Purpose of This PDQ Summary
Overview
Etiopathogenesis

Chemotherapy-Induced Complications Head/Neck Radiation-Induced Complications

Oral and Dental Management Prior to Cancer Therapy

Chemotherapy Patients Assessment of Hematopoietic Stem Cell Transplant Patients

Management Following Cancer Therapy
Oral Mucositis

Chemotherapy and Hematopoietic Stem Cell Transplantation Patients         Management of mucositis

Infection

Bacterial Infection Fungal Infection         Candidiasis         Noncandidal fungal infections Viral Infections         Herpes virus         Nonherpes group virus infections

Hemorrhage
Neurotoxicity
Graft-versus-Host Disease
Posttransplantation Dental Treatment
Relapse and Second Malignancy
Oral Toxicities Not Related to Chemotherapy or Radiation Therapy

Bisphosphonate-associated Osteonecrosis (BON)         Diagnosis of BON         Management of BON         Discontinuation of bisphosphonate therapy         Spontaneous and asymptomatic BON         Effects on quality of life         New trends

Head/Neck Radiation Patients

Preradiation Evaluation and Disease Stabilization Oral Complications of Head and Neck Radiation         Management of oral mucositis         Early infections         Taste dysfunction         Late reactions         Caries         Tissue necrosis         Mandibular dysfunction

Conditions Affected By Both Chemotherapy and Head/Neck Radiation

Xerostomia         Topical oral antimicrobials Dysgeusia Fatigue Nutritional Compromise

Psychosocial Issues
Special Considerations in Pediatric Populations
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Changes to This Summary (11/06/2008)
Questions or Comments About This Summary
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Purpose of This PDQ Summary

This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of oral complications of chemotherapy and head/neck radiation. This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board.

Information about the following is included in this summary:

• Etiology.
• Management.
• Pediatric considerations.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients during and after cancer treatment. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

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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. The oral cavity is highly susceptible to direct and indirect toxic effects of cancer chemotherapy and ionizing radiation.[1,2] This risk is due to multiple factors including high cellular turnover rates for the lining mucosa, a diverse and complex microflora, and trauma to oral tissues during normal oral function.[3] 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 drugs and radiation therapies.

While oral complications may mimic selected systemic disorders, unique oral toxicities emerge in the context of specific oral anatomic structures and their functions.

Frequencies of oral complications vary by cancer therapy; estimates include the following:

• 10% related to adjunctive chemotherapy.
• 40% related to primary chemotherapy.
• 80% related to hematopoietic stem cell transplantation in which myeloablative conditioning regimens are used (refer to the Assessment of Hematopoietic Stem Cell Transplant Patients section for information on reduced-intensity regimens).
• 100% related to head and neck radiation therapy to fields involving the oral cavity.

The most common oral complications related to cancer therapies are mucositis, infection, salivary gland dysfunction, taste dysfunction, and pain. These complications can lead to secondary complications such as dehydration, dysgeusia, and malnutrition. In myelosuppressed cancer patients, the oral cavity can also be a source of systemic infection. Radiation of the head and neck can irreversibly injure oral mucosa, vasculature, muscle, and bone. This can result in xerostomia, rampant dental caries, trismus, soft tissue necrosis, and osteonecrosis.

Severe oral toxicities can compromise delivery of optimal cancer therapy protocols. For example, dose reduction or treatment schedule modifications may be necessary to allow for resolution of oral lesions. In cases of severe oral morbidity, the patient may no longer be able to continue cancer therapy; treatment is then usually discontinued. These disruptions in dosing due to oral complications can directly affect patient survivorship.

Management of oral complications of cancer therapy includes identification of high-risk populations, patient education, initiation of pretreatment interventions, and timely management of lesions. Assessment of oral status and stabilization of oral disease prior to cancer therapy are critical to overall patient care. This care should be both preventive and therapeutic as indicated to minimize risk for oral and associated systemic complications.

Future research targeted at developing technologies to reduce incidence and severity of oral mucositis, improve infection management, protect salivary gland function, and minimize risk of chronic sequelae is needed. Development of new technologies to prevent cancer therapy-induced complications, especially oral mucositis, could substantially reduce risk for oral pain, oral and systemic infections, and number of days in the hospital; and improve quality of life and reduce health care costs. New technologies could also provide a setting in which novel classes of chemotherapeutic drugs, utilized at increased doses, could lead to enhanced cancer cure rates and durability of disease remission.

References

1. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.  [PUBMED Abstract]
   
   
2. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
3. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001. 
   
