Pets with Cancer

ORAL COMPLICATIONS

by Kevin A. Hahn, D.V.M., Ph.D., D.A.C.V.I.M. (Oncology)

Etiology

Identification of high-risk patients enables the veterinary care providers to initiate pretreatment evaluation and to recommend prophylactic measures to minimize the incidence and morbidity associated with oral toxicity. The most significant risk factors for the development of oral complications during and following treatment are pre-existing oral or dental disease, inadequate oral care during therapy, and any factors that may compromise oral mucosal integrity. Additional risk factors (not in rank order) include the type of malignancy (involved sites and histology); the antineoplastic agents used, the dose, and the administration schedule; the radiation field, the dose, and the administration schedule; severity and duration of anticipated myelosuppression; and patient age. Pre-existing oral conditions such as dental calculus, broken teeth, faulty restorations, periodontal disease, gingivitis, and prosthodontic appliances contribute to the development of local infections and may serve as a focus for systemic infections. Bacterial and fungal colonization of dental calculus, plaque, dental pulp, periodontal pockets, operculum defects, dentures, and dental appliances constitute a reservoir of pathogenic and opportunistic organisms that may develop into local or systemic infections during episodes of immune suppression or neutropenia. Other sources of irritation may exacerbate mucosal thinning and atrophy, producing local ulceration (stomatitis).
Chemotherapy-induced complications: Because gastrointestinal epithelial cells have a cell turnover rate similar to leukocytes, the period of greatest damage to the oral mucosa frequently correlates with the white blood cell nadir. Resolution of oral toxicity generally coincides with granulocyte recovery. The lips, tongue, floor of the mouth, buccal mucosa, and soft palate are more severely affected by drug toxicity than the hard palate and gingiva; this may be due to their faster rate of epithelial cell turnover. The role of vascularity in stomatitis may be inferred from the effect of topical cryotherapy in preventing or lessening mucositis from agents such as fluorouracil (5-FU). The antineoplastic agents most likely to cause mucositis include Bleomycin, doxorubicin, 5-FU, Methotrexate, Vinblastine, and vincristine. The risk is exacerbated when chemotherapeutic agents that typically produce mucosal toxicity are given in high doses, in frequent repetitive schedules, or in combination with ionizing irradiation (e.g., conditioning regimens prior to bone marrow transplant).
Radiation-induced complications: Local irradiation to the head and neck region not only can cause the specific histologic and physiologic changes of the oral mucosa caused by cytotoxic therapy, but also can result in structural and functional alterations of underlying supportive tissues, including salivary glands and bone. High-dose radiation to tooth-bearing bone causes hypoxia, reduction in vascular supply to the bone, and tissue breakdown leading to bone exposure, infection, and necrosis. Both ionizing radiation to the head and neck regions and antineoplastic agents impair cell division, disrupting normal replacement of the oral mucosa. Radiation damage, however, is anatomically site-specific. It is dependent upon the amount and kind of radiation used, total dose administered, and field size and fractionation. Radiation-induced damage also differs from that induced by chemotherapy in that tissue volumes treated with radiation continue to remain in jeopardy throughout the life of the patient; they are more easily damaged by subsequent toxic drug or radiation exposures, and normal physiologic repair mechanisms are compromised as a result of permanent cellular depopulation.

Surgery-induced complications: In patients with osteoradionecrosis involving the mandible or facial bones, surgical debridement may be disfiguring, and reconstruction efforts may be futile unless tissue oxygenation is improved prior to surgery. Hyperbaric oxygen therapy has been shown to stimulate new capillary formation (angiogenesis) in affected tissues and is being used as an adjunct to surgical debridement in humans.

Prevention

The incidence of oral complications in patients who do not have head and neck malignancies can be reduced significantly when an aggressive approach to oral care is initiated prior to treatment. Primary preventive measures, such as well-balanced nutritional intake, adequate oral hygiene, and early detection of oral problems, are important pretreatment interventions. A veterinary care provider familiar with the oral complications of cancer treatment should examine the patient prior to treatment (with chemotherapy as well as with radiation therapy to the head and neck). Ideally, this examination is performed 2-4 weeks prior to treatment to permit adequate healing of any required dental procedures. The examination allows the veterinarian to determine the condition of the oral mucosa and supportive structures prior to therapy and to initiate necessary interventions that may reduce oral complications during and after therapy. A program of oral hygiene should be initiated and the pet owner should be instructed about the importance of good oral hygiene prior to initiating treatment.

Specific Oral Complications

Mucositis/Stomatitis: The terms mucositis and stomatitis are often used interchangeably but may include some general distinctions. Mucositis describes a toxic inflammatory reaction affecting the gastrointestinal (GI) tract from mouth to anus, which may result from exposure to chemotherapeutic agents or ionizing radiation. Mucositis typically manifests as an erythematous, burn-like lesion or as random, focal-to-diffuse, ulcerative lesions. It may be exacerbated by local factors. Stomatitis refers to any inflammatory reaction affecting the oral mucosa, with or without ulceration, and may be caused or intensified by local factors. Stomatitis can range from mild to severe; the patient with severe stomatitis is unable to take anything by mouth. In common practical usage, however, mucositis and stomatitis are indiscriminately used to describe the same phenomena. Erythematous mucositis may appear as early as three days after exposure to chemotherapy, but more typically within five to seven days. Progression to ulcerative mucositis typically occurs within seven days after the start of chemotherapy. Veterinary care providers should be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate GI (mucosal) toxicity. Combination, or high-dose, chemotherapy may produce severe mucositis. Drugs administered by continuous infusion or frequent, repetitive, intermittent schedules (e.g., vincristine) are more likely to cause mucositis than equivalent amounts of the same drugs given by single bolus infusion. Mucositis is self-limited when uncomplicated by infection and typically heals completely within 2 to 4 weeks. Systematic assessment of the oral cavity following treatment permits early identification of toxicity and initiation of oral hygiene measures designed to prevent or decrease further complications. Once mucositis has developed, its severity and the patient's hematologic status guide appropriate oral management. Meticulous oral hygiene and palliation of symptoms become the focus of care. In the absence of controlled clinical trials, many of the management recommendations are anecdotal.
Infection: Oral mucositis can be complicated by infection in the immunocompromised patient. Not only can the mouth itself become infected, but the loss of the oral epithelium as a protective barrier results in local infections and provides a portal of entry for microorganisms into the systemic circulation. Once mucosal integrity is affected, indigenous oral flora, as well as nosocomial and opportunistic organisms can cause local and systemic infections. As the absolute neutrophil count falls below 1,000 per cubic millimeter, the incidence and severity of infection rises. Patients with prolonged neutropenia are at higher risk for the development of serious infectious complications. Nonpharmacologic approaches to preventing infection and prophylaxis with antimicrobials are being evaluated in controlled trials. Antibiotics used during prolonged neutropenia alter oral flora, creating a favorable environment for fungal overgrowth that may be exacerbated by concurrent steroid therapy. The majority of oral bacterial infections are gram-negative due to the shift in the colonization of the oral cavity from predominantly gram-positive to enteric gram-negative organisms.
Hemorrhage: Hemorrhage may occur during treatment-induced thrombocytopenia and/or coagulopathy. Sites of underlying periodontal disease may bleed spontaneously or from minimal trauma. Oral bleeding may be minimal, with petechiae located on the lips, soft palate, or floor of the mouth, or it may be severe, with oral hemorrhage, especially in the gingival crevices. Spontaneous gingival oozing may occur when platelet counts diminish to less than 50,000 per cubic millimeter.

Xerostomia: Xerostomia is a marked reduction in salivary gland secretion. Clinical symptoms and signs of xerostomia include dryness, a sore or burning sensation (especially involving the tongue), cracked lips, slits or fissures at the corners of the mouth, changes in the tongue surface, and increased frequency and/or volume of fluid intake. A preventive oral care regimen must be initiated to halt destruction. Xerostomia can result from the inflammatory and degenerative effects of ionizing radiation on salivary gland parenchyma, especially serous acinar cells. These changes are often rapid and irreversible, especially when the salivary glands are included in the radiation fields. Salivary flow measurably decreases within 1 week after starting treatment and diminishes progressively with continued treatment. The degree of dysfunction is related to the radiation dose and volume of glandular tissue in the radiation field. Xerostomia alters the mouth's buffering capacity and mechanical cleansing ability, often contributing to dental caries and progressive periodontal disease.

Radiation necrosis: Necrosis and infection of previously irradiated tissue (osteoradionecrosis) is a serious complication for patients who have undergone radiation for head and neck tumors. Radiation-induced oral complications require aggressive dental therapy before, during, and after radiation therapy to minimize the occurrence of severe sequelae (permanent xerostomia, ulcerative caries, radiation-induced osteomyelitis, and osteoradionecrosis).

Intervention Options

Oral care considerations: Routine systematic oral hygiene is extremely important in reducing the incidence and severity of the effects of oncologic treatment such as radiation caries, mucositis, and stomatitis. In patients with mild, occasional xerostomia or with resection involving oral structures, an inspection identifies areas that require attention. Oral hygiene methods include rinsing/irrigation and mechanical plaque removal. Telling pet owners how to perform mouth care is just as important as informing them how to administer a medication. After meals, the oral cavity should be rinsed and/or wiped; wiping of the oral cavity is almost always necessary for patients with xerostomia. Rinsing the oral cavity may not be sufficient for thorough cleansing of the oral tissues; mechanical plaque removal is often necessary. After a routine is developed, mechanical plaque removal may be necessary to assist rinsing. Mechanical plaque removal includes use of gauze, toothettes, toothbrush, and interdental aids such as floss, proxybrush, wooden wedge, or denture brush. Toothettes do not thoroughly cleanse the dentition, although they work very well to clean surgical areas following maxillectomy or hemi-mandibulectomy. Toothettes are also good for cleaning the maxillary/mandibular alveolar ridges of edentulous areas, the palate, the palate with a prominent torus, and the tongue. If xerostomia is present, plaque is thicker and heavier and will not rinse away. Oral care products should be selected carefully; those that produce symptoms or injure the mucosa should not be used. Rinses containing alcohol should be avoided. Since the flavoring agents in toothpastes can irritate and/or burn gingiva and mucosa, a mild toothpaste should be chosen, such as a child's toothpaste. Lip care is important and should include using a moisturizer.
Management of mucositis/stomatitis: Oral care protocols generally include atraumatically cleansing the oral mucosa, moisturizing the lips and oral cavity, and relieving pain and inflammation. A soft toothbrush or foam swab (toothette) cleans teeth effectively and atraumatically. Options for cleansing and debriding agents include "salt and soda" (one-half teaspoon each of salt and sodium bicarbonate in eight ounces of warm water), normal saline, sodium bicarbonate (one teaspoon in eight ounces of water), sterile water, and hydrogen peroxide (diluted 1:1 with water or normal saline). Indications for use of hydrogen peroxide include crusting and need for gentle debridement. Use should be time-limited (for 1 or 2 days maximum) since chronic use may impair timely healing of stomatitis. In patients with stomatitis, irrigation/rinsing with mild saline or salt and soda should be performed every 2 hours. Gentle wiping with wet gauze immersed in a saline solution aids in debris removal. Toothettes may be too harsh for some areas. Irrigation should be performed prior to topical medication, as removal of debris and saliva allows penetration to the oral tissues and prevents material from accumulating. Frequent rinsing cleans and lubricates tissues, prevents crusting, and soothes sore gingiva and/or mucosa. Frequent rinsing also removes debris and prevents debris and bacteria from accumulating. Agents that produce symptoms or injure the mucosa should not be used. Toothpaste may be used if tolerated; however, over-the-counter mouthwashes generally contain alcohol and should be eliminated. Glycerin is hygroscopic (i.e., takes up and retains moisture) and may dry tissues. Topical anesthetics may minimize pain temporarily but are frequently formulated with excipient ingredients (additives) that can intensify and prolong mucositis. Systemic analgesics (including opioids) are indicated to alleviate discomfort, but veterinarians need to be aware of agents that produce gastrointestinal irritation and/or affect hemostasis.
Management of infection: Prophylaxis against fungal superinfections is generally recommended and includes use of topical antifungal agents such as nystatin-containing mouthwashes and clotrimazole troches. Although topical antifungal prophylaxis and treatment may clear superficial oropharyngeal infections, topical agents are not well absorbed and are ineffective against more deeply invasive fungal infections, which typically involve the esophagus and lower gastrointestinal tract. For this reason, systemic agents are indicated for treating all except superficial fungal infections in the oral cavity. Chlorhexidine oral rinse has been used in combination with fluoride gel to control cariogenic flora in humans. Veterinarians should note that 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 in the context that xerostomia may change flora to more cariogenic types.

Management of candidiasis: Candidiasis is a yeast infection that is generally an overgrowth of the fungus Candida albicans. The management of candidiasis may include: 1) Cleaning the oral cavity prior to taking antifungal medication; irrigation and mechanical plaque removal may be necessary; 2) Discarding toothbrush and replace with a new one after each use; 3) Disinfecting any object or appliance used in the mouth (e.g., mouthpiece used during radiation therapy); 4) Using a suspension instead of a troche if xerostomia is present (if a troche is preferred, the patient's mouth should be rinsed first or allowed to drink water).

Management of hemorrhage: The use of toothbrushes and dental floss in patients with platelet counts of less than 50,000 per cubic millimeter is controversial because of the potential to induce bleeding with routine oral care. Topical thrombin can be used for local hemostasis in patients with minor oral hemorrhage secondary to thrombocytopenia.

Management of xerostomia: It is imperative that patients who have xerostomia have excellent oral hygiene maintained to prevent dental problems. Periodontal disease can be accelerated and caries can become rampant, unless preventive measures are instituted. To prevent dental decay when xerostomia is involved, pet owners should: 1) Perform systematic oral hygiene at least 4 times per day (after meals and before retiring at night); 2) Rinse the mouth with a solution of salt and baking soda 4-6 times per day (1/2 teaspoon salt and 1/2 teaspoon baking soda in 1 cup warm water) to clean and lubricate the oral tissues and to buffer the oral environment; 3) Avoid foods and liquids with a high sugar content; and 4) Have free access to water to alleviate mouth dryness.

Other Considerations

Client education and patient supportive care are important for pets are experiencing oral complications related to cancer therapy. It is important to closely monitor patients' distress, ability to cope, and their response to treatment (quality of life), to show concern for the problems they are experiencing, and to educate and support the pet owner. With full support from the veterinary staff it can be expected that the patient and the pet owner will be able to deal with these complications.