotherapy and no differences in incidence, severity, or duration of OM were seen.69 Therefore, this mouth rinse is not recommended.There is weak evidence that allopurinol mouthwashes, which may prevent formation of oxygenderived free radicals, can be effective in treating OM induced by 5-FU.70

Natural honey has been reported to reduce radiationinduced OM71 and multi-center, randomized trials are warranted to validate this finding.

Infection Systemic infection by Candida albicans, krusei, glabrata, and dublinensis species is a significant cause of morbidity and mortality in neutropenic cancer patients. Unfortunately, prevention of colonization remains elusive.72 Topical therapies have been shown to provide additional effect even in patients receiving systemic antifungal prophylaxis including fluconazole and amphotericin B.72,73 Patients must be assessed on a regular basis in order to identify clinical signs of candidal infection, especially with the increasing emergence of azole-resistant species in myelosuppressive therapy and in H&N RT. Reduced oral colonization by Candida species has been seen with chlorhexidine rinses.39,74

Chlorhexidine has also been shown to be an effective inhibitor of oral streptococci and may impact the risk of systemic infection as well as reduce risk of dental caries due to streptococcal species.75

Pain Topical oral medications can reduce the need for systemic analgesics, and should be considered prior to use of systemic analgesics and continued when systemic medications are needed.

Topical anesthetics are commonly used for local oral pain but, unfortunately, most agents have only a short anesthetic effect. Agents include lidocaine, dyclonine and diphenhydramine.30,76 Viscous lidocaine is frequently recommended for oropharyngeal pain management, although there is a need for more studies that assess the benefits and the potential for toxicity in cancer patients.77 Lidocaine may cause a burning sensation, eliminate taste, affect the gag reflex, promote trauma, and may have cardiovascular and CNS effects if absorbed systemically. Dyclonine HCl may be better accepted than lidocaine.

Topical anesthetic agents have often been combined with coating agents to produce magic mouthwashes. Studies of these rinses have generally found no advantages of these combined agents over saline rinses.There is reasonable evidence to support the use of bland rinses and single topical anesthetics over these mixtures.

A single-center study indicated that a morphine mouthwash reduces the severity and the duration of OM-associated pain in patients with head and neck carcinoma.78 Recently, formulations of topical oral transmucosal fentanyl citrate have been found tolerable in H&N RT patients with OM.79

Doxepin rinse has been examined in a preliminary trial, with evidence of prolonged action of more than four hours of pain relief following use in cancer patients. There is no burning associated with topical use of this tricyclic antidepressant.80 The mechanism of action of doxepin appears to be an initial anesthetic effect followed by a prolonged analgesic effect.81

Benzydamine HCl results in reduced pain and reduced use of systemic analgesics including opioids in patients with OM.80,82

Oral capsaicin in a taffy-candy produced temporary pain reduction in 11 patients with OM-associated pain.83 The findings suggest that the pain of mucositis is partially mediated by substance P. However, the practicality and acceptance of this approach to OM pain relief have not been demonstrated.

Dry Mouth In patients with dry mouth, symptomatic management with mouth wetting agents is considered if salivation is not increased with systemic sialogogues. Oral pilocarpine was not found to be beneficial for radiation-induced xerostomia in a phase III placebocontrolled study.84 The majority of agents for topical application are based on methylcellulose. Some products have incorporated fluoride, salivary enzymes, and mucins. Comparative assessments of mouth wetting agents have been conducted and can serve as a guide for choosing between commercial products.85

Caries Prevention Prevention of dental demineralization and caries is critical in patients with hyposalivation, as dental breakdown can begin early following H&N RT and progress rapidly. In these patients extraction may be associated with risk of osteonecrosis, limiting treatment options.

Topical fluoride applications have been the mainstay of caries prevention following studies in the 1970s. High-concentration fluoride delivered in custommade vinyl carriers have become the gold standard.86,87 In addition, other high-potency fluoride brush-on techniques have been recommended.88 Studies in cancer patients are needed to determine the most effective form and concentration of fluoride and means and frequency of application. In addition, studies on recently developed remineralization products remain a necessity in cancer patients.

Chlorhexidine rinse and gel have been assessed for caries risk in cancer patients.86,89 Chlorhexidine has the potential to control the infectious component of demineralization and caries.

Chronic Oral GVHD Management of chronic oral GVHD includes systemic and topical immunosuppressive agents. Topical azathiopine was found to be effective in the management of painful, ulcerative oral lesions caused by GVHD.90 When oral GVHD remains active, the topical use of cyclosporin A may represent a useful adjunctive approach.91 Recently, an effective approach has been reported using topical tacrolimus.92

Conclusion The potential for prevention and therapy, with limited risk of systemic uptake, side effects, and drug interaction, makes local delivery of various medications to mucosal tissues desirable. In addition, local administration can supplement systemic delivery of medication.The oral mucosa, gingiva, and dentition are accessible to topical therapies, but vehicles and forms of delivery of various agents need to be developed and assessed in cancer patients. Forms of delivery include topical gels or creams, rinses, lozenges, and chewing gum. Considerations in development of topical products for cancer patients include texture and viscosity of the product, taste, stability, and shelf life. Patients receiving cancer therapy require assessment of the vehicle, as oral pain, nausea, and enhanced gag reflexes may affect compliance.93 Taste may change during the course of cancer therapy and taste aversions can develop. Therefore, clinical trials must be conducted in the target population. Future drug development of topical agents will enhance the ability to prevent and treat oral complications of cancer and cancer therapy.

Advances in the Prevention and Management of Oral Mucositis

By Jenny Maxon, RN. January 2007

Introduction
Oncology nurses are at the forefront of delivering the bulk of the treatment and care required by cancer patients. Among their many responsibilities, oncology nurses play a critical role in the prevention, identification, and management of side effects, including oral mucositis. Oral mucositis (OM) is one of the most debilitating and common side effects of treatment for cancer, particularly in patients undergoing high doses of therapy prior to stem cell transplantation (SCT). The overall impact of OM is enormous for patients, caregivers, and the medical system, as it can be directly related to reduced overall survival in patients, as well as reduced quality of life and increased medical costs.1,2,3,4,5,6 Oral mucositis is a condition characterized by damage to the epithelium of the oral-pharyngeal cavity and gastrointestinal (GI) tract from radiation and/or chemotherapy. Epithelial cells are more susceptible to the cytotoxic effects of radiation and chemotherapy because of their relatively high rate of turnover compared to cells in other organs. In most instances, epithelial cells of the mucous membranes have a more rapid turnover than the cancer being treated and are vulnerable to damage by cytotoxic agents and radiation. In patients with OM, there is a breakdown in the saliva barrier, a disruption of epithelial cells, and thinning of the epithelium, often with ulceration. Until recently, OM represented a significant unmet medical need in the oncology setting, with its enormous impact and no proven therapeutic approach to reduce or prevent its occurrence or severity. However, the past year has brought significant advances in the understanding and management of OM. The approval of new agents, such as Kepivance (palifermin), for the management of OM represents a major breakthrough for patients, as well as their doctors and families.7 The prevention or reduction of OM with agents such as Kepivance improves quality of life and reduces the overall medical costs of stem cell transplantation. Recent advances in the management of oral mucositis include: Management of OM Reducing the Impact of OM New Methods of Assessment for OM

y y y

Managing Oral Mucositis

Prevention Versus Management: The best strategy for managing OM would be to prevent it from occurring altogether. Preventing OM and the resulting downstream sequelae may ultimately lead to a significantly improved quality of life, reduced medical costs, and perhaps most importantly, optimal long-term survival. During 2004, the results from clinical trials evaluating several novel anti-mucositis agents were presented.8,9,10,11,12,13 The results from clinical trials evaluating Kepivance, a novel keratinocyte growth factor led to its approval by the Food and Drug Administration as the first agent for the prevention of OM. Kepivance: Kepivance is a recombinant keratinocyte growth factor that increases cellular proliferation, mediates epithelial cell repair, reduces TNF-alpha and IFN-gamma, decreases epithelial cell apoptosis, and exerts an anti-apoptotic effect via Bcl-2 up-regulation. All of these properties aid in the prevention and healing of oral mucositis. Kepivance is currently approved for the treatment and prevention of severe OM in patients with hematologic cancers undergoing highdose chemotherapy with or without radiation prior to SCT. The pivotal clinical trial that led to the approval of Kepivance evaluated 212 patients with hematological malignancies treated with a conditioning regimen of cyclophosphamide, etoposide, and total body irradiation (CyTBIVP16), a standard regimen used to treat lymphoid malignancies.8,9 Patients were randomly allocated to receive placebo or Kepivance 60 micrograms/kg for each of 3 days prior to initiation of cytotoxic therapy and 3 days following stem cell infusion. Mucositis was graded using the WHO scale.14 Kepivance reduced the duration and severity of OM and led to decreased resource utilization and improved patient QOL. (See Table 1) Grade 3-4 OM developed in 98% of patients in the placebo group, compared to 63% of the patients treated with Kepivance. Grade 3-4 OM lasted an average of 9 days in patients treated with placebo, compared to an average of 6 days in patients treated with Kepivance. Notably, Kepivance had the greatest impact on severe OM; grade 4 OM occurred in 62% of the placebo group and lasted an average of 6 days, compared to the Kepivance group, in which only 20% of patients developed grade 4 OM lasting an average of 2 days. Only 31% of patients who received Kepivance received parenteral feeding, compared to 55% of patients who received placebo. The overall quantity and duration of narcotic use for pain relief was significantly less for patients receiving Kepivance. In addition, febrile neutropenia occurred in 92% of the placebo group, compared to 75% in the Kepivance group. Importantly, there were no adverse effects on engraftment, relapses or the development of secondary leukemia. Reported adverse events included skin rash, pruritis, erythema, cough, edema, taste alteration, white film coating mouth or tongue, rhinitis, arthralgia, sensation of tongue thickness, perianal pain, numbness, taste loss and paresthesia. However, these side effects were reversible and did not interfere with treatment.

Table 1: Primary Endpoints of Study Comparing Kepivance and Placebo

Kepivance (n= 106) Placebo (n= 106) P value

Incidence of WHO grades 3-4 mucositis Median duration of grades 3-4 mucositis in those affected Incidence of WHO grade 4 mucositis Median duration of WHO grade 4 mucositis in those affected Incidence of febrile neutropenia Median duration of opioid analgesic use for mucositis Median cumulative dose of opioids administered for mucositis (in morphine equivalents) Incidence of parenteral feeding