   

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Etiopathogenesis

Oral complications associated with cancer chemotherapy and radiation result from complex interactions among multiple factors.[1,2] The most prominent contributors are direct lethal and sublethal damage to oral tissues, attenuation of immune and other protective systems, and interference with normal healing. Principal causes can be attributed to both direct stomatotoxicity and indirect stomatotoxicity. Direct toxicities are initiated via primary injury to oral tissues. Indirect toxicities are caused by nonoral toxicities that secondarily affect the oral cavity, including myelosuppression, loss of tissue-based immune cells, and loss of protective salivary constituents.

Understanding of mechanisms associated with oral complications continues to increase. Unfortunately, there are no universally effective agents or protocols to prevent toxicity. Elimination of pre-existing dental/periapical, periodontal, and mucosal infections; institution of comprehensive oral hygiene protocols during therapy; and reduction of other factors that may compromise oral mucosal integrity (e.g., physical trauma to oral tissues) can reduce frequency and severity of oral complications in cancer patients (refer to the Oral and Dental Management Prior to Cancer Therapy and the Management Following Cancer Therapy sections for further information).[3,4]

Complications can be acute (developing during therapy) or chronic (developing months to years after therapy). In general, cancer chemotherapy causes acute toxicities that resolve following discontinuation of therapy and recovery of damaged tissues. In contrast, radiation protocols typically cause not only acute oral toxicities, but induce permanent tissue damage that result in lifelong risk for the patient.

Risk factors for oral complications derive from both direct damage to oral tissues secondary to chemotherapy and indirect damage due to regional or systemic toxicity. For example, therapy-related toxicity to oral mucosa can be exacerbated by colonizing oral microflora when local and systemic immune function is concurrently compromised. Frequency and severity of oral complications are directly related to extent and type of systemic compromise.

Ulcerative oral mucositis occurs in approximately 40% of patients receiving chemotherapy. In approximately 50% of these patients, the lesions are severe and require medical intervention including modification of their cytotoxic cancer therapy. Normal oral mucosal epithelium is estimated to undergo complete replacement every 9 to 16 days. Intensive chemotherapy can cause ulcerative mucositis that initially emerges approximately 2 weeks after initiation of high-dose chemotherapy.[5-11] As noted above, the chemotherapy directly impairs replication of basal epithelial cells; other factors, including proinflammatory cytokines and metabolic products of bacteria may also play a role. Labial mucosa, buccal mucosa, tongue, floor of mouth, and soft palate are more severely affected by chemotherapy than attached, heavily keratinized tissues such as hard palate and gingiva; this may be due to their faster rate of epithelial cell turnover. Topical cryotherapy may ameliorate mucositis caused by agents such as 5-fluorouracil (5-FU) by reducing vascular delivery of these toxic agents to replicating oral epithelium.[12] It is difficult to predict whether a patient will develop mucositis strictly on the basis of the classes of drugs that are administered. Several drugs are associated with propensity to damage oral mucosa; these include methotrexate, doxorubicin, 5-FU, busulfan, bleomycin, and the platinum coordination complexes including cisplatin and carboplatin. Anecdotal evidence suggests that patients who experience mucositis with a specific chemotherapy regimen during the first cycle will typically develop comparable mucositis during subsequent courses of that regimen.

Other oral complications typically include infections of the mucosa, dentition/periapices, and periodontium. Prevalence of these infections has been substantiated in multiple studies.[1,13-21] Specific criteria for determining risk of infectious flare during myelosuppression have not been developed. Guidelines for assessment primarily address severity of the chronic lesion and recent (e.g., <90 days) history of acute symptoms. Resolution of oral toxicity, including mucositis and infection, generally coincides with granulocyte recovery. This relationship may be temporally but not causally related. For example, oral mucosal healing in hematopoietic stem cell transplantation patients is only partially dependent on rate of engraftment, especially neutrophils. Hypothetically, neutrophil recovery would seem to promote elimination of the potential for oral microflora to adversely affect already-damaged mucosa; mucosal healing would thereby be enhanced.

