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Oral complications of cancer and cancer therapy

Overview

Aetiology / Pathophysiology

Pre-treatment Assessment And Interventions

Specific Oral Complications

Intervention Options

Psychosocial Considerations

CancerMail from the National Cancer Institute

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

PDQ Supportive Care/Screening/Prevention Information

OVERVIEW

Aggressive treatment for malignant disease may produce unavoidable toxicities to normal cells. The mucosal lining of the gastrointestinal tract, including the oral mucosa, is a prime target for treatment-related toxicity by virtue of its rapid cell turnover rate. Although changes in soft tissue structures within the oral cavity presumably reflect the changes that occur throughout the gastrointestinal tract, the following sections focus on oral complications of antineoplastic drug and radiation therapies.

Oral toxicities may compromise the clinician's ability to give full antineoplastic therapy, potentially requiring dose reduction or treatment schedule modifications, including delays. At times, treatment cessation may be indicated. Oral complications of cancer therapy occur in most patients treated for head and neck malignancies and in approximately 40% of patients receiving chemotherapy for malignancies in other sites. Significant oropharyngeal toxicity can also occur with radiation to the head and neck.

The most common oral complications observed after chemotherapy and radiation treatments are mucositis, local infection, pain, and hemorrhage. Secondary effects include dehydration and malnutrition. In addition, irradiation of the head and neck can irrevocably injure the salivary glands, oral mucosa, musculature, and alveolar bone, resulting in xerostomia, dental disease, and osteoradionecrosis.

Management of the oral complications of cancer therapy involves identification of high-risk populations, initiation of pretreatment interventions (baseline evaluation, treatment or correction of pre-existing oral disease, or appropriate prophylaxis), and management of complications once they develop.

ETIOLOGY/PATHOPHYSIOLOGY

Identification of high-risk patients enables health 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.[1,2]

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.[3-6] 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. Sources of irritation, such as faulty restorations, overhanging fillings, or any device attached to the teeth, 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.[7] Resolution of oral toxicity generally coincides with granulocyte recovery.[7] 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.[8] 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).[9]

The antineoplastic agents most likely to cause mucositis include bleomycin, dactinomycin, doxorubicin, etoposide, floxuridine, 5-FU, hydroxyurea, methotrexate, mitomycin, vinblastine, vincristine, and vinorelbine. 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.[10-12] 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.[13,14]

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.[11]

  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.[15] 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.[16]

Oral Manifestations of Chemotherapy: Mucositis and Ulceration

The gastrointestinal mucosa (GI), because of its high cellular turnover rate, is highly susceptible to the toxic effects of many chemotherapeutic agents. Inflammation and ulceration of the mucosal lining of the mouth, pharynx, esophagus and the entire GI tract may occur. The patient may experience pain, nausea, vomiting and diarrhea. Medications commonly associated with mucositis include: bleomycin, cytarabine (Ara-C), dactinomycin, daunorubicin, doxorubicin Adriamycin), 5-fluorouracil (5-FU) and methotrexate. Other agents may also be cytotoxic.

Oral Manifestations of Radiation Therapy to the Head and Neck: Mucositis

The mucosa becomes edematous, erythematous, pseudomembranous, and sometimes ulcerated. Pain varies considerably in severity and may be intensified by certain foods. The patient may develop problems in swallowing and speaking. Mucositis usually occurs after the second week of radiation therapy. The lips, buccal mucosa, soft palate, borders of tongue and floor of mouth are at greater risk of mucositis. Severe symptoms usually resolve within six weeks following completion of therapy.

Many drugs induce leukopenia, which can result in an increased risk of infections. The usual
clinical signs of inflammation (redness, pain, welling, heat) may not be present during periods of
significant immunosuppression. If pain is present, the symptomatic areas of possible infection
(operculum, periodontal pockets or mucosal ulcerations) should be cultured if the patient develops
a fever of unknown origin. Infection may be caused by organisms usually found in the mouth such
as candida species, herpes simplex, streptococci and staphylococci. Infections may also be caused
by opportunistic organisms not commonly found in the mouth such as aspergillus, mucor, gran-
negative bacilli and coliform bacteria. Candidiasis may have the typical appearance of soft white
plaques or present as generalized erythematous painful tissue. Angular cheilosis is a common
candida-related oral manifestation. Oral infections may lead to systemic infection or
sepsis and can be life threatening.