63% 6 days 20% 2 days 75% 7 days 212 mg

98% 9 days 62% 6 days 92% 11 days 535 mg

P<0.001 P<0.001 P<0.001 P=0.004 P<0.001 P<0.001 P<0.001

31%

55%

P<0.001

Quality of life (QOL) was also assessed in this trial using a categorical scale (Likert scale), with patients reporting a 38% reduction in median scores of mouth and throat soreness. Other patient-reported sequelae of mucositis indicated significantly higher scores for physical and functional well-being in those treated with Kepivance compared to placebo, including the ability to drink, eat, talk and sleep. AES-14: Clinical data was reported on another novel anti-mucositis agent, AES-14 (Saforis ). AES-14 is L-glutamine delivered in a proprietary base that provides delivery enhancement directly to the oral mucosa. L-glutamine is thought to reduce mucosal injury caused by chemotherapy and radiation, as it is a primary glycolytic nutrient for mucosal epithelial cells and lymphocytes, as well as an important shuttle of nitrogen between tissues.15 At the 2004 ASCO Annual Meeting, researchers presented results of a randomized, double-blind, placebo-controlled, crossover, multi-center trial to determine the efficacy of AES-14 in reducing the severity and duration of OM.10 In this trial, 326 breast cancer patients received an anthracycline-based chemotherapy treatment regimen along with AES-14 or placebo over two subsequent crossover cycles. AES-14 reduced the incidence of clinically significant OM by 22% compared to the placebo group. Unexpectedly, patients who crossed over from AES-14 to placebo had a 36% lower incidence of OM, suggesting a carryover benefit. The pharmacokinetic results of AES-14 in healthy volunteers were also presented, indicating no appreciable differences between the AES-14 and L-glutamine plasma levels or ammonia levels (the latter is a metabolite of L-glutamine), further supporting the safety of this agent. At the 2004 San Antonio Breast Cancer Symposium (SABCS), AES-14 was evaluated in a larger phase III, randomized, placebo-controlled trial including 2,084 women with breast cancer undergoing anthracycline and cyclophosphamide-based chemotherapy.11 Patients who developed grades 2-3 OM (based on the WHO and OMAS scale) were randomized to AES-14 or placebo. The duration of overall OM was reduced by 29% in patients treated with AES-14 compared to placebo (p=0.0479). The incidence of severe OM was reduced by 80% in patients treated with AES-14 compared to placebo (p=0.0136). The safety of AES-14 was comparable to that of placebo. AES-14 is now in the latter phases of clinical trials for the evaluation of OM in various settings. Ethyol: Ethyol (amifostine) is a radiation protector and the only drug that has been approved by the FDA for this use in patients receiving radiation therapy for cancers of the head and neck. Previous clinical trials have demonstrated that Ethyol can reduce both acute and late radiation-induced side effects.16,17 At the 2004 ASH meeting, researchers reported the results from a retrospective study in which patients with multiple myeloma were treated with a regimen consisting of vincristine, doxorubicin and dexamethasone (VAD), high-dose melphalan and an autologous SCT.12 One group of patients received Ethyol prior to transplant, while the other group of patients did not. Opioid analgesics were necessary in only 20% of patients treated with Ethyol, compared to 69% of patients not treated with Ethyol. Furthermore, parenteral nutrition was necessary in only 10% of patients treated with Ethyol, compared with 50% of patients not treated with Ethyol. Importantly, there was no statistical difference in disease response between the two groups of patient, suggesting that Ethyol did not protect cancer cells against the antitumor activity of treatment. Future randomized, placebo-controlled studies will be necessary to determine the role of Ethyol in the management of OM. Mucotrol (MF5232): The oral hydrogel wafer, Mucotrol (MF5232), was recently approved as a medical device for the treatment or management of pain associated with OM.13 Mucotrol includes extracts from licorice root and aloe vera and

dissolves in the mouth of a patient. The clinical trial prompting FDA approval was a randomized, placebo-controlled trial that included 30 patients who were undergoing treatment for cancer and had developed OM. Overall, patients benefited from Mucotrol compared to the placebo group. Future clinical trials directly comparing Mucotrol to other pain relievers for mucositis are necessary to determine the true clinical benefit of Mucotrol in cancer patients with OM.

Impact of Oral Mucositis

The impact of OM is far-reaching for patients, caregivers and the medical system. Oral mucositis results in severe physical consequences for patients, impacting their quality of life and resulting in life-threatening complications. Ultimately, the development of OM not only impacts long-term outcomes, but also leads to a significant financial and emotional burden for patients and the medical system.3,4,5,6 Physical Impact: Oral mucositis is known to cause severe pain, often leading to the need for narcotics, as well as significantly reducing the ability of patients to chew, swallow, or talk. This can lead to dehydration, malnutrition, anorexia, cachexia, and tube feeding or TPN. This, in turn, prolongs hospitalization, reduces quality of life and increases medical costs. Patients often become depressed or agitated, as well as fatigued, when suffering from OM and its sequelae. In addition, ulceration with OM can lead to systemic infection with downstream effects including anti-infective use, a delay in treatment, hospitalization, increased medical costs, and ultimately, the potential for suboptimal long-term survival.5,6 Oral mucositis is also recognized as a key dose-limiting toxicity in cancer treatment that includes mucositis-inducing agents. Financial Impact: In addition to the side effects caused by OM and the negative consequences on long-term outcomes in patients who suffer from severe OM, the financial burden accrued in medical expenses that are directly attributable to OM can be significant. Physicians have established that severe ulcerative mucositis may increase costs by as much as $43,000 compared to less severe mucositis.3 Results from an analysis of the recent phase 3 trials comparing Kepivance to placebo were presented at the 2004 meeting of the American Society of Hematology (ASH). Daily hospital rates for patients undergoing autologous stem cell transplants including total body irradiation were reported to be $2,702.4 The downstream costs of OM (bacteremia, febrile neutropenia, intubation, total parenteral nutrition) raised the cost to more than $5,000 per day. Overall, the mean cost per patient was $61,160 for patients who received Kepivance, compared to $76,104 for those who received placebo. Factors such as hospitalization, anti-infective use, TPN, narcotic use, or other associated effects of OM contribute to the mounting medical costs for patients and the healthcare system.

Assessing Oral Mucositis

In order to manage OM, it is important to assess it properly. The assessment of OM can fall into 3 categories: Understanding the Stages of OM Grading OM Risk Assessment for OM

y y y

Stages of OM: Some researchers believe that better treatments can be developed by understanding the underlying mechanisms of OM. Recently, researchers have developed a 5-stage model that is an overview of the process of mucositis.18(Table 2) Table 2: Stages of OM
5-Stage Model for the Development of OM Initiation Upregulation Damage to DNA of epithelial cells by chemotherapy and/or radiation therapy Damaged DNA sends signals or chemical messages that initiate proinflammatory cytokines and an inflammatory response. The chemical messages and cytokines ultimately result in epithelial cell death. The cytokines and chemical messages also initiate a positive feedback loop, causing more destruction to epithelial cells. The outer layer of the mouth may still look normal. Mucosal ulceration begins. The ulceration process also initiates further inflammation, further increasing cellular damage and pain

Signal Amplification Ulceration Healing

Several of the phases occur simultaneously and, depending on the type of therapy, can be repeated. Grading OM: Consistent grading is very important for evaluating the impact of intervention in OM. Historically, the most commonly used grading systems were the WHO grading system (See Table 3) and the NCI-CTC grading system.14,19 At present, most researchers are still utilizing the WHO grading system and a consensus is trying to be reached to determine the most accurate way in which to grade OM. Both the NCI and WHO have separate grading systems for conventional-dose chemotherapy, high-dose chemotherapy with stem cell support, and radiation therapy. There are also specific grading systems used by various radiation oncology groups. The main criticism of these assessment scales is that combinations of signs, symptoms, and functional changes observed can be confounding and interfere with accurate grading. Table 3: WHO Grading System

WHO GRADING SYSTEM Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 No mucositis Irritation of the oral mucosa with pain; no overt ulceration and patient is able to eat a normal diet Sores are evident in the oral mucosa, but patient is still able to swallow solid food Patients need to be on a liquid diet, as they experience extreme sensitivity swallowing solid food. Patients are not able to swallow. Total parenteral nutrition or tube feeding is necessary.

Because of the perceived weaknesses of existing OM grading systems, a new international grading system was established called the Oral Mucositis Assessment Scale (OMAS)(See Table 4).20OMAS measures ulceration on a 0-3 scale, erythema on a 0-2 scale, and evaluates pain, difficulty swallowing, and impact on food intake. For studies of severe OM, food intake evaluation may be the most valuable assessment tool and is graded as normal, only soft solid foods, or no foods or liquids. The major criticism of the OMAS grading system is that it requires more examiner experience and time than the NCI-CTC and WHO grading systems. There are, however, other more detailed grading systems than the OMAS scale, which at present are used specifically for research purposes.21 Table 4: Oral Mucositis Assessment Scale (OMAS)
OMAS Ulceration Erythema

0 = no lesion 1 = < 1 cm2 2 = 1 cm2 3 cm2 3 = > 3 cm2

0 = none 1 = not severe 2 = severe

Risk Assessment: Thus far, several variables have been noted that appear to place a patient at a higher risk of OM than others. Currently, the most important known risk factors for OM are the specifics of the cancer therapy, such as the dose and schedule of radiation and/or chemotherapy. All chemotherapy drugs can cause OM; however, specific chemotherapy agents, as well as the dose and schedule of the drug or regimen, can increase the risk of developing OM. Oral mucositis is particularly severe in patients with head and neck cancer receiving radiation and chemotherapy and almost all patients receiving an autologous or allogeneic stem cell transplant. 3 Once OM is established, management is focused on treating local infection, particularly with candida albicans and herpes simplex since there are specific and active treatments for these disorders, reducing pain, and preventing its progression. Patients undergoing high-dose cytotoxic therapy and stem cell support represent a group of patients that are in clear need of preventive measures of OM, as it is estimated that nearly all patients who undergo high-dose chemotherapy and/or high-dose radiation prior to a stem cell or bone marrow transplantation will develop OM.8 The high doses of therapy typically involved in stem cell transplant procedures are particularly damaging to the mucosal lining of the mouth. In this patient population, maintaining therapeutic dose levels of treatment is a crucial component to optimal outcomes, necessitating a medical need to reduce the incidence or severity of OM so that treatment doses do not need to be reduced or delayed. Furthermore, with the use of such myelosuppressive therapy, patients are placed at an increased risk for infection, coupled with a reduced ability to fight life-threatening infection. These issues stress the fact that it is imperative that OM be prevented if possible in patients undergoing high-dose therapeutic regimens. Results from a retrospective study indicated that transplant patients with severe OM had a four-fold increase in mortality over their counterparts.5 Furthermore, an additional retrospective analysis of patient complaints following stem cell transplantation revealed that mouth sores were the single most debilitating side effect from treatment.[6] Results using the new OMAS revealed that transplant patients with severe OM had an increased incidence and duration of fever and infection, as well as more use of total parenteral nutrition (TPN).4 Kepivance is specifically indicated for this group of patients and it is administered 3 days prior to cytotoxic therapy in an attempt to completely prevent OM altogether. Michelet, et al conducted a large retrospective study of 633 autologous PBSC transplant patients that was designed to determine prognostic factors for ulcerative oral mucositis (UOM).22 Mulitivariate logistic regression analysis showed that the most important risk for OM was conditioning regimens and the most significant risk for UOM was delayed neutrophil recovery. The contribution of neutrophil engraftment is less clear and requires further study. It may well be linked with an inability to protect tissues once they become ulcerated and bacterial influences are possible. Numerous factors, including pre-existing oral infections and trauma/irritation, appear to contribute to OM as well (as opposed to being causative). Patient gender and age are suspected to play a role in susceptibility of developing OM and these roles continue to be evaluated in clinical studies. Researchers from the Mayo Clinic and Mayo Foundation performed a meta-analysis on 402 men and 329 women who received 5-FU chemotherapy and found that women reported OM both

more often and with greater severity than did men, suggesting that female gender may be a consideration when establishing risk stratification for OM.23 There is also growing evidence that genetics plays a role in patient susceptibility to OM resulting from certain types of chemotherapy.24 Additionally, genetic variance relative to production of inflammatory cytokines will likely be shown to be important. Results presented at the 2004 meeting of the American Society of Hematology (ASH) indicated that levels of C-reactive protein (CRP) allow for early identification of patients who are at an increased risk of developing OM after melphalan and autologous stem cell transplantation for multiple myeloma.25 These results will be validated in a prospective trial. Results from another trial presented at 2004 ASH indicated that graft-versus-host-disease (GVHD) prophylaxis with sirolimus/tacrolimus (ST) appears to decrease the risk of OM compared with tacrolimus/methotrexate (TM) in patients undergoing HLA-matched sibling allogeneic transplants after cyclophosphamide-total body irradiation conditioning.26 Patients treated with prophylaxis of ST had significantly reduced severe OM, which led to reduction in TPN use, as well as a reduced duration of TPN use, a reduction of narcotic use in the hospital, and a reduced time from transplant to discharge. Results from yet another clinical trial presented at 2004 ASH evaluating possible patient or treatment variables with an increased risk of developing OM revealed that patients undergoing high melphalan doses based on body surface area (BSA) measurements are at an increased risk of developing OM if pre-transplant variables include low creatinine clearance (CrCl), high lactate dehydrogenase (LDH) levels, and/or low pulmonary diffusion capacity (DLCO).27

Conclusion
Oral mucositis is a common and debilitating side effect in all patients undergoing stem cell transplantation and many other patients undergoing cancer treatment. The severity of OM ranges from a slight irritation of the mucosal lining to severe ulceration and the downstream complications associated with its development can have enormous consequences on patient quality of life, delivery of care, medical costs, and ultimately, long-term outcomes. The approval of Kepivance provides caregivers with a new tool to help reduce the severity and duration of OM in susceptible patients. Research is ongoing to determine the optimal way to use Kepivance and other novel agents in various settings with the hope of further reducing the severity and duration of OM as a side effect of cancer treatment. Ultimately, further research and understanding of OM will help establish reliable methods for preventing and managing this complication, which will have a major impact on patient well-being and an improvement in the outcomes of cancer treatment.