Head and neck irradiation can cause a wide spectrum of oral complications (refer to the list of Oral Complications of Radiation Therapy below). Ulcerative oral mucositis is a virtually universal toxicity resulting from this treatment; there are clinically significant similarities as well as differences compared with oral mucositis caused by chemotherapy.[2,22,5,6,23,24] Head and neck radiation can also induce damage that results in permanent dysfunction of vasculature, connective tissue, salivary glands, muscle, and bone. Loss of bone vitality occurs secondary to both injury to osteocytes, osteoblasts, and osteoclasts as well as from a relative hypoxia due to reduction in vascular supply. These changes can lead to soft tissue necrosis and osteonecrosis that result in bone exposure, secondary infection, and severe pain.[21]

Oral Complications of Radiation Therapy

• Acute complications:
  • Oral mucositis.
  • Infection:
    • Fungal.
    • Bacterial.
  • Salivary gland dysfunction:
    • Sialadenitis.
    • Xerostomia.
  • Taste dysfunction.



• Chronic complications:
  • Mucosal fibrosis and atrophy.
  • Xerostomia.
  • Dental caries.
  • Soft tissue necrosis.
  • Osteonecrosis.
  • Taste dysfunction:
    • Dysgeusia.
    • Ageusia.
  • Muscular/cutaneous fibrosis.
  • Infections:
    • Fungal.
    • Bacterial.

Unlike chemotherapy, however, radiation damage is anatomically site-specific; toxicity is localized to irradiated tissue volumes. Degree of damage is dependent on treatment regimen-related factors including type of radiation used, total dose administered, and field size/fractionation. Radiation-induced damage also differs from chemotherapy-induced changes in that irradiated tissue tends to manifest permanent damage that places the patient at continual risk for oral sequelae. The oral tissues are thus more easily damaged by subsequent toxic drug or radiation exposure, and normal physiologic repair mechanisms are compromised as a result of permanent cellular damage.

References

1. Peterson DE: Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr (9): 61-71, 1990.  [PUBMED Abstract]
   
   
2. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.  [PUBMED Abstract]
   
   
3. Peters E, Monopoli M, Woo SB, et al.: Assessment of the need for treatment of postendodontic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 76 (1): 45-8, 1993.  [PUBMED Abstract]
   
   
4. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998.  [PUBMED Abstract]
   
   
5. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.  [PUBMED Abstract]
   
   
6. Peterson DE: Research advances in oral mucositis. Curr Opin Oncol 11 (4): 261-6, 1999.  [PUBMED Abstract]
   
   
7. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
8. Epstein JB, Chow AW: Oral complications associated with immunosuppression and cancer therapies. Infect Dis Clin North Am 13 (4): 901-23, 1999.  [PUBMED Abstract]
   
   
9. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
10. Toljanic JA, Bedard JF, Larson RA, et al.: A prospective pilot study to evaluate a new dental assessment and treatment paradigm for patients scheduled to undergo intensive chemotherapy for cancer. Cancer 85 (8): 1843-8, 1999.  [PUBMED Abstract]
    
    
11. De Pauw BE, Donnelly JP: Infections in the immunocompromised host: general principles. In: Mandell GL, Bennett JE, Dolin R, eds.: Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone, 2000, pp 3079-90. 
    
    
12. 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): 2234-8, 1993.  [PUBMED Abstract]
    
    
13. Donnelly JP: Infection in the neutropenic and haematopoietic stem cell transplant recipient. Curr Opin Infect Dis 13 (4): 337-342, 2000.  [PUBMED Abstract]
    
    
14. Kennedy HF, Morrison D, Kaufmann ME, et al.: Origins of Staphylococcus epidermidis and Streptococcus oralis causing bacteraemia in a bone marrow transplant patient. J Med Microbiol 49 (4): 367-70, 2000.  [PUBMED Abstract]
    
    
15. Schubert MM: Oro-pharyngeal mucositis. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 812-20. 
    
    
16. Giamarellou H, Antoniadou A: Infectious complications of febrile leukopenia. Infect Dis Clin North Am 15 (2): 457-82, 2001.  [PUBMED Abstract]
    
    
17. Graber CJ, de Almeida KN, Atkinson JC, et al.: Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 27 (5): 537-42, 2001.  [PUBMED Abstract]
    
    
18. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001. 
    
    
19. Akintoye SO, Brennan MT, Graber CJ, et al.: A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (5): 581-8, 2002.  [PUBMED Abstract]
    
    
20. Raber-Durlacher JE, Epstein JB, Raber J, et al.: Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer 10 (6): 466-73, 2002.  [PUBMED Abstract]
    
    
21. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.  [PUBMED Abstract]
    
    
22. 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. Int J Radiat Oncol Biol Phys 24 (2): 359-67, 1992.  [PUBMED Abstract]
    
    
23. Symonds RP: Treatment-induced mucositis: an old problem with new remedies. Br J Cancer 77 (10): 1689-95, 1998.  [PUBMED Abstract]
    
    
24. Plevová P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: a review. Oral Oncol 35 (5): 453-70, 1999.  [PUBMED Abstract]
    
    

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Oral and Dental Management Prior to Cancer Therapy

Severity of oral complications in cancer patients can be reduced significantly when an aggressive approach to stabilizing oral care is initiated prior to treatment.[1-3] Primary preventive measures, such as appropriate nutritional intake, effective oral hygiene practices, and early detection of oral lesions are important pretreatment interventions.