Oral Manifestations of Radiation Therapy to the Head and Neck: Infection

Secondary infections are common. While candidiasis is most common, all bacterial, mycotic and
viral organisms may cause infections.

 References:

1. Sonis ST, Woods PD, White BA: Pretreatment oral assessment. Journal of the National Cancer Institute Monographs 9: 29-32, 1990.

2. Peterson DE: Oral toxicity of chemotherapeutic agents. Seminars in Oncology 19(5): 478-491, 1992.

3. Hickey AJ, Toth BB, Lindquist SB: Effect of intravenous hyperalimentation and oral care on the development of oral stomatitis during cancer chemotherapy. Journal of Prosthetic Dentistry 47(2): 188-193, 1982.

4. Overholser CD, Peterson DE, Williams LT, et al.: Periodontal infection in patients with acute nonlymphocytic leukemia. Archives of Internal Medicine 142(3): 551-554, 1982.

5. Toth BB, Frame RT: Dental oncology: the management of disease and treatment-related oral/dental complications associated with chemotherapy. Current Problems in Cancer 7(10): 7-35, 1983.

6. Peterson DE, Sonis ST: Oral complications of cancer chemotherapy: present status and future studies. Cancer Treatment Reports 66(6): 1251-1256, 1982.

7. Lockhart PB, Sonis ST: Relationship of oral complications to peripheral blood leukocyte and platelet counts in patients receiving cancer chemotherapy. Oral Surgery, Oral Medicine, and Oral Pathology 48(1): 21-28, 1979.

8. Barrett AP: Gingival lesions in leukemia: a classification. Journal of Periodontology 55(10): 585-588, 1984.

9. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72(7): 2234-2238, 1993.

10. Dreizen S: Stomatotoxic manifestations of cancer chemotherapy. Journal of Prosthetic Dentistry 40(6): 650-655, 1978.

11. Dudjak LA: Mouth care for mucositis due to radiation therapy. Cancer Nursing 10(3): 131-140, 1987.

12. Jansma J, Vissink A, Bouma J, et al.: A survey of prevention and treatment regimens for oral sequelae resulting from head and neck radiotherapy used in Dutch radiotherapy institutes. International Journal of Radiation Oncology, Biology, Physics 24(2): 359-367, 1992.

13. Dreizen S: Description and incidence of oral complications. Journal of the National Cancer Institute Monographs 9: 11-15, 1990.

14. Marx RE: A new concept in the treatment of osteoradionecrosis. Journal of Oral and Maxillofacial Surgery 41(6): 351-357, 1983.

15. Mansfield MJ, Sanders DW, Heimback RD, et al.: Hyperbaric oxygen as an adjunct in the treatment of osteoradionecrosis of the mandible. Journal of Oral Surgery 39(8): 585-589, 1981.

16. Marx RE, Ames JR: The use of hyperbaric oxygen therapy in bony reconstruction of the irradiated and tissue-deficient patient. Journal of Oral and Maxillofacial Surgery 40(7): 412-420, 1982.

PRETREATMENT ASSESSMENT AND INTERVENTIONS

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.[1] Primary preventive measures, such as well-balanced nutritional intake, adequate oral hygiene, and early detection of oral problems, are important pretreatment interventions.[2] A dentist and/or hygienist 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 dentist 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 patient should be instructed about the importance of good oral hygiene prior to receiving treatment.

  References:

1. Sonis S, Kunz A: Impact of improved dental services on the frequency of oral complications of cancer therapy for patients with non-head-and-neck malignancies. Oral Surgery, Oral Medicine, and Oral Pathology 65(1): 19-22, 1988.

2. Beck SL: Prevention and management of oral complications in the cancer patient. In: Hubbard SM, Greene PE, Knobf MT, Eds.: Current issues in cancer nursing practice. Philadelphia, PA: J.B. Lippincott Company, 1990, pp 27-38.

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 such as those identified in the Etiology/Pathophysiology section of this statement. 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. Clinicians should be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate GI (mucosal) toxicity. High-dose chemotherapy, such as that employed in the treatment of leukemia and bone marrow transplantation (BMT) regimens, may produce severe mucositis. Drugs administered by continuous infusion or frequent, repetitive, intermittent schedules (e.g., bleomycin, cytarabine, methotrexate, and fluorouracil) 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.[1]

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. In an effort to standardize measurements of mucosal integrity, oral assessment scales have been developed to grade the level of stomatitis by characterizing alterations in the lips, tongue, mucous membranes, gingiva, teeth, throat, quality of saliva, and voice.[2-6] Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of stomatitis.[7,8] These evaluative tools vary in complexity.

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. Some established guidelines for oral care include oral assessments twice daily for hospitalized patients and frequent oral care (minimum of every four hours and at bedtime) that increases in frequency as the severity of mucositis increases.

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, local and systemic infections can be caused by indigenous oral flora, as well as nosocomial and opportunistic organisms. 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.[9] Dreizen and colleagues [10] reported that approximately 80% of oral infections in patients with solid tumors are caused by Candida albicans and other fungi, with herpes simplex virus (HSV) and gram-negative bacilli accounting for approximately 10% each. In patients with hematologic malignancies, 50% of oral infections are due to Candida albicans, 25% to HSV, 15% to gram-negative bacilli, and 10% to gram-positive cocci.[9] HSV is the most common symptomatic oral viral infection. Dormant HSV can be reactivated during periods of immunosuppression due to cytotoxic chemotherapy.

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. Clinicians may elect to routinely culture the mouth and other potential portals of microbial entry in patients who are expected to have prolonged bone marrow hypoplasia (surveillance cultures). Specimens that reveal a predominant organism among normal flora or a single isolate are of value in identifying an infectious focus in patients with compromised immunity and in those who may not exhibit typical manifestations of infection due to incipient or frank neutropenia. Surveillance cultures also guide empirical antimicrobial selection.[11] Because of the morbidity and mortality associated with disseminated fungal infection, early detection and treatment of local infections is imperative.

  Hemorrhage

Hemorrhage may occur during treatment-induced thrombocytopenia and/or coagulopathy.[12] 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, difficulty wearing dentures, and increased frequency and/or volume of fluid intake. A preventive oral care regimen including topical fluoride application 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.[13-15] 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.[14] The degree of dysfunction is related to the radiation dose and volume of glandular tissue in the radiation field. The 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 portion.

Xerostomia alters the mouth's buffering capacity and mechanical cleansing ability, often contributing to dental caries and progressive periodontal disease.[16] The development of dental caries also is greatly accelerated in the presence of xerostomia due to the absence of protective immunoproteins that are a component of saliva.

Saliva is necessary for the normal execution of oral functions such as taste, swallowing, and speech. Unstimulated whole salivary flow rates of less than 0.1 mL/minute are considered indicative of xerostomia (normal salivary flow rate = 0.3-0.5 mL/minute).[17] Xerostomia produces the following changes in the mouth:

1. Saliva does not lubricate and becomes thick and ropy, which is annoying to the patient.
2. Buffering capacity is eliminated. In a very clean dry mouth, pH is generally 4.5, and demineralization can occur.
3. Oral flora becomes more pathogenic.
4. Plaque becomes thick and heavy, and debris remains present due to the patient's inability to cleanse the mouth.
5. No minerals (calcium, phosphorus, fluoride) are deposited on teeth.
6. Acid production after sugar exposure results in further demineralization of the teeth and leads to dental decay.

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).[18]  

References:

1. Ziga S: Stomatitis/mucositis. In: Yasko J, Ed.: Guidelines for Cancer Care: Symptom Management. Reston VA: Reston Publishing Company, Inc., 1983, pp 212-223.

2. Beck S: Impact of a systematic oral care protocol on stomatitis after chemotherapy. Cancer Nursing 2(3): 185-199, 1979.

3. Daeffler R: Oral hygiene measures for patients with cancer: I. Cancer Nursing 3(5): 347-356, 1980.

4. Daeffler R: Oral hygiene measures for patients with cancer: III. Cancer Nursing 4(1): 29-35, 1981.

5. Beck SL: Prevention and management of oral complications in the cancer patient. In: Hubbard SM, Greene PE, Knobf MT, Eds.: Current issues in cancer nursing practice. Philadelphia, PA: J.B. Lippincott Company, 1990, pp 27-38.

6. Aitken TJ: Gastrointestinal manifestations in the child with cancer. Journal of Pediatric Oncology Nursing 9(3): 99-109, 1992.

7. Western Consortium for Cancer Nursing Research: Development of a staging system for chemotherapy-induced stomatitis. Cancer Nursing 14(1): 6-12, 1991.

8. Donnelly JP, Muus P, Schattenberg A, et al.: A scheme for daily monitoring of oral mucositis in allogeneic BMT recipients. Bone Marrow Transplantation 9(6): 409-413, 1992.

9. Ostchega Y: Preventing and treating cancer chemotherapy's oral complications. Nursing 10(8): 47-52, 1980.

10. Dreizen S, Bodey GP, Valdivieso M: Chemotherapy-associated oral infections in adults with solid tumors. Oral Surgery, Oral Medicine, and Oral Pathology 55(2): 113-120, 1983.

11. Schimpff SC: Surveillance cultures. Journal of the National Cancer Institute Monographs 9: 37-42, 1990.

12. Peterson DE, Sonis ST: Oral complications of cancer chemotherapy: present status and future studies. Cancer Treatment Reports 66(6): 1251-1256, 1982.

13. Eneroth CM, Henrikson CO, Jakobsson PA: The effect of irradiation in high doses on parotid glands. Acta Oto-Laryngologica 71: 349-356, 1971.

14. Shannon IL, Starcke EN, Wescott WB, et al.: Effect of radiotherapy on whole saliva flow. Journal of Dental Research 56(6): 693, 1977.

15. Shannon IL, Trodahl JN, Starcke EN: Radiosensitivity of the human parotid gland (39988). Proceedings of the Society for Experimental Biology and Medicine 157: 50-53, 1978.

16. Peterson DE, Sonis ST, Eds.: Oral Complications of Cancer Chemotherapy. The Hague: Martins Nijhoff Publishing, 1983.

17. Sreebny LM, Valdini A: Xerostomia: a neglected symptom. Archives of Internal Medicine 147: 1333-1337, 1987.

18. Jansma J, Vissink A, Spijkervet FK, et al.: Protocol for the prevention and treatment of oral sequelae resulting from head and neck radiation therapy. Cancer 70(8): 2171-2180, 1992.

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, stomatitis, and candidiasis. 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 patients how to perform mouth care is just as important as informing them how to take 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. Dentures need to be cleaned often and should be brushed, then rinsed, after meals. Rinsing the oral cavity may not be sufficient for thorough cleansing of the oral tissues; mechanical plaque removal is often necessary, even for those who are edentulous. After a routine is developed, the patient should know if mechanical plaque removal is 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

Although mucositis continues to be one of the dose-limiting toxicities of fluorouracil (5-FU), cryotherapy may be an option in prevention of oral mucositis. Since 5-FU has a short half-life (5-20 minutes), patients are instructed to swish ice chips in their mouths for 30 minutes, beginning 5 minutes prior to 5-FU administration.[1]

Oral care protocols generally include atraumatically cleansing the oral mucosa, moisturizing the lips and oral cavity, and relieving pain and inflammation.[2] 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. Data are available concerning the therapeutic effect of chamomile and chlorhexidine.

In patients with stomatitis, irrigation/rinsing with mild saline or salt and soda should be performed every 2 hours. Gentle wiping with a 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. A salt and soda preparation neutralizes acids and dissolves thick secretions.

Moisturizing can be achieved with water-soluble lubricating jelly. Diclonine hydrochloride 0.5% or 1%, lidocaine 2% viscous, carbamide peroxide 10% (urea peroxide 10%), or one of the many extemporaneously prepared mixtures incorporating viscosity-building or coating agents such as milk of magnesia, kaolin with pectin suspension, mixtures of aluminum and/or magnesium hydroxide suspensions (many antacids), or sucralfate suspension combined with topical anesthetic agents may provide topical analgesia.

Agents that produce symptoms or injure the mucosa should not be used. Patients may use toothpaste 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 clinicians need to be aware of agents that produce gastrointestinal irritation and/or affect hemostasis. A separate statement on pain is also available in PDQ.

Although not adequately supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that decrease the severity of mucositis.[3-6] Prostaglandin E2 was not effective as a prophylaxis of oral mucositis following bone marrow transplant.[7]

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.[3,4,8].

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 is a broad spectrum antimicrobial with 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 (GI) absorption, thereby limiting adverse systemic effects. Its use 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.[9-11] 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.[12,13] Clinicians 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. Patients with candidiasis should be instructed to:

1. Clean the oral cavity prior to taking antifungal medication; irrigation and mechanical plaque removal may be necessary.
2. Remove dentures while medication is being applied to the oral tissues.
3. Disinfect and treat both dentures and the mouth.
4. Discard toothbrush and replace with a new one after each use.
5. Disinfect any object or appliance used in the mouth (e.g., mouthpiece used during radiation therapy).
6. Use a suspension instead of a troche if xerostomia is present (if a troche is preferred, the patient should rinse or drink water first).

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 experience xerostomia maintain excellent oral hygiene 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, patients should:

1. Perform systematic oral hygiene at least 4 times per day (after meals and before retiring at night).
2. Use a fluoridated toothpaste when brushing.
3. Apply a prescription-strength fluoride gel daily at bedtime to clean teeth (fluoride is ineffective on plaque-coated teeth).
4. Rinse 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.
5. Avoid foods and liquids with a high sugar content.
6. Sip water to alleviate mouth dryness.

The use of topical fluoride has demonstrable benefit in minimizing caries formation.[14-16] During radiation treatment, it has been recommended that topical 1% sodium fluoride gel should be applied daily into mouth guards, which are then placed over the upper and lower teeth.[17] The guards are allowed to remain in place for 5 minutes, after which the patient should not eat or drink for 30 minutes.[18]

Management of xerostomia includes the use of saliva substitutes or sialagogues.[16,19] Saliva substitutes or artificial saliva preparations (oral rinses containing hydroxyethyl-, hydroxypropyl-, or carboxymethylcellulose) are palliative agents that relieve the discomfort of xerostomia by temporarily wetting the oral mucosa and replacing some missing constituents of saliva. Sialagogues pharmacologically stimulate saliva production from intact responsive salivary glandular tissues, restoring normal salivary flow.[20] 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). Treatment is initiated at 5 mg orally, three times daily, and dose is titrated to optimize clinical response and minimize adverse effects. Some patients may experience increased benefit at higher daily doses; however, the incidence of adverse effects increases proportionally with dose. Patients' evening (or bedtime) dose may be increased to 10 mg within one week after starting pilocarpine. Subsequently, morning and afternoon doses may also be increased to a maximum 10 mg/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.[21,22] Nausea, chills, rhinorrhea, vasodilation, increased lacrimation, bladder pressure (urinary urgency and frequency), dizziness, asthenia, headache, diarrhea, and dyspepsia are also reported, typically at dosages greater than 5 mg, three times daily.[21-23] Pilocarpine typically increases salivary flow within 30 minutes after ingestion; however, maximal response may only be achieved after continual use.[24] Pilocarpine may exert a radioprotective effect on salivary glands if given during radiation therapy to the head and neck.[25]

Capsaicin

It has been suggested that capsaicin preparations may be effective in controlling oral mucositis pain. Capsaicin and its analogues are the active (hot) ingredients in chili peppers that produce burning pain by stimulating polymodal nociceptors, the predominant pain receptors found in skin and mucous membranes. The receptors are described as polymodal because they are multiply sensitive to noxious heat and mechanical and chemical stimuli.[26-28] It has been demonstrated experimentally that after ingesting capsaicin-containing foods or after capsaicin application to the oral mucosa, the severity of pain is directly proportional to the concentration of capsaicin present. After a single exposure, acute burning pain occurs promptly and wanes gradually. If capsaicin exposure is repeated promptly, before the burning sensation from a previous exposure has dissipated, sensitization (i.e., more intense pain) may occur.[29] Conversely, if capsaicin exposure is repeated after the burning sensation from a previous exposure has dissipated, nociceptor desensitization occurs.[30] Capsaicin's clinical potential derives from the fact that it elevates the threshold for pain in areas to which it is applied.[26,27] The pain threshold can be further elevated by gradually increasing the capsaicin concentration in a series of repeated applications.[28] Capsaicin's desensitization effect is generalizable to other painful stimuli as well. When capsaicin is applied to inflamed oral mucosa, mucositis pain diminishes as the burning sensation caused by capsaicin subsides.

Thus far, capsaicin formulations for intraoral use are investigational. In the United States, 0.025% and 0.075% topical capsaicin lotions and creams are available without a prescription for external use only; none of the commercial products are formulated for use within the oral cavity or on other mucosal surfaces. There exists one case report in which a patient with pain due to post therapeutic neuralgia applied commercially available capsaicin 0.025% cream intraorally. The patient experienced symptomatic improvement within 2 days and pain was abolished after 4 weeks of treatment.[31] In addition, Berger et al. [32] have described an extemporaneous formulation of cayenne pepper candy (taffy). The investigators varied the amount of cayenne pepper in their formulation, permitting them to escalate the capsaicin concentration to which patients were exposed. Patients who became desensitized to a low capsaicin concentration tolerated exposure to higher concentrations more easily. Theoretically, when the concentration of capsaicin is increased to produce burning pain approximately equal to a patient's mucositis pain, mucositis pain may diminish or disappear as the sensation from capsaicin dissipates. All patients reported relief from mucositis pain, and pain was abolished in 2 of 11 patients, with continued use of the candy (4-6 candies over 2-4 days). Two patients discontinued using cayenne pepper candies due to adverse effects.

Thus far, evidence that capsaicin produces symptomatic relief for mucositis pain is encouraging but limited to anecdotal reports and a small case series. Of no small concern, however, it is not yet known what effects capsaicin may have on compromised human gastrointestinal mucosa at doses and for durations that may be useful in treating mucositis. Further evaluation is certainly warranted; however, clinical evaluation and acceptance among clinicians who lack facilities to extemporaneously prepare capsaicin products will limit its development until a uniformly consistent formulation becomes available.

References:

1. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72(7): 2234-2238, 1993.

2. Jansma J, Vissink A, Spijkervet FK, et al.: Protocol for the prevention and treatment of oral sequelae resulting from head and neck radiation therapy. Cancer 70(8): 2171-2180, 1992.

3. Beck SL: Prevention and management of oral complications in the cancer patient. In: Hubbard SM, Greene PE, Knobf MT, Eds.: Current issues in cancer nursing practice. Philadelphia, PA: J.B. Lippincott Company, 1990, pp 27-38.

4. Sonis S, Clark J: Prevention and management of oral mucositis induced by antineoplastic therapy. Oncology (Huntington NY) 5(12): 11-18, 1991.

5. Elzawawy A: Treatment of 5-fluorouracil-induced stomatitis by allopurinol mouthwashes. Oncology 48(4):282-284, 1991.

6. Wadleigh RG, Redman RS, Graham ML, et al.: Vitamin E in the treatment of chemotherapy-induced mucositis. American Journal of Medicine 92(5): 481-484, 1992.

7. Labar B, Mrsic M, Pavletic Z, et al.: Prostaglandin E2 for prophylaxis of oral mucositis following BMT. Bone Marrow Transplantation 11(5): 379-382, 1993.

8. Dreizen S, Bodey GP, Valdivieso M: Chemotherapy-associated oral infections in adults with solid tumors. Oral Surgery, Oral Medicine, and Oral Pathology 55(2): 113-120, 1983.

9. Ferretti GA, Ash RC, Brown AT, et al.: Chlorhexidine for prophylaxis against oral infections and associated complications in patients receiving bone marrow transplants. Journal of the American Dental Association 114(4): 461-467, 1987.

10. McGaw WT, Belch A: Oral complications of acute leukemia: prophylactic impact of a chlorhexidine mouth rinse regimen. Oral Surgery, Oral Medicine, and Oral Pathology 60(3): 275-280, 1985.

11. Ferretti GA, Brown AT, Raybould TP, et al.: Oral antimicrobial agents - chlorhexidine. Journal of the National Cancer Institute Monographs 9: 51-55, 1990.

12. Keene HJ, Fleming TJ: Prevalence of caries-associated microflora after radiotherapy in patients with cancer of the head and neck. Oral Surgery, Oral Medicine, and Oral Pathology 64(4): 421-426, 1987.

13. Epstein JB, McBride BC, Stevenson-Moore P, et al.: The efficacy of chlorhexidine gel in reduction of streptococcus mutans and lactobacillus species in patients treated with radiation therapy. Oral Surgery, Oral Medicine, and Oral Pathology 71(2): 172-178, 1991.

14. Dudjak LA: Mouth care for mucositis due to radiation therapy. Cancer Nursing 10(3): 131-140, 1987.

15. Peterson DE, Sonis ST: Oral complications of cancer chemotherapy: present status and future studies. Cancer Treatment Reports 66(6): 1251-1256, 1982.

16. Levine MJ, Aguirre A, Hatton MN, et al.: Artificial salivas: present and future. Journal of Dental Research 66(Special Issue): 693-698, 1987.

17. Dreizen S, Daly TE, Drane JB, et al.: Oral complications of cancer radiotherapy. Postgraduate Medicine 61(2): 85-92, 1977.

18. Schubert MM, Williams BE, Lloid ME, et al.: Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Cancer 69(10): 2469-2477, 1992.

19. Fox PC: Systemic therapy of salivary gland hypofunction. Journal of Dental Research 66(Special Issue): 689-692, 1987.

20. LeVeque FG, Montgomery M, Potter D, et al.: A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients. Journal of Clinical Oncology 11(6): 1124-1131, 1993.

21. Rieke JW, Hafermann MD, Johnson JT, et al.: Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized clinical trials. International Journal of Radiation Oncology, Biology, Physics 31(3): 661-669, 1995.

22. Johnson JT, Ferretti GA, Nethery WJ, et al.: Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. New England Journal of Medicine 329(6): 390-395, 1993.

23. Fox PC, van der Ven PF, Baum BJ, et al.: Pilocarpine for the treatment of xerostomia associated with salivary gland dysfunction. Oral Surgery, Oral Medicine, and Oral Pathology 61(3): 243-248, 1986.

24. Greenspan D, Daniels TE: Effectiveness of pilocarpine in postradiation xerostomia. Cancer 59(6): 1123-1125, 1987.

25. Wolff A, Atkinson JC, Macynski AA, et al.: Pretherapy interventions to modify salivary dysfunction. Journal of the National Cancer Institute Monographs 9: 87-90, 1990.

26. Jancso N, Jancso-Gabor A, Szolcsanyi J: Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. British Journal of Pharmacology and Chemotherapy 31(1): 138-151, 1967.

27. Szolcsanyi J: A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in medication of pain. Journal de Physiologie (Paris) 73(3): 251-259, 1977.

28. Dray A: Mechanism of action of capsaicin-like molecules on sensory neurons. Life Sciences 51: 1759-1765, 1992.

29. Green BG: Evidence that removal of capsaicin accelerates desensitization on the tongue. Neuroscience Letters 150: 44-48, 1993.

30. Green BG: Temporal characteristics of capsaicin sensitization and desensitization on the tongue. Physiology and Behavior 49(3): 501-505, 1991.

31. Hawk RJ, Millikan LE: Treatment of oral postherpetic neuralgia with topical capsaicin. International Journal of Dermatology 27: 336, 1988.

32. Berger A, Henderson M, Nadoolman W, et al.: Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. Journal of Pain and Symptom Management 10(3): 243-248, 1995.

PSYCHOSOCIAL CONSIDERATIONS

Education, supportive care, and symptomatic medications are important for patients experiencing oral complications related to cancer therapy. It is important to closely monitor patients' distress, ability to cope, and their response to treatment, to show concern for the problems they are experiencing, and to educate and support care givers. Visiting nurses' monitoring of care at home is appropriate in cases of severe gingivitis and mucositis if the patient is too debilitated to travel to an out-patient office visit. Home care nurses can evaluate physical and psychosocial status as well as provide education and support to care givers who may also be experiencing psychological distress. With full support from staff and added support from family, it can be expected that the patient will be able to deal with these complications.

References:

1. Holland JC, Lesko LM: Chemotherapy, endocrine therapy and immunotherapy. pp 146-162.