Management of Oral Complications During and After Chemotherapy and/or Radiation Therapy

Routine Oral Care Oral Mucositis Infection Bleeding Dry Mouth Tooth Decay Taste Changes Fatigue Malnutrition and Nutritional Support Pain Jaw Stiffness Tissue and Bone Loss
Routine Oral Care

Continuing good dental hygiene during and after cancer treatment can reduce complications such as cavities, mouth sores, and infections. It is important to clean the mouth after eating. The following are guidelines for everyday oral care during chemotherapy and radiation therapy: Tooth brushing
y y y y
Brush teeth and gums with a soft bristle brush 2 to 3 times a day for 2 to 3 minutes. Rinse the toothbrush in hot water every 15 to 30 seconds to soften the bristles, if needed. If it is necessary to use a foam toothbrush, use it with an antibacterial rinse, when possible. Allow the toothbrush to air dry between brushings.

Choose toothpaste with care:

y y y

Use a mild-tasting toothpaste; flavoring may irritate the mouth. If toothpaste irritates the mouth, brush with a solution of 1 teaspoon of salt added to 4 cups (1 quart) of water. Use a fluoride toothpaste.

Rinsing
y y y
Rinse the mouth 3 or 4 times while brushing. Avoid rinses containing alcohol. One of the following rinses made with salt and/or baking soda may be used:

y y y

1 teaspoon of salt in 4 cups of water. 1 teaspoon of baking soda in 1 cup (8 ounces) of water.

teaspoon salt and 2 tablespoons baking soda in 4 cups of water. An antibacterial rinse may be used 2 to 4 times a day for gum disease. Rinse for 1 to 2 minutes. If dry mouth occurs, rinsing may not be enough to clean the teeth after a meal. Brushing and flossing may be needed.

Flossing
y
Floss gently once a day.

Lip care
y
Use lip care products to prevent drying and cracking.

Oral Mucositis

Mucositis is an inflammation of mucous membranes in the mouth. The terms "oral mucositis" and "stomatitis" are often used in place of each other, but their meanings are different.
y y
Mucositis is an inflammation of mucous membranes in the mouth. It usually appears as red, burn-like sores or as ulcer -like sores throughout the mouth. Stomatitis is an inflammation of tissues in the mouth, such as the gums, tongue, roof and floor of the mouth, and tissues inside the lips and cheeks. It includes infections of mucous membranes.

Mucositis may be caused by either radiation therapy or chemotherapy. In patients receiving chemotherapy, mucositis will heal by itself, usually in 2 to 4 weeks when there is no infection. Mucositis caused by radiation therapy usually lasts 6 to 8 weeks, depending on the duration of treatment. The following problems may occur:
y y y y
Pain. Infection. Bleeding, in patients receiving chemotherapy. Patients undergoing radiation therapy usually do not have a bleeding risk. Inability to breathe and eat normally.

Swishing ice chips in the mouth for 30 minutes may help prevent mucositis from developing in patients who are given fluorouracil. Medication may be given to help prevent mucositis or keep it from lasting as long in patients who undergo high-dose chemotherapy and bone marrow transplant. Care of mucositis during chemotherapy and radiation therapy focuses on cleaning the mouth and relieving the symptoms.

Treatment of mucositis caused by either radiation therapy or chemotherapy is generally the same. After mucositis has developed, proper treatment depends on its severity and the patient's white blood cell count. The following are guidelines for treating mucositis during chemotherapy, stem cell transplantation, and radiation therapy: Cleaning the mouth
y y y y y
Clean the teeth and mouth every 4 hours and at bedtime, more often if the mucositis becomes worse. Use a soft bristle toothbrush. Replace the toothbrush often. Use water-soluble lubricating jelly to moisturize the mouth. Use bland rinses or plain sterile water. Frequent rinsing removes particles and bacteria from the mouth, prevents crusting of sores, and moistens and soothes sore gums and the lining of the mouth. The following rinse may be used to neutralize acid and dissolve thick saliva:

y y

teaspoon salt and 2 tablespoons baking soda in 4 cups of water. If crusting of sores occurs, the following rinse may be used: Equal parts hydrogen peroxide and water or saltwater (1 teaspoon of salt in 4 cups of water).

This should not be used for more than 2 days because it will keep mucositis from healing.

Relieving pain
y y y y y
Try topical medications for pain. Rinse the mouth before applying the medication onto the gums or lining of the mouth. Wipe mouth and teeth gently with wet gauze dipped in saltwater to remove particles. Painkillers may provide relief when topical medications do not. Nonsteroidal anti-inflammatory drugs (NSAIDS, aspirin -type painkillers) should not be used by patients receiving chemotherapy because these patients have a bleeding risk. Capsaicin, the active ingredient in hot peppers, may be used to increase a person's ability to tolerate pain. When capsaicin is put on inflamed tissues in the mouth, mucositis pain may decrease as the burning feeling from the capsaicin decreases. The side effects of capsaicin are not known. Zinc supplements taken during radiation therapy may help treat mucositis as well as dermatitis (inflammation of the skin). Povidone- iodine mouthwash that does not contain alcohol may help delay or decrease mucositis caused by radiation therapy.

Infection

Damage to the lining of the mouth and a weakened immune system make it easier for infection to occur. Oral mucositis breaks down the lining of the mouth, allowing germs and viruses to get into the bloodstream. When the immune system is weakened by chemotherapy, even good bacteria in the mouth can cause infections, as can disease-causing organisms picked up from the hospital or other sources. As the white blood cell count gets lower, infections may occur more often and become more serious. Patients who have low white blood cell counts for a long time are more at risk of developing serious infections. Dry mouth, common during radiation therapy to the head and neck, may also raise the risk of infections in the mouth. Preventive dental care during chemotherapy and radiation therapy can reduce the risk of mouth, tooth, and gum infections. The following types of infections may occur: Bacterial infections Treatment of bacterial infections in patients who have gum disease and receive high-dose chemotherapy may include the following:
y y y
Medicated and peroxide mouth rinses. Brushing and flossing. Wearing dentures as little as possible.

Bacterial infections in patients undergoing radiation therapy are usually treated with antibiotics. Fungal infections The mouth normally contains fungi that can exist on or in the body without causing any problems. An overgrowth of fungi, however, can be serious and requires treatment. Antibiotics and steroid drugs are often used when a patient receiving chemotherapy has a low white blood cell count. These drugs change the balance of bacteria in the mouth, making it easier for a fungal overgrowth to occur. Fungal infections are common in patients treated with radiation therapy. Drugs may be given to prevent fungal infections from occurring. Treatment of surface fungal infections in the mouth only may include mouthwashes and lozenges that contain antifungal drugs. These are used after removing dentures, brushing the teeth, and cleaning the mouth. An antibacterial rinse should be used on dentures and dental appliances and to rinse the mouth. Deeper fungal infections, such as those in the esophagus or intestines, are treated with drugs taken by mouth or injection. Viral infections Patients receiving chemotherapy, especially those with weakened immune systems, are at risk of mild to serious viral infections. Finding and treating the infections early is important. Drugs may be used to prevent or treat viral infections. Herpesvirus infections may recur in radiation therapy patients who have these infections.
Bleeding

Bleeding may occur during chemotherapy when anticancer drugs affect the ability of blood to clot. Areas of gum disease may bleed on their own or when irritated by eating, brushing, or flossing. Bleeding may be mild (small red spots on the lips, soft palate, or bottom of the mouth) or severe, especially at the gumline and from ulcers in the mouth. When blood counts drop below certain levels, blood may ooze from the gums. With close monitoring, most patients can safely brush and floss throughout the entire time of decreased blood counts. Continuing regular oral care will help prevent infections that may further complicate bleeding problems. The dentist or doctor can provide guidance on how to treat bleeding and safely keep the mouth clean when blood counts are low. Treatment for bleeding during chemotherapy may include the following:
y y y
Medications to reduce blood flow and help clots form. Topical products that cover and seal bleeding areas. Rinsing with a mixture of one part 3% hydrogen peroxide to 2 or 3 parts saltwater solution (1 teaspoon of salt in 4 cups of water) to help clean oral wounds. Rinsing must be done carefully so clots are not disturbed.

Dry Mouth

Dry mouth (xerostomia) occurs when the salivary glands produce too little saliva. Saliva is needed for taste, swallowing, and speech. It helps prevent infection and tooth decay by neutralizing acid and cleaning the teeth and gums. Radiation therapy can damage salivary glands, causing them to make too little saliva. When dry mouth (xerostomia) develops, the patient's quality of life suffers. The mouth is less able to clean itself. Acid in the mouth is not neutralized, and minerals are lost from the teeth. Tooth decay and gum disease are more likely to develop. In addition, there is some evidence that salivary glands may be damaged by certain types of

chemotherapy drugs given alone or in combination. Symptoms of dry mouth include the following:
y y y y y y y
Thick, stringy saliva. Increased thirst. Changes in taste, swallowing, and speech. A sore or burning feeling (especially on the tongue). Cuts or cracks in the lips or at the corners of the mouth. Changes in the surface of the tongue. Difficulty wearing dentures.

Salivary glands may not recover completely after radiation therapy ends. Saliva production drops within 1 week after starting radiation therapy to the head and/or neck and continues to decrease as treatment continues. The severity of dry mouth depends on the dose of radiation and the number of glands irradiated. The salivary glands in the upper cheeks near the ears are more affected than other salivary glands. Partial recovery of salivary glands may occur in the first year after radiation therapy, but recovery is usually not complete, especially if the salivary glands were directly irradiated. Salivary glands that were not irradiated may become more active to offset the loss of saliva from the destroyed glands. Careful oral hygiene can help prevent mouth sores, gum disease, and tooth decay caused by dry mouth. The following are guidelines for managing dry mouth:
y y y y y
Clean the mouth and teeth at least 4 times a day. Floss once a day. Use a fluoride toothpaste when brushing. Apply fluoride gel once a day at bedtime, after cleaning the teeth. Rinse 4 to 6 times a day with a solution of salt and baking soda (mix teaspoon salt and teaspoon baking soda in 1 cup of warm water). Avoid foods and liquids that contain a lot of sugar. Sip water to relieve mouth dryness.

A dentist can provide the following treatments:

y y y y
Solutions to replace minerals in the teeth. Rinses to fight infection in the mouth. Saliva substitutes or medications to stimulate the salivary glands. Fluoride treatments to prevent tooth decay.

Tooth Decay

Dry mouth and changes in the balance of oral bacteria increase the risk of tooth decay. Meticulous oral hygiene (as described in Routine Oral Care) and regular care by a dentist can help prevent cavities.
Taste Changes

Changes in taste are common during chemotherapy and radiation therapy. Change in the sense of taste (dysgeusia) is a common side effect of both chemotherapy and head and/or neck radiation therapy. Foods may have no taste or may not taste as they did before therapy. These taste changes are caused by damage to the taste buds, dry mouth, infection, and/or dental problems. Chemotherapy patients may experience unpleasant taste related to the spread of the drug within the mouth. Radiation may cause a change in sweet, sour, bitter, and salty tastes.

In most patients receiving chemotherapy and in some patients undergoing radiation therapy, taste returns to normal a few months after therapy ends. For many radiation therapy patients, however, the change is permanent. In others, the taste buds may recover 6 to 8 weeks, or later, after radiation therapy ends. Zinc sulfate supplements may help with the recovery for some patients.
Fatigue

Cancer patients who are undergoing high-dose chemotherapy and/or radiation therapy often experience fatigue (lack of energy) that is related to either the cancer or its treatment. Some patients may have difficulty sleeping. The patient may feel too tired to perform routine oral care, which may further increase the risk for mouth ulcers, infection, and pain. (Refer to the PDQ summary on Fatigue for more information.)
Malnutrition and Nutritional Support

Loss of appetite can lead to malnutrition. Patients undergoing treatment for head and neck cancers are at high risk for malnutrition. The cancer itself, poor diet before diagnosis, and complications from surgery, radiation therapy, and chemotherapy can lead to nutritional shortfalls. Patients can lose the desire to eat due to nausea, vomiting, trouble swallowing, sores in the mouth, or dry mouth. When eating causes discomfort or pain, the patient's quality of life and nutritional well-being suffer. The following suggestions may help patients with cancer meet their nutritional needs:
y y y y
Change the texture of food. Serving food chopped, ground, or blended can reduce the amount of time it needs to stay in the mouth before being swallowed. Eat between-meal snacks to add calories and nutrients. Choose foods high in calories and protein. Take supplements that provide vitamins, minerals, and calories.

Nutritional counseling may be helpful during and after treatment. Nutritional support may include liquid diets and enteral feedings. Many patients treated for head and neck cancers who receive radiation therapy alone are able to eat soft foods. As treatment progresses, most patients will include or switch to liquid diets using high-calorie, high-protein nutritional drinks. Some patients may need enteral tubefeeding to meet their nutritional needs. Almost all patients who receive chemotherapy and head and/or neck radiation therapy at the same time will require enteral nutritional support within 3 to 4 weeks. Studies show that patients benefit when they begin enteral feedings at the start of treatment, before weight loss occurs. Normal eating by mouth begins again when treatment is finished and the site that received radiation is healed. The return to normal eating often needs a team approach, including a speech and swallowing therapist to ease the adjustment back to solid foods. Tubefeedings are decreased as a patient's intake by mouth increases, and are stopped when the patient is able to get enough nutrients by mouth. Although most patients will regain their ability to eat solid foods, many will have lasting complications such as taste changes, dry mouth, and trouble swallowing. These complications can interfere with meeting their nutritional needs and with their quality of life.
Pain

Certain anticancer drugs can cause nerve damage that may result in oral pain. If an anticancer drug is causing the pain, stopping the drug usually stops the pain. Because there may be many causes of oral pain during cancer treatment, a careful diagnosis is important. This

may include obtaining a medical history, performing physical and dental exams, and taking xrays of the teeth. Tooth sensitivity may occur in some patients weeks or months after chemotherapy has ended. Fluoride treatments and/or toothpaste for sensitive teeth may relieve the discomfort. Pain in the teeth or jaw muscles may occur from tooth grinding or stress. Pain in the teeth or jaw muscles may occur in patients who grind their teeth or clench their jaws, often because of stress or the inability to sleep. Treatment may include the following:
y y y y
Muscle relaxers. Drugs to treat anxiety. Physical therapy (moist heat, massage, and stretching). Mouthguards to wear while sleeping.

Jaw Stiffness

A long-term complication of radiation therapy is the growth of benign tumors in the skin and muscles. These tumors may make it difficult for the patient to move the mouth and jaw normally. Oral surgery may also affect jaw mobility. Management of jaw stiffness may include the following:
y y y y
Physical therapy. Oral appliances. Pain treatments. Medication.

Tissue and Bone Loss

Radiation therapy can cause tissue and bone in the treated area to waste away. When tissue death occurs, ulcers may form in the soft tissues of the mouth, grow in size, and cause pain or loss of feeling. Infection becomes a risk. As bone tissue is lost, fractures can occur. Preventive care can lessen the severity of tissue and bone loss. Treatment of tissue and bone loss may include the following:
y y y y y y y y
Eating a well-balanced diet. Wearing removable dentures or appliances as little as possible. Not smoking. Not drinking alcohol. Using topical antibiotics. Using painkillers. Undergoing surgery to remove dead bone or to reconstruct bones of the mouth and jaw. Receiving hyperbaric oxygen therapy, a method of delivering oxygen under pressure to the surface of a wound to help it heal.

Candidiasis
From Wikipedia, the free encyclopedia Jump to: navigation, search

Candidiasis

Classification and external resources

Agar plate culture of Candida albicans

ICD-10

B37.

ICD-9

112

DiseasesDB

1929

MedlinePlus

001511

eMedicine

med/264 emerg/76 ped/312 derm/67

MeSH

D002177

Candidiasis or thrush is a fungal infection (mycosis) of any of the Candida species (all yeasts), of which Candida albicans is the most common.[1][2] Also commonly referred to as a yeast infection, candidiasis is also technically known as candidosis, moniliasis, and oidiomycosis.[3]:308 Candidiasis encompasses infections that range from superficial, such as oral thrush and vaginitis, to systemic and potentially life-threatening diseases. Candida infections of the latter category are also referred to as candidemia and are usually confined to severely immunocompromised persons, such as cancer, transplant, and AIDS patients as well as non-trauma emergency surgery patients.[4] Superficial infections of skin and mucosal membranes by Candida causing local inflammation and discomfort are common in many human populations.[2][5][6] While clearly attributable to the presence of the opportunistic pathogens of the genus Candida, candidiasis describes a number of different disease syndromes that often differ in their causes and outcomes.[2][5]

Contents
[show]
y

[edit] Classification
Candidiasis may be divided into the following types:[3]:308-311
y y y y y y y y y y y y y

Oral candidiasis (Thrush) Perlche (Angular cheilitis) Candidal vulvovaginitis Candidal intertrigo Diaper candidiasis Congenital cutaneous candidiasis Perianal candidiasis Candidal paronychia Erosio interdigitalis blastomycetica Chronic mucocutaneous candidiasis Systemic candidiasis Candidid Antibiotic candidiasis (Iatrogenic candidiasis)

[edit] Signs and symptoms

Most candidial infections are treatable and result in minimal complications such as redness, itching and discomfort, though complication may be severe or fatal if left untreated in certain populations. In immunocompetent persons, candidiasis is usually a very localized infection of the skin or mucosal membranes, including the oral cavity (thrush), the pharynx or esophagus, the gastrointestinal tract, the urinary bladder, or the genitalia (vagina, penis).[1] Candidiasis is a very common cause of vaginal irritation, or vaginitis, and can also occur on the male genitals. In immunocompromised patients, Candida infections can affect the esophagus with the potential of becoming systemic, causing a much more serious condition, a fungemia called candidemia.[5][6] Children, mostly between the ages of three and nine years of age, can be affected by chronic mouth yeast infections, normally seen around the mouth as white patches. However, this is not a common condition.[citation needed] Symptoms of candidiasis may vary depending on the area affected. Infection of the vagina or vulva may cause severe itching, burning, soreness, irritation, and a whitish or whitish-gray cottage cheese-like discharge, often with a curd-like appearance. These symptoms are also present in the more common bacterial vaginosis.[citation needed] In a 2002 study published in the Journal of Obstetrics and Gynecology, only 33 percent of women who were self-treating for a yeast infection actually had a yeast infection, while most had either bacterial vaginosis or a mixed-type infection.[7] Symptoms of infection of the male genitalia include red patchy sores near the head of the penis or on the foreskin, severe itching, or a burning sensation. Candidiasis of the penis can also have a white discharge, although uncommon.[citation needed] However, having

no symptoms at all is common, and a more severe form of the symptoms may emerge later, even up to three months of initial contact.[citation needed]

[edit] Causes
See also: Candida albicans

Candida yeasts are commonly present in humans, and their growth is normally limited by the human immune system and by other microorganisms, such as bacteria occupying the same locations (niches) in the human body.[8] C. albicans was isolated from the vaginas of 19% of apparently healthy women, i.e., those that experienced few or no symptoms of infection. External use of detergents or douches or internal disturbances (hormonal or physiological) can perturb the normal vaginal flora, consisting of lactic acid bacteria, such as lactobacilli, and result in an overgrowth of Candida cells causing symptoms of infection, such as local inflammation.[9] Pregnancy and the use of oral contraceptives have been reported as risk factors,[10] while the roles of engaging in vaginal sex immediately and without cleansing after anal sex and using lubricants containing glycerin remain controversial.[citation needed] Diabetes mellitus and the use of anti-bacterial antibiotics are also linked to an increased incidence of yeast infections.[10] Diet has been found to affect rates of symptomatic Candidiases in some animal infection models,[11] and hormone replacement therapy and infertility treatments may also be predisposing factors.[12] Wearing wet swimwear for long periods of time is also believed to be a risk factor.[13] A weakened or undeveloped immune system or metabolic illnesses such as diabetes are significant predisposing factors of candidiasis.[14] Diseases or conditions linked to candidiasis include HIV/AIDS, mononucleosis, cancer treatments, steroids, stress, and nutrient deficiency. Almost 15% of people with weakened immune systems develop a systemic illness caused by Candida species.[citation needed] In extreme cases, these superficial infections of the skin or mucous membranes may enter into the bloodstream and cause systemic Candida infections. In penile candidiasis, the causes include sexual intercourse with an infected individual, low immunity, antibiotics, and diabetes. Male genital yeast infection is less common, and incidence of infection is only a fraction of that in women; however, yeast infection on the penis from direct contact via sexual intercourse with an infected partner is not uncommon.[15] Candida species are frequently part of the human body's normal oral and intestinal flora. Treatment with antibiotics can lead to eliminating the yeast's natural competitors for resources, and increase the severity of the condition[citation needed]. In the western hemisphere approximately 75% of females are affected at some time in their life.

[edit] Diagnosis

Micrograph of esophageal candidiasis. Biopsy specimen; PAS stain.

Diagnosis of a yeast infection is done either via microscopic examination or culturing. For identification by light microscopy, a scraping or swab of the affected area is placed on a microscope slide. A single drop of 10% potassium hydroxide (KOH) solution is then added to the specimen. The KOH dissolves the skin cells but leaves the Candida cells intact, permitting visualization of pseudohyphae and budding yeast cells typical of many Candida species. For the culturing method, a sterile swab is rubbed on the infected skin surface. The swab is then streaked on a culture medium. The culture is incubated at 37 C for several days, to allow development of yeast or bacterial colonies. The characteristics (such as morphology and colour) of the colonies may allow initial diagnosis of the organism that is causing disease symptoms.

[edit] Treatment
In clinical settings, candidiasis is commonly treated with antimycoticsthe antifungal drugs commonly used to treat candidiasis are topical clotrimazole, topical nystatin, fluconazole, and topical ketoconazole. For example, a one-time dose of fluconazole (150-mg tablet taken orally) has been reported as being 90% effective in treating a vaginal yeast infection.[16] This dose is only effective for vaginal yeast infections, and other types of yeast infections may require different dosing. In severe infections amphotericin B, caspofungin, or voriconazole may be used. Local treatment may include vaginal suppositories or medicated douches. Gentian violet can be used for breastfeeding thrush, but when used in large quantities it can cause mouth and throat ulcerations in nursing babies, and has been linked to mouth cancer in humans and to cancer in the digestive tract of other animals.[17] Chlorhexidine gluconate oral rinse is not recommended to treat candidiasis[18] but is effective as prophylaxis;[19] chlorine dioxide rinse was found to have similar in vitro effectiveness against candida.[20] C. albicans can develop resistance to antimycotic drugs,[21] recurring infections may be treatable with other anti-fungal drugs, but resistance to these alternative agents may also develop.

[edit] History
The genus Candida and species C. albicans was described by botanist Christine Marie Berkhout in her doctoral thesis at the University of Utrecht in 1923. Over the years, the classification of the genera and species has evolved. Obsolete names for this genus include Mycotorula and Torulopsis. The species has also been known in the past as Monilia albicans and Oidium albicans. The current classification is nomen conservandum, which means the name is authorized for use by the International Botanical Congress (IBC).[22] The genus Candida includes about 150 different species, however, only a few are known to cause human infections: C. albicans is the most significant pathogenic species. Other Candida species pathogenic in humans include C. tropicalis, C. glabrata, C. krusei, C. parapsilosis, C. dubliniensis, and C. lusitaniae.

[edit] Society and culture

Some alternative medicine proponents postulate a widespread occurrence of "systemic candidiasis" (or candida hypersensitivity syndrome, yeast allergy, or gastrointestinal candida

overgrowth). The view was most widely promoted in a book published by Dr. William Crook,[23] which hypothesized that a variety of common symptoms such as fatigue, PMS, sexual dysfunction, asthma, psoriasis, digestive and urinary problems, multiple sclerosis, and muscle pain, could be caused by subclinical infections of Candida albicans.[23] Crook suggested a variety of remedies to treat these symptoms, ranging from dietary modification, prescription antifungals, to colonic irrigation. With the exception of the few dietary studies in the urinary tract infection section conventional medicine has not used most of these alternatives, since there is limited scientific evidence to prove their effectiveness, or that subclinical "systemic candidiasis" is a viable diagnosis.

The Dentist's Role in Managing Oral Complications of Cancer Therapies

Written by J. Mark Barry, DDS, MBA

More than a million new cases of cancer are diagnosed in the United States each year.1 In light of oral complications of cancer therapies, it is vital for the dental team to assume a more comprehensive role in the management of these patients. Optimal management of the cancer patient involves an interdisciplinary approach that requires assessment, communication, and interaction among the healthcare team during all stages of cancer therapy. Timely and effective dental management of cancer patients is an area that both the medical and dental profession may overlook. When an individual is diagnosed with a life-threatening cancer that requires extensive therapy, the condition of the oral cavity may not be a priority. The patient is more concerned about survival and the implications of the prospective treatments. Nevertheless, oral complications from cancer therapies can seriously compromise patients health and quality of life, as well as affect their ability to complete the planned cancer treatment. Oral complications can be so severe that patients may not be able to tolerate the prescribed therapy and may either discontinue or postpone scheduled treatments.1 Therefore, it is paramount that the dentist is educated and prepared to treat these patients when they are seen in the office. The 4 major types of cancer therapy that affect the oral cavity are head and neck irradiation, chemotherapy, blood and bone marrow transplant, and head and neck surgery.2 Oral complications occur in almost 100% of head and neck radiation patients, up to 75% of blood and bone marrow transplant recipients, and almost 40% of patients receiving chemotherapy.1 Common oral complications of cancer treatments include the following: (1) Mucositis: this is marked by inflammation and ulceration of the mucosal lining of the oral cavity.3 (2) Infection: mylosuppression results in neutropenia, which makes the patient susceptible to bacterial, viral, and fungal infections.4 (3) Xerostomia: the subjective complaint of dry mouth results from a decrease in the production of saliva.5 Prolonged oral complications of radiation therapy include the following: (1) Rampant caries: postradiation damage to the salivary glands creates an environment conducive to significant dental decay.6 (2) Trismus: this results from a loss of elasticity of the masticatory muscles, restricting normal opening of the mouth.1 (3) Osteoradionecrosis: these complications of radiation therapy are associated with hypovascularity and necrosis of bone followed by trauma-induced or spontaneous mucosal breakdown, leading to a nonhealing wound.7 The 3 stages of managing the cancer patient include diagnosis and pretherapy assessment, oral care during therapy, and oral care after completion of cancer therapy. DIAGNOSIS AND PRETHERAPY ASSESSMENT The pretherapy stage is that period of time from diagnosis of the cancer to the initiation of treatment. Patient education, optimal oral hygiene, adequate nutrition, and avoiding tobacco and alcohol are critical components in helping to prevent or minimize oral complications.1 A thorough dental examination should be conducted to include the following: (1) Hard and soft tissues, including periodontal status and oral hygiene. The condition of existing restorations, tooth mobility, and tooth vitality are also evaluated. (2) Previous oral trauma and history of mucocutaneous disorders such as herpes simplex infection, aphthous ulcers, and candidiasis. (3) Observation of salivary function/flow by expressing saliva from the parotid duct. (4) Obtaining appropriate radiographs (panoramic and intraoral bite-wing radiographs at a minimum).

(5) Coordinating a plan with the patient, family, and oncologist for treatment of emergent care as well as long-term maintenance. The dentist should obtain the following information from the oncologist: (1) The patients current health history, cancer diagnosis, and prognosis. (2) If chemotherapy is planned, the anticipated number of treatment cycles and route of administration of the chemotherapeutic agents. (3) A baseline complete blood count. (4) If radiation is planned, the cumulative radiation dose, schedule, and site to be irradiated. The patient who receives a cumulative dose of more than 7,000 rad (70 Gy) has a signifi-cantly greater chance of developing osteoradionecrosis than patients receiving less than 5,000 rad (50 Gy).2 Patients should be counseled regarding expected oral complications from cancer therapy. A thorough dental prophylaxis and oral hygiene instruction to include the use of an extrasoft toothbrush with daily flossing is needed to minimize future oral problems. Denture patients should remove their dentures at night and soak them in a cleanser. Patients with re-movable appliances should be told to scrub the prosthesis daily with a denture brush. Sources of odontogenic infection should be eliminated. Nonrestorable fractured teeth, advanced caries, teeth with a poor periodontal prognosis, partially erupted third molars with the potential for pericoronitis, and teeth within the radiation field that have unresolved apical lesions should be considered for extraction. Ideally, extractions for patients undergoing radiation therapy should be performed about 3 weeks before the initiation of therapy, with the minimum being 14 days. For chemotherapy, it is recommended to allow 3 to 5 days in the maxilla, 5 to 7 days in the mandible, and 7 to 10 days for third molars.2 Conventional endodontic therapy should be accomplished on teeth outside the radiation field that present with necrotic or infected periapical lesions. It is important to take impressions during the pretherapy phase so that custom fluoride trays and/or occlusal splints to protect against a bruxism habit can be fabricated.2 DURING CANCER THERAPY Cancer treatment usually lasts approximately 30 to 45 days, however, some individuals may receive chemotherapy for several years depending on the type of cancer and protocol used.2 A cycle of chemotherapy typically consists of administration over a 3-day to 5-day period, followed by immunosuppression marked by a decreased neutrophil count, and then recovery sufficient to proceed with the next course of chemotherapy. While elective dental treatment should be deferred during cancer therapy, there may be times when emergency treatment must be performed. If dental treatment is necessary during chemotherapy, the oncologist should be consulted and a complete blood count requested. The risk of infection and septicemia is greatest when the patients neutrophil count is below 1,000/mm3.8 A decreased platelet count can also occur as a result of chemotherapy, placing the patient at risk for hemorrhage. Emergency treatment should only be performed if the absolute neutrophil count is greater than 1,000/mm3 and the platelet count is greater than 50,000/mm3. Antibiotic prophylaxis and/or aggressive use of antibiotics should be considered for the neutropenic patient.8 If the patient has a central venous catheter for the delivery of chemotherapy, then the American Heart Association regimen for antibiotic prophylaxis should be implemented.1 The importance of good oral hygiene before, during, and after cancer therapy cannot be over-emphasized. In conjunction with a regimented oral hygiene program, the use of oral rinses has been proven to be quite effective. Alkaline saline (salt/bicarbonate) mouthrinses soothe and hydrate gingival and mucosal tissues, clean, lubricate tissues, remove debris, dissolve and dilute thick saliva, and neutralize acids.3 The use of chlorhexidine gluconate 0.12% has been recommended for many years to control plaque accumulation in patients undergoing cancer therapy. However, routine use is not advisable because of the possible emergence of Gram-negative bacilli infections in the oropharynx, the alcohol content may be irritating to patients with mucositis, and the potential for chlorhexidine to interfere with nystatin preparations during candidiasis treatment.9 Chemotherapeutic agents predominantly affect the rapidly dividing cells of the target tumor, resulting in mucositis and ulceration of the mucosal lining of the mouth, pharynx, and esophagus. The eroded or denuded surfaces may provide a port of entry for infectious organisms to the systemic circulation.2 Mucositis is usually associated with ulceration, pain, and bleeding. The patient may describe a burning sensation of the mucosa within 7 to 10 days of beginning chemotherapy. The initial clinical manifestation is erythema and inflammation. Over the next 3 to 5 days erosion and ulceration develop and persist for the next 2 weeks until the termination of chemotherapy.10 During radiation therapy, patients will typically develop mucositis during the second week of radiation therapy. The condition slowly subsides a few weeks after completion of radiation treatment.8 The inflammatory response of the radiation-induced mucositis varies in degree depending on the dosage, target area, and duration of treatment.4 Topical anesthetics and coating agents can be effective in providing symptomatic relief for oral mucositis. Diphenhydramine or Benadryl elixir (Parke-Davis) mixed 1:1 with Kaopectate (UpJohn) coats the mucosa and soothes the pain associated with mucositis. The patient should rinse and expectorate with this mixture every 2 hours.3 Viscous lidocaine can also be used as a coating agent. The patient will rinse for 30 seconds and expectorate.8 When these topical anesthetics are used, the patient should be warned not to swallow and should be aware of the possibility of an increased gag reflex. The patient with chemotherapy-induced mucositis is at high risk for developing a secondary herpes simplex virus infection. Mucositis complicated by herpes infection tends to be more severe and has a longer duration. For leukemia patients as well as those re-ceiving a bone marrow transplant, reactivation of the herpes virus occurs in 50% to 80% of patients who are seropositive for herpes.2 Prophylactic acyclovir (Glaxo Wellcome) is often used in bone marrow transplant patients. However, it is not routinely used with patients who have chemotherapy-induced mucositis.2 The prophylactic regimen for acyclovir is 400 mg 2 times a day for up to a year and then re-evaluation. Patients with a prior history of herpes infection or a positive culture for herpes should be given an acute regimen as follows: acyclovir (200 mg) 5 times a day for 7 days.11

Table. Preventive/Therapeutic Guide for the Cancer Patient. 1.1 % neutral NaFl gel, dentifrice (5,000 ppm) chlorhexidine gluconate 0.12 % (Not recommended for routine use during cancer therapy.) Pre +ox +ox During +ox +ox Post +ox +ox

5% NaFl varnish (22,600 ppm) alkaline saline (salt/bicarbonate) rinse diphenhydramine/Kaopectate 1:1 viscous lidocaine acyclovir (200 mg) x 50 1 tab bid (prophylactic regimen) acyclovir (200 mg) x 35 1 cap 5x/day x 7 days (acute or prodrome) nystatin ointment (15-g tube), apply to affected area qid clotrimazole (Mycelex) troches (10 mg) x 70, 1 troche 5x per day Oral Balance gel (Laclede) Omni Plaque Fighter Spray (Omni Oral Pharmaceuticals) Biotene gum with xylitol (Laclede) Pilocarpine HCl (Salagen) tablets Key: radiation therapy + chemotherapy o

+ox

+ox +ox +ox +ox x o +ox +ox +ox +ox +ox

+ox

+ + + + + +

blood and bone marrow transplant x

Fungal or candidial infections of the oral mucosa are common in patients undergoing chemotherapy. Once established in the oral cavity, candidiasis has the potential for infecting the esophagus and becoming a systemic infection. Mild cases should respond to nystatin ointment or clotrimazole troches (Mycelex, Bayer). (See Table for regimen.) More severe infections or nystatin-resistant patients should be treated with amphotericin B, administered intravenously, to prevent systemic dissemination.8 POST-CANCER THERAPY After chemotherapy, it is important to establish a regular recall schedule with a dental prophylaxis provided every 3 to 4 months. Before the commencement of routine dental treatment, it is necessary to confirm a normal hematological status. Due to immunosuppression, leukemia patients or bone marrow recipients are at continued risk of herpes infection. The use of prophylactic acyclovir may be indicated for these patients during the post-cancer therapy stage.2 Several long-term oral complications from radiation therapy may adversely affect the patients quality of life. Xerostomia is the most common and significant dental problem in irradiated patients. The severity depends on the radiation dosage, location, and the salivary glands that are exposed. Xerostomia can cause discomfort, affect the fit of removable prostheses, and make it difficult to chew and swallow. Radiation-induced xerostomia is rapid in onset, pronounced, and irreversible. Because xerostomia is almost certain to persist after therapy, appropriate management is paramount to prevent the progression of extensive dental caries.6 Figure 1 shows a 70-year-old African American male with a history of head and neck radiation status post 10 years. Only 4 visible teeth remain, and several other teeth are severely broken down with remaining tooth structure at or below the gingiva. Treatment of radiation xero-stomia and accompanying discomfort includes replacement therapy and/or stimulation of salivary flow, caries prevention with antimicrobials and fluoride treatments, and the prevention of secondary fungal infections. Topical salivary substitutes moisturize the oral cavity. Oral Balance (Laclede) is a long-lasting lubricant gel that adheres to the mucosa and provides symptomatic relief from oral dryness for several hours. It contains the antimicrobial factors lactoferrin, lactoperoxidase, and lysozyme. Omni Plaque Fighter Spray (Omni Oral Pharmaceuticals) contains 1.2% poloxamer 407 dimeticone, an agent that coats and protects the mucosa for several hours. Chewing gums with xylitol as a nonfermentable sweetener have shown encouraging results in reducing caries.12 Xylitol is a 5-carbon sugar alcohol that has demonstrated anticariogenic properties. Due to its nonfermentable property, xylitol-containing chewing gums such as Biotene (Laclede) can contribute to stabilizing the carious process.13 If functioning salivary gland tissue remains after radiation therapy, then prescribing salivary stimulants such as Pilo-carpine HCl (Ciba Vision) may be beneficial. Stimulated saliva contains antibacterial enzymes and buffering components that neutralize acids. The use of Pilocarpine HCl may eliminate or reduce the need for the patient to sip water frequently or use salivary substitutes. Patients may find it helpful to use Pilocarpine HCl 30 to 60 minutes before mealtime to assist in mastication.2 Pilocarpine HCl is available in solution 1 mg/cc, 3 tsp daily, or 5-mg tablets (Salagen), 3 to 4 tabs daily. Contraindications to Pilo-carpine HCl include uncontrolled asthma, narrow angle glaucoma, and allergy to the drug.10 Chlorhexidine gluconate 0.12% can be used to help reduce the level of Streptococcus mutans in patients receiving head and neck radiation.14 Treatment with chlorhexidine gluconate 0.12% consists of a 14-day regimen (bid), which is adequate to achieve a therapeutic endpoint. Any more than 2 weeks of treatment is not effective and therefore should be discouraged. Chlorhexidine gluconate is a highly effective antimicrobial rinse and will suppress S. mutans from 12 to 26 months.12 While chlorhexidine acts to decrease the microbial load initially, the daily and long-term use of fluoride is critical in preventing caries in patients receiving radiation therapy. Neutral sodium fluoride and stannous fluoride products are commonly used for home care. Most 0.4% SnF2 gels have a pH of about 4.7, and the 0.63% SnF2 rinses have a pH of 2.8 to 3.5. Because xerostomic patients lack the buffering capacity of saliva, the acidity of the SnF2 products may etch teeth, composite restorations, and porcelain restorations, as well as irritate gingival tissues. The 1.1% neutral NaF products (5,000 ppm) have a more neutral pH, do

Figure 1. Devastating effect of radiation-induced caries.

not etch teeth or dental materials, and are not irritating to the mucosa.2 While long-term studies have shown that the use of these neutral NaF gels reduces the incidence of caries, compliance is a common problem with the use of trays or brush-on techniques.15 One recommendation is to have the patient use a 1.1% neutral NaF (5,000 ppm) dentifrice.15 In addition to the daily use of the neutral 1.1% NaF gels and dentifrices (5,000 ppm), fluoride varnishes such as Duraphat (Colgate Oral Pharmaceuticals) can be used. These contain 5% NaF (22,600 ppm) and are intended for office use.12 They are effective in preventing carious lesions on smooth surfaces.16 The fluoride varnish is painted on the teeth and can be applied every 2 to 3 months. It also is very effective in reducing tooth and root sensitivity. Radiation-induced xero-stomia will result in an oral environment that promotes the overgrowth of Candida albicans. Patients are likely to require treatment with antifungal medications in addition to the therapies prescribed for dry mouth. The same regimen of antifungal medications described during cancer therapy may be used in the post-cancer therapy stage.3 The post-radiation therapy patient should be placed on a 3-month dental prophylaxis schedule. Good oral hygiene and patient education becomes a lifelong commitment. Note that the exposure to radiation may cause some patients to develop trismus resulting from fibrosis of the mastication muscles. During the post-radiation period, these patients can be placed on a daily regimen of opening and closing exercises using tongue depressors taped together.6 Muscle relaxers such as cyclobenzaprine (Flexeril, McNeil) and antianxiety medications such as diazepam (Valium, Roche Pharmaceuticals) may also be useful in helping to treat trismus. For the patient requiring fabrication of a removable prosthesis, a thorough evaluation of salivary function and load-bearing tissues should be performed. The limited blood supply to the hard and soft tissues of the mandible may mean that the patient will not be able to tolerate a removable prosthesis. Implants can be considered as an option 12 to 18 months following radiation therapy. If possible, an implant-supported prosthesis is preferable to a conventional denture.2 Osteoradionecrosis is one of the most severe and serious complications of radiation therapy. It involves a nonhealing wound caused by trauma or spontaneous mucosal breakdown exposing hypovascular bone. Patients complain of pain and foul odor, which is due to the accumulation of debris in the defect and exposure of bone to oral fluids. The incidence of osteoradionecrosis is greater for the mandible than for the maxilla, likely because of the greater vascularity of the maxilla.7 Periodontal therapy for irradiated patients should be approached with caution. Flap surgery with or without osseous recontouring should be avoided due to the potential for osteoradionecrosis. Special care should be taken to avoid tissue trauma when providing deep scaling and root planing. If extractions must be performed during the post-radiation period, then primary closure and perioperative antibiotics should be employed. If extensive surgery is required, prophylactic hyperbaric oxygen therapy with antibiotics is advisable.2 CONCLUSION The dental profession is primarily responsible for the management of oral care for patients undergoing cancer treatment. The dentist should play a key role in early recognition and care as well as in educating the oncologist about the timeliness of such care. Patients should understand that intervention by the dentist could prevent potentially devastating consequences. A long-term partnership between the patient and dentist is paramount in maintaining excellent oral hygiene over a lifetime. The result will be a much-improved quality of life for these patients.

Conditions Affected By Both Chemotherapy and Head/Neck Radiation

Xerostomia

Xerostomia is caused by a marked reduction in salivary gland secretion [1,2] and has a significant impact on quality of life.[3] Symptoms and signs of xerostomia include dryness, burning sensation of the tongue, fissures at lip commissures, atrophy of dorsal tongue surface, difficulty in wearing dentures (edentulous patients), and increased thirst. Radiation therapy can damage salivary glands, causing xerostomia (symptoms of dry mouth) and salivary hypofunction. In addition, selected chemotherapeutic agents (singly or in combination) have been implicated in causing salivary dysfunction; however, this effect has not been well documented. Ionizing radiation to salivary glands results in inflammatory and degenerative effects on salivary gland parenchyma, especially serous acinar cells. Salivary flow decreases within 1 week after starting radiation treatment and xerostomia becomes apparent when doses exceed 10 Gy. Doses larger than 54 Gy are generally considered to induce irreversible dysfunction. The degree of dysfunction is related to the radiation dose and volume of glandular tissue in the radiation field. Parotid glands may be more susceptible to radiation effects than submandibular, sublingual, and other minor salivary glandular tissues. Salivary gland tissues that have been excluded from the radiation portal may become hyperplastic, partially compensating for the nonfunctional glands at

other oral sites. Generally stated, some degree of salivary gland recovery is seen over the first 6 months after radiation therapy. Maximum recovery is generally reported by 12 months posttherapy, but it is usually incomplete and the overall degree of dryness can range from mild to severe. One study demonstrated successful surgical submandibular gland transfer to the submental space resulting in a functioning gland even after radiation with appropriate shielding.[4] Xerostomia alters the mouths buffering capacity and mechanical cleansing ability, thereby contributing to dental caries and progressive periodontal disease. Development of dental caries also is accelerated in the presence of xerostomia due to reduction in delivery to the dentition of antimicrobial proteins normally contained in saliva. Saliva is necessary for the normal execution of oral functions such as taste, swallowing, and speech. Unstimulated whole salivary flow rates less than 0.1 mL per minute are considered indicative of xerostomia (normal salivary flow rate = 0.30.5 mL/minute). Xerostomia produces the following changes in the mouth that collectively cause patient discomfort and increased risk for oral lesions:
y y y y y
Salivary viscosity increases, with resultant impaired lubrication of oral tissues. Buffering capacity is compromised, with increased risk for dental caries. Oral flora becomes more pathogenic. Plaque levels accumulate due to the patients difficulty in maintaining oral hygiene. Acid production after sugar exposure results in further demineralization of the teeth and leads to dental decay.

Patients who experience xerostomia must maintain excellent oral hygiene to minimize risk for oral lesions. Periodontal disease can be accelerated and caries can become rampant unless preventive measures are instituted. Multiple preventive strategies should be considered (refer to the list on the Oral and Dental Management of the Xerostomic Patient below). The following is an example of a patient protocol: Perform systematic oral hygiene at least 4 times a day (after meals and at bedtime):
y y y y y
Use a fluoridated toothpaste when brushing. Apply a prescription-strength fluoride gel at bedtime to clean teeth. Rinse with a solution of salt and baking soda 4 to 6 times a day ( tsp salt and tsp baking soda in 1 cup warm water) to clean and lubricate the oral tissues and to buffer the oral environment. Avoid foods and liquids with a high sugar content. Sip water to alleviate mouth dryness.

Oral and Dental Management of the Xerostomic Patient [2]

y
Plaque removal:

y y y y y y y y y y

Tooth brushing. Flossing.

Other oral hygiene aids. Remineralizing solutions: Fluoride and calcium/phosphates. Topical high concentration fluorides. Children: topical and systemic.

Adults: topical. Topical antimicrobial rinses: Chlorhexidine solutions/rinses (Peridex). Povidone iodine oral rinses. Tetracycline oral rinses.

Sialogogues:

y y y y

pilocarpine (Salagen) cevimeline (Evoxac) bethanechol antholetrithione (Sialor)

[Note: Prescription-strength fluorides should be used because nonprescription fluoride preparations are inadequate in the face of moderate-to-high dental caries risk. If drinking water does not have adequate fluoride content to prevent dental decay, then oral fluoride (i.e., drops, vitamins, etc.) should be provided.] Use of topical fluoride has demonstrable benefit in minimizing caries formation. During radiation treatment, it has been recommended that topical 1% sodium fluoride gel be applied daily into mouth guards that are 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. Management of xerostomia also includes use of saliva substitutes or sialagogues. Saliva substitutes or artificial saliva preparations (oral rinses containing hydroxyethylcellulose, hydroxypropylcellulose, or carboxymethylcellulose) are palliative agents that relieve the discomfort of xerostomia by temporarily wetting the oral mucosa. Sialagogues pharmacologically stimulate saliva production from intact salivary glandular tissues.[1,5] Submandibular gland transfer has been used for xerostomia.[6] 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; 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 patients 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/day). 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. Nausea, chills, rhinorrhea, vasodilation, increased lacrimation, bladder pressure (urinary urgency and frequency), dizziness, asthenia, headache, diarrhea, and dyspepsia are also reported, typically at doses higher than 5 mg 3 times a day. Pilocarpine usually increases salivary flow within 30 minutes after ingestion. Maximal response may occur only after continual use. In a randomized study of 249 patients with head and neck cancer, however, 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.[7] Cevimeline (30 mg 3 times a day) also appears anecdotally to have efficacy in managing radiation-induced xerostomia. Although to date cevimeline is only approved for use in the management of Sjgren syndrome, appropriate clinical trials are under way and its efficacy should soon be established. While cevimeline has greater selective affinity for M3 muscarinic receptors than pilocarpine, whether this can prove advantageous for treating radiation xerostomia remains unclear. 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 head and neck cancer. Studies have reported varying degrees of effectiveness.[8,9] 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.[10]
Topical oral antimicrobials

Oral antimicrobials may also be of value. For example, chlorhexidine gluconate is a broad spectrum antimicrobial with in vitro activity against gram-positive and gram-negative organisms, yeast, and other fungal organisms. It also has the desirable properties of sustained binding to oral surfaces and minimal gastrointestinal absorption, thereby limiting adverse systemic effects. Use of chlorhexidine gluconate in the prophylaxis of oral infections shows promise in reducing inflammation and ulceration, as well as in reducing oral microorganisms in high-risk patient groups. Chlorhexidine gluconate 0.12% oral rinse may be used in conjunction with prophylactic topical and systemic antimicrobials in the high-risk patient populations. Chlorhexidine oral rinse has been used in combination with fluoride gel to control cariogenic flora. Chlorhexidine oral rinse may be used as a mouthwash and gargle, but should not be ingested. Commercially marketed formulations may also contain appreciable quantities of alcohol, which may exacerbate xerostomia. This may be particularly important since xerostomia may cause a shift toward a more cariogenic flora.
Dysgeusia

Dysgeusia can be a prominent symptom in patients who are receiving chemotherapy or head/neck radiation.[11-16] Etiology is likely associated with several factors including direct neurotoxicity to taste buds, xerostomia, infection, and psychologic conditioning. Patients receiving cancer chemotherapy may experience unpleasant taste secondary to diffusion of drug into the oral cavity. In addition, chemotherapy patients often describe dysgeusia in the early weeks after cessation of the cytotoxic therapy. The symptom in general is reversible, however, and taste sensation returns to normal in the ensuing months. By comparison, however, a total fractionated radiation dose higher than 3,000 Gy reduces acuity of sweet, sour, bitter, and salt tastes. Damage to the microvilli and outer surface of the taste cells has been proposed as the principal mechanism for loss of the sense of taste. In many cases, taste acuity returns in 2 to 3 months after cessation of radiation. However, many other patients develop permanent hypogeusia. Zinc supplementation (zinc sulfate 220 mg 2 times a day) has been reported to be useful in some patients; the overall benefit of this treatment remains unclear.[17-19]
Fatigue

Cancer patients undergoing high-dose chemotherapy and/or radiation can experience fatigue related to either disease or its treatment.[20] These processes can produce sleep deprivation or metabolic disorders which collectively contribute to compromised oral status. For example, the fatigued patient will likely have impaired compliance with mouthcare protocols designed to otherwise minimize risk of mucosal ulceration, infection, and pain. In addition, biochemical abnormalities are likely involved in many patients. The psychosocial component can also play a major role, with depression contributing to the overall status. (Refer to the PDQ summary on Fatigue for more information.)
Nutritional Compromise

Patients with head and neck cancer are at high risk for nutritional problems. The malignancy itself, poor nutrition before diagnosis, and the complications of surgery, radiation, and

chemotherapy all contribute to malnutrition.[21] In cancer patients, loss of appetite can also occur secondary to mucositis, xerostomia, taste loss, dysphagia, nausea, and vomiting. Quality of life is compromised as eating becomes more problematic. Oral pain with eating may lead to selection of foods that do not aggravate the oral tissues, often at the expense of adequate nutrition. Nutritional deficiencies can be minimized by modifying the texture and consistency of the diet and by adding more frequent meals and snacks to increase calories and protein. Ongoing nutrition assessment and counseling with a registered dietitian should be part of the patients treatment plan.[22] Many patients who receive radiation therapy alone are able to tolerate soft foods; however, as treatment progresses, most patients must transition to liquid diets using high-calorie, high-protein liquid nutritional supplements, and some may require enteral feeding tubes to meet their nutritional needs. Almost all patients receiving concurrent chemotherapy and radiation therapy will become fully dependent on enteral nutritional support within 3 to 4 weeks of therapy. Numerous studies have demonstrated the benefit of enteral feedings initiated at the onset of treatment, before significant weight loss has occurred.[23,24] Oral nutrition is reinstituted after treatment has concluded and the radiated site has adequately healed. Oral nutrition often requires a team approach. The assistance of a speech and swallowing therapist to assess for any swallowing dysfunction resulting from surgery or treatment is often necessary and beneficial in easing the transition back to solid foods. The number of tube feedings can be decreased as a patient's oral intake increases, with tube feeding being discontinued when 75% of a patient's nutrition needs are being met orally. Although most patients will resume adequate oral intake, many will continue to experience chronic complications such as taste changes, xerostomia, and varying degrees of dysphagia that can affect their nutritional status and quality of life.
Introduction Oral cancer is cancer that develops inside the mouth, usually on the surface of the tongue, the lips or the gums. In rare cases, it can also develop in the salivary glands, or in the tonsils.

How common is oral cancer? Approximately 2,700 new cases of oral cancer are diagnosed every year in England and Wales. The condition is more common in men than in women, and most cases develop in people who are 40 years of age, or over. Symptoms of oral cancer include a persistent lump or sore on the lip or in the mouth, pain in the neck and/or a lump in the neck. Oral cancer can have many causes, but the majority of cases are caused by tobacco, including smoking cigars, pipes and chewing tobacco, and excessive alcohol consumption. Both tobacco and alcohol can damage the tissue inside the mouth, triggering cell changes that can lead to cancer.

Oral cancer can be cured if it is detected early enough using a combination of radiotherapy and surgery. However, many people only realise that they have oral cancer once it has progressed to an advanced state, making it more difficult to treat. It is estimated that 920 people die from oral cancer in England and Wales every year. The best way to prevent oral cancer is to avoid smoking or chewing tobacco, to drink alcohol in moderation, and to eat a healthy, balanced diet that includes at least five portions of fruit and vegetables a day. Symptoms Oral cancer tends not to cause any noticeable symptoms during the initial stages of the disease. This is why it is important to have regular dental check-ups, particularly if you are a smoker, and/or a heavy drinker because a dentist may often be able to detect the condition during an examination. You should have a dental check-up at least every two years. However, more frequent check-ups may be recommended if you have a history of tooth, or gum, disease. Symptoms of oral cancer include:

red, or red and white patches on the lining of your mouth, or tongue,

     

mouth ulcer(s) that do not heal, a swelling in your mouth that lasts for more than three weeks, pain when swallowing, a tooth, or teeth, that become loose for no obvious reason, a persistent pain in the neck, and a hoarse voice.

You should be aware that there are many other conditions that can cause similar symptoms. If you have these symptoms, you should therefore not assume that it means that you have oral cancer. However, you should report these symptoms to your GP as soon as possible. Causes

Cancer begins with an alteration to the structure of DNA that is found in all human cells. This is known as a genetic mutation. The DNA provides the cells with a basic set of instructions, such as when to grow and reproduce. The mutation in the DNA changes these instructions, so that the cells carry on growing. This causes the cells to reproduce in an uncontrollable manner, creating a lump of tissue known as a tumour. Most cases of oral cancer are what are known as squamous cell carcinomas. These are cancers that begin on the surface level of tissue, such as the tongue, or the inside of the mouth. The cancer can then spread to other parts of the body, a process that is known as metastasis.

Tobacco and alcohol The two leading causes of oral cancer are tobacco use and excessive alcohol consumption. Both of these substances are carcinogenic, which means that they contain chemicals that can damage the DNA in cells, leading to cancer. The risks of oral cancer increase significantly in somebody who is both a heavy smoker and a heavy drinker, as tobacco and alcohol have a synergistic effect, which means that their combined risk is greater than the sum of their individual risk. For example, research has shown that if you smoke 40 cigarettes a day, but do not drink alcohol, you are five times more likely to develop oral cancer than someone who does not drink or smoke. In the same way, if you do not smoke, but drink an average of 30 pints a week, your risk also increases by a factor of five. However, if you smoke more than 40 cigarettes a day, and you drink an average of 30 pints a week, you are 38 times more likely to develop oral cancer.

Other risk factors

Other risk factors for oral cancers include:

a diet that is high in red meat, processed meat, and fried food,

being exposed to the Human Papillomavrius (HPV), which is a blood-borne virus that is often spread during unprotected sex,

having gastro-oesophageal reflux disease (GORD), which is a digestive condition where acid from your stomach leaks back up through your oesophagus (gullet), and

regularly chewing betel nuts which are mildly addictive seeds, taken from the betel palm tree, and are popular in south east Asian countries. They have a stimulant effect similar to coffee. Betel nuts also have a carcinogenic effect, which can be made worse if they are chewed in combination with tobacco.

Some cases of oral cancer have also been linked to exposure to certain substances, such as asbestos, formaldehyde and sulphuric acid. Excessive exposure to sunlight, or the overuse of sun lamps, or sunbeds, has also been linked to some cases of lip cancer. Diagnosis If you have any of the possible symptoms of mouth cancer, your GP will carry out a physical examination and ask you about your symptoms. If a diagnosis of oral cancer is suspected, you will be referred to a specialist for further testing, usually an oncologist (a doctor who specialises in the treatment of cancer) or an ear, nose and throat (ENT) specialist. Biopsy

It may be necessary to remove a small sample of affected tissue to check for cancerous cells. This procedure is known as a biopsy. Most biopsies are carried out under general anaesthetic, but if the suspected cancerous cells are on the surface of the tissue, it may be possible to carry out a fine needle aspiration biopsy (FNA). This can often be performed using a local anaesthetic on an out-patient basis, which means that you will not have to stay in hospital overnight. During a FNA, the doctor will use a needle and a syringe to remove a small sample of tissue for testing. Although it is not painful, it can feel uncomfortable, and you may experience some bruising after the procedure. Further tests

If the biopsy shows the presence of cancer, further testing will be required to check how advanced it is and how far it spread. This is known as the stage of the cancer. Cancer spreads from the site of the initial tumour into the lymphatic system. The lymphatic system is a series of glands (or nodes) that are spread throughout your body, much like your blood circulation system. These glands produce many of the specialised cells needed by your immune system. Once the cancer reaches the lymphatic system, it is capable of spreading to any other part of your body, including your bones, blood, and organs. However, it is uncommon for oral cancer to spread any further than the surrounding lymph nodes, although in some cases, it may also spread to surrounding bones, such as the jaw bone. Therefore, the tests will examine your lymph nodes, bones, and the tissue near to the site of your initial tumour in order to check for the presence of other tumours. The tests that may be used include:

   

an X-ray, a magnetic resonance imaging (MRI) scan, a computerised tomography (CT) scan, and a positron emission tomography (PET) scan.

A PET scan involves injecting a part of your body with a radioactive 'tracer' chemical which can be seen on a special camera. Further biopsies on nearby lymph nodes may also be carried out.

Treatment Many primary care trusts (PCTs) operate what is known as multi-disciplinary teams (MDTs) for the treatment of oral cancer. An MDT is made up of a number of different specialists, including:

 

a surgeon, a clinical oncologist (a specialist in the non-surgical treatment of cancer, using techniques such as radiotherapy and chemotherapy),

      

a pathologist (a specialist in diseased tissue), a radiologist (a specialist in radiotherapy), a dentist, a dietitian, a social worker, a psychologist, and a speech and language therapist.

You may also be assigned a nurse who specialises in the treatment of oral cancer, who is known as a clinical nurse specialist (CNS). The CNS will be your first point of contact between yourself and the members of the MDT. The CNS will provide information and advice about your treatment plan and the various support services that are available. Before treatment begins Before treatment for oral cancer begins, you will be given a full dental examination, and any necessary dental work will need to be carried out. The radiotherapy will make your teeth more sensitive and vulnerable to infection, so it is important that you have a good level of dental hygiene before treatment begins. A hygienist will also be able to give you advice about how to maintain good dental hygiene. If you are smoking and drinking alcohol it is recommended that you stop because quitting will increase the chances of your treatment being successful. Your CNS will be able to provide you with help and support if you are finding quitting smoking difficult. Your MDT will recommend a treatment plan for you, but the final decision about what treatment you receive will be yours. You may find it useful to draw up a list of questions at home to ask the specialists. For example, you may want to know the advantages and disadvantages of a particular treatment, its possible side effects, what you can expect during recovery, and what rehabilitation will be required after the treatment has finished. In some circumstances, it may be possible to talk to other people who have had treatment for oral cancer, so that you can discuss both your and their experience. Surgery

For oral cancer, the aim of surgical treatment is to remove any affected tissue, while minimising damage to the rest of the mouth. Photodynamic therapy (PDT)

If the cancer is in its early stages, it may be possible to remove any tumours using a type of laser surgery known as photodynamic therapy (PDT). PDT involves taking a medicine that makes your tissue sensitive to the effects of light. A laser is then used to remove the tumour. Other forms of surgery

If your cancer is more advanced, it may be necessary to remove part of your mouth lining and, in some cases, facial skin. The removed skin can be replaced using a skin flap; a piece of skin that is taken from your forearm, or chest, which is then grafted (joined) to the affected area. If your tongue is affected, it will be necessary to remove part of the tongue. This is known as a partial glossectomy. The tongue is then reconstructed using grafted tissue. If the cancer has spread to your jawbone it will need to be surgically removed. The jawbone can be replaced by taking some bone from another part of your body and grafting it in place. Occasionally, other bones, such as cheekbones, may have to be removed in order to completely remove the cancer. These bones can be replaced with prosthetics, which are molded pieces of plastic that are designed to replicate the shape and appearance of any removed bones. Modern prosthetics are usually very realistic, and although they will take time to get used to, your physical appearance should be largely unaffected. During surgery, your surgeon may remove lymph nodes that are near the site of the initial tumour. This is known as a neck dissection. Neck dissections are often carried out as a preventative measure, as the nodes may contain small amounts of cancerous cells that cannot be detected through testing. Radiotherapy

Radiotherapy uses doses of radiation to kill cancerous cells. It may be possible to remove the cancer using radiotherapy alone, but it is usually used after surgery in order to prevent the cancer from reoccurring. The treatment is normally given every day over the course of 3-7 weeks, depending on the size and spread of your cancer.

While it kills cancerous cells, radiotherapy can also affect healthy tissue and has a number of side effects. These include:

         

sore, red skin (like sunburn), mouth ulcers, sore mouth and throat, dry mouth, loss of taste, loss of appetite, tiredness, nausea, stiff jaw, and bad breath.

Your MDT will monitor any side effects that you have and, where possible, provide treatment for them. For example, protective gels can be used to treat mouth ulcers, and medicines are available that help to treat the symptoms of dry mouth. The side-effects of radiotherapy can be distressing, but it is important to realise that most of them will pass once the radiotherapy is complete. Internal radiotherapy Internal radiotherapy is a type of radiotherapy that is often used to treat cancers of the tongue that are in their early stages. It involves sticking radioactive wires, or needles, directly into the tumour while you are under a general anaesthetic. The wires, or needles then release a dose of radiation into the tumour. While the internal radiotherapy is taking place, you will be kept in a single room at the hospital. While the levels of radiation you are receiving are generally safe, your treatment staff will only be able to spend short periods of time in the room with you. This is because they are dealing with radiation every day, so it is necessary to minimise any exposure as a precaution. Visits by friends and family will also have to be restricted due to the risk of exposure, and pregnant women and children will be unable to visit you. Most courses of internal radiotherapy last between one to eight days.

The radioactive implants will cause your mouth to become swollen, and you will experience some pain five to 10 days after the implants are removed. However, the pain should subside within a few weeks. During this time, you may find it more comfortable to eat cool, plain, soft foods, and avoid drinking spirits, or smoking. Chemotherapy Chemotherapy is often used in combination with radiotherapy when the cancer is widespread, or if it is thought that there is a significant risk of the cancer returning. Chemotherapy involves the use of powerful cancer-killing medicines. These medicines damage the DNA of the cancerous cells, interrupting their ability to reproduce. The medicines that are used in chemotherapy can sometimes damage healthy tissue, as well as the cancerous tissue and, unfortunately, adverse side effects are common. Side effects of chemotherapy can include:

   

nausea, vomiting, hair loss, and tiredness.

However, the side effects should stop once the treatment has finished. Chemotherapy can also weaken your immune system, making you more vulnerable to infection. Monoclonal antibody therapy Monoclonal antibodies are antibodies that are genetically engineered in a laboratory. They are designed to directly target and attack cancer cells. This is why monoclonal antibody therapy is sometimes referred to as targeted therapy. The type of monoclonal antibody therapy that is involved in the treatment of oral cancer uses a medicine known as cetuximab. Cetuximab targets special proteins that are found on the surface of cancer cells, known as epidermal growth factor receptors (EGFR). EGFRs help the cancer to grow, so by targeting these proteins, cetuximab is designed to prevent the cancer from spreading. It is usually used in combination with chemotherapy and radiotherapy.

Cetuximab is given through a drip into your vein which then slowly administers the first dose, over the space of a few hours. After this, further doses are given on a weekly basis and they should only take an hour. The side effects of cetuximab are usually mild. They include:

    

skin rashes, nausea, diarrhoea, breathlessness, and conjunctivitis (inflammation of the eyes).

Cetuximab has been known to trigger allergic reactions in some people, such as a swollen tongue, or throat. Occasionally, these allergic reactions can be severe and life-threatening. This is known as an infusion reaction. Infusion reactions occur in around 3% of people receiving cetuximab. Most infusion reactions happen within 24 hours of the first time somebody begins treatment, so you will be closely monitored once your treatment begins. If you begin experiencing symptoms of an infusion reaction, anti-allergy medicines, such as corticosteroids, can be used to relieve them. Due to these precautionary measures, deaths from infusion reaction in people taking cetuximab are very rare, occurring in less than 0.1% of cases. Complications

Dysphagia Dysphagia means difficulty swallowing. It is easy to take for granted your ability to swallow food and liquid but, in reality, the process relies on a complex interaction of muscles which can be easily disrupted. Both surgery and radiotherapy can affect your tongue, mouth, or throat, resulting in dysphagia. Dysphagia is a potentially serious problem because aside from the obvious risk of malnutrition, there is a chance that small particles of food could enter your airways and become lodged in your lungs. This can trigger a chest infection, known as aspiration pneumonia.

Videofluoroscopy

If you are experiencing problems with your swallowing, your swallowing reflex will need to be assessed by a speech and language therapist (SLT). One way that a SLT can assess this reflex is to carry out a test known as a videofluoroscopy. A videofluoroscopy involves adding a special dye to both liquid and food which you then swallow. The special dye allows the SLT to study your swallowing reflexes by using X-rays and checking whether there is a risk of food entering your lungs. If this is the case, it may be necessary in the short-term, to provide you with a feeding tube, which will be directly connected to your stomach. The SLT will teach you exercises so that you can 'relearn' how to swallow properly. Your ability to swallow will improve over time as you learn the exercises, and the damaged tissue is allowed to heal. However there is a chance that your swallowing reflex will never fully recover. In some circumstances, it may be necessary to alter your diet in order to make swallowing easier. A nutritionist will be able to provide you with dietary advice.

Speech therapy Much like swallowing, your ability to speak clearly is governed by a complex interaction of muscles, bones, and tissue, including your tongue, teeth, lips, and soft palate (a section of tissue that is found at the back of the mouth). Both radiotherapy and surgery can affect this process, making pronouncing certain sounds and words difficult. In more severe cases, you may experience problems in making yourself understood. A SLT will be able to help you improve your verbal communication skills by teaching you a series of exercises that develop your range of vocal movements, as well as teaching you new ways to produce sounds. Prevention Tobacco

If you are currently using tobacco, you should quit. This includes all forms of tobacco including:

  

cigarettes, pipe tobacco, cigars,

 

cigarillos, snuff (powdered tobacco that is designed to be snorted into the nose), and

chewing tobacco.

All of these products will increase your chances of developing oral cancer, as well as lung and bladder cancer. Quitting smoking (or using other tobacco products) will bring both short and long-term health benefits. For example, if you manage to go without smoking for 10 years, your risk of developing oral cancer will be the same as somebody who has never smoked. The NHS Smoking Helpline can offer you advice and encouragement to help you quit smoking. You can call on 0800 022 4 332, or visit the NHS Go Smokefree website. Your GP, or pharmacist, will also be able to provide you with help and advice about giving up smoking. Alcohol

Make sure that you stay within the recommended guidelines for alcohol consumption in order to reduce your risk of developing oral cancer, as well as liver cancer. The recommended daily amount of alcohol consumption is three to four units for men, and two to three units for women. A unit of alcohol is equal to about half a pint of normal strength lager, a small glass of wine, or a pub measure (25ml) or spirits. If you are worried about your drinking and you are finding it difficult to reduce your alcohol consumption, you can call 'Drinkline', which is a national helpline designed to help people who have problems with alcohol. Their telephone number is 0800 917 8282. Diet

Research has shown that eating a 'Mediterranean-style diet' can help reduce your risk of getting oral cancer. This is a diet that is high in fresh vegetables (particularly tomatoes), citrus fruits such as oranges, grapefruits and lemons - plus olive oil, and fish oil. Eating five portions of a variety fruit and vegetables a day will also help to prevent oral cancer, as well as other types of cancer.

Fruit and vegetables contain special chemicals, known as antioxidants, which are thought to help protect cells from becoming damaged. Leafy vegetables, such as lettuce, spinach, and cabbage, are thought to provide the most protection against cancer. Your diet should also be low in fat, and high in starchy foods, such as wholemeal bread, cereals, and potatoes. Self-examination

If you are in a high risk group for getting oral cancer, you should regularly check your mouth for symptoms of oral cancer. If detected early enough, treatment for oral cancer is much more likely to be successful and relatively non-invasive. High risk groups include:

   

smokers (or other tobacco users), heavy drinkers (more than four units a day), men, and those who are 40 years of age, or over.

Use a mirror to check the inside of your mouth, your tongue, and the space under your tongue, for any changes in colour. Also, run your finger around your mouth and tongue to check for any lumps. You should report anything unusual to your dentist, or your GP.

Pathogenesis of Oral Mucositis

The pathological process for oral mucositis starts at the cellular level when chemotherapy or radiation therapy begins. The pathogenesis of oral mucositis is not fully understood but involves direct and indirect mechanisms. Radiation and chemotherapy cause direct injury to the oral epithelium by interfering with the normal turnover time of oral epithelium and by inducing apoptosis. Indirect effects contribute to oral mucositis by the release of inflammatory mediators, loss of protective salivary constituents, and therapy induced neutropenia. Due to the severity of most cancer treatments these cells are not immediately replaced, leaving the lining of the mouth thin and susceptible to injury and infection. In many cases, the lining of the mouth may even shed completely and become inflamed, and ulcerated. The degree of

pain is usually related to the extent of the tissue damage. If the damage is intense, patients may have trouble eating, speaking, or even opening their mouth.

The Five Phases of Oral Mucosal Barrier Injury1

y y
Initiation: Generation of oxidative stress and reactive oxygen species (by chemotherapeutic agents or radiation) Up-regulation: With generation of messengers, DNA damage/cell death, up-regulation of genes and increased production of a number of chemical messengers, e.g. cytokines

Signaling and Amplification: Some of the messengers (particularly pro-inflammatory cytokines) appear to amplify the mucosal injury caused by chemotherapeutic agents/radiation. During this phase, the tissue appears to be relatively healthy with only minor erythema

Ulceration with inflammation: Inflammatory responses together with bacterial colonisation. This phase is characterized by painful lesions

Healing: mucosa appears normal but has been altered and patient is now at increased risk of future episodes or oral mucositis and its complications with subsequent anti cancer therapy.