The involvement of a dental team experienced with oral oncology may reduce the risk of oral complications via either direct examination of the patient or in consultation with the community-based dentist. The evaluation should occur as early as possible prior to treatment.[4-6] The examination allows the dentist to determine status of the oral cavity prior to cancer therapy, and to initiate necessary interventions that may reduce oral complications during and after that therapy. Ideally, this examination should be performed at least 1 month prior to cancer treatment to permit adequate healing from any required invasive oral procedures. A program of oral hygiene should be initiated with emphasis on maximizing patient compliance on a continuing basis.

Oral evaluation and management of patients scheduled to undergo myeloablative chemotherapy should occur as early as possible prior to initiation of therapy (refer to the list on Oral Disease Stabilization Prior to Chemotherapy and/or Hematopoietic Stem Cell Transplantation below). To maximize outcomes, the oncology team should clearly advise the dentist as to the patient’s medical status and oncology treatment plan. In turn, the dental team should delineate and communicate a plan of care for oral disease management before, during, and after cancer therapy.[6]

Oral Disease Stabilization Prior to Chemotherapy and/or Hematopoietic Stem Cell Transplantation

• Data provided by oncology to dental medicine:
  • Underlying disease:
    • Cancer: type, stage, prognosis.
    • Aplastic anemia status, complete blood cell count (CBC).
    • Other.
  • Type of transplant:
    • Autologous.
    • Allogeneic:
      • Matched.
      • Mismatched related.
      • Mismatched unrelated.
    • Syngeneic.
    • Nonmyeloablative.
  • Planned date of transplant.
  • Conditioning regimen:
    • Chemotherapy.
    • Total-body irradiation.
  • Current hematologic status and immunologic status.
  • Present medications.
  • Other medical considerations:
    • Splenectomy.
    • Cardiac disease (including murmurs).
    • Pulmonary disease.
    • Indwelling venous access line.



• Data provided by dental medicine to oncology:
  • Dental caries (amount/severity).
  • Number of teeth requiring restorations.
  • Endodontic disease.
  • Teeth with pupal infection.
  • Teeth requiring endodontic treatment.
  • Periodontal disease status.
  • Number of teeth requiring extraction.
  • Other urgent care required.
  • Time necessary to complete stabilization of oral disease.

The overall goal is to complete a comprehensive oral care plan that eliminates or stabilizes oral disease that could otherwise produce complications during or following chemotherapy. Achieving this goal will most likely reduce risk of oral toxicities with resultant reduced risk for systemic sequelae, reduced cost of patient care, and enhanced quality of life. If the patient is unable to receive the medically necessary oral care in the community, the oncology team should assume responsibility for oral management.

Specific interventions are directed to:

• Mucosal lesions.
• Dental caries and endodontic disease.
• Periodontal disease.
• Ill-fitting dentures.
• Orthodontic appliances.
• Temporomandibular dysfunction.
• Salivary abnormalities.

Guidelines for dental extractions, endodontic management, and related interventions can be utilized as appropriate.[7,8] Antibiotic prophylaxis prior to invasive oral procedures may be warranted in the context of central venous catheters; the current American Heart Association (AHA) protocol for infective endocarditis and oral procedures is frequently utilized for these patients.

Stages of assessment have been described relative to the hematopoietic stem cell transplant patient (see the table below on Oral Complications of Hematopoietic Stem Cell Transplantation).[6] This model provides a useful classification for neutropenic cancer patients in general. Type, timing, and severity of oral complications represent the interaction of local and systemic factors that culminate in clinical expression of disease. Correlating oral status with systemic condition of the patient is thus critically important.

In recent years, selected conditioning regimens characterized by reduced intensity for myelosuppression have been utilized in patients. These regimens may or may not result in reduced severity of oral complications, including mucositis and infection risk. The guidelines listed in the table below can be adjusted to reflect these varying degrees of risk, based on the specific conditioning regimen to be used.

Phase I: Prior to Chemotherapy

Oral complications are related to current systemic and oral health, oral manifestations of underlying disease, and oral complications of recent cancer or other medical therapy. During this period, oral trauma and clinically significant infections, including dental caries, periodontal disease, and pulpal infection, should be eliminated. Additionally, patients should be educated relative to the range and management of oral complications that may occur during subsequent phases. Baseline oral hygiene instructions should be provided.

Phase II: Neutropenic Phase

Oral complications arise primarily from direct and indirect stomatotoxicities associated with high-dose chemotherapy or chemoradiotherapy and their sequelae. Mucositis, xerostomia, and those lesions related to myelosuppression, thrombocytopenia, and anemia predominate. This phase is typically the period of high prevalence and severity of oral complications.

Oral mucositis usually begins 7 to 10 days after initiation of cytotoxic therapy, and remains present for approximately 2 weeks after cessation of that therapy. Viral, fungal, and bacterial infections may arise, with incidence dependent on the use of prophylactic regimens, oral status prior to chemotherapy, and duration/severity of neutropenia. Frequency of infection declines upon resolution of mucositis and regeneration of neutrophils. The patient may remain at risk, however, depending on status of overall immune reconstitution.

Xerostomia secondary to anticholinergic drugs and taste dysfunction is initially detected in this phase; the toxicity typically resolves within 2 to 3 months.

Phase III: Hematopoietic Recovery

Frequency and severity of acute oral complications typically begin to decrease approximately 3 to 4 weeks after cessation of chemotherapy. Healing of ulcerative oral mucositis in the setting of marrow regeneration contributes to this dynamic. Although immune reconstitution is developing, oral mucosal immune defenses may not be optimal. Thus, the patient remains at risk for selected infection, including candidal and herpes simplex virus infections. Mucosal bacterial infections during this phase occur less frequently unless: engraftment is delayed or the patient has acute graft-versus-host disease (GVHD) or is receiving GVHD therapy.

The hematopoietic stem cell transplant patient represents a unique cohort at this point. For example, risk for acute oral GVHD typically emerges during this time in allogeneic graft recipients.

Phase IV: Immune Reconstitution/Recovery from Systemic Toxicity

Oral lesions are principally related to chronic chemotherapy-associated or chemoradiation therapy–associated toxicity. Late viral infections and xerostomia predominate. Mucosal bacterial infections are infrequent unless the patient has severe chronic GVHD. Risk exists for graft failure, cancer relapse, and second malignancies. The hematopoietic stem cell transplant patient may develop oral manifestations of chronic GVHD during this period.

Phase V: Long-term Survival

Long-term survivors of cancer treated with high-dose chemotherapy alone or chemoradiotherapy will generally have few significant permanent oral complications.

Risk for radiation-induced chronic complications is related to the total dose and schedule of radiation therapy. Xerostomia is the most frequently reported oral complication of total-body irradiation. Other significant complications include craniofacial growth and developmental abnormalities in pediatric patients, and emergence of second malignancies of the head/neck region.

References

1. 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. 
   
   
2. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.  [PUBMED Abstract]
   
   
3. Epstein JB: Infection prevention in bone marrow transplantation and radiation patients. NCI Monogr (9): 73-85, 1990.  [PUBMED Abstract]
   
   
4. Woo SB, Matin K: Off-site dental evaluation program for prospective bone marrow transplant recipients. J Am Dent Assoc 128 (2): 189-93, 1997.  [PUBMED Abstract]
   
   
5. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
6. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
7. Williford SK, Salisbury PL 3rd, Peacock JE Jr, et al.: The safety of dental extractions in patients with hematologic malignancies. J Clin Oncol 7 (6): 798-802, 1989.  [PUBMED Abstract]
   
   
8. Overholser CD, Peterson DE, Bergman SA, et al.: Dental extractions in patients with acute nonlymphocytic leukemia. J Oral Maxillofac Surg 40 (5): 296-8, 1982.  [PUBMED Abstract]
   
   

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Management Following Cancer Therapy

Routine systematic oral hygiene is important for reducing incidence and severity of oral sequelae of cancer therapy. The patient must be informed of the rationale for the oral hygiene program as well as the potential side effects of cancer chemotherapy and radiation therapy.[1] Effective oral hygiene is important throughout cancer treatment, with emphasis on oral hygiene beginning prior to initiation of that treatment.[2-4]

Management of patients undergoing either high-dose chemotherapy or upper-mantle radiation share selected common principles. These principles are based on baseline oral care (refer to the list of Routine Oral Hygiene Care below) and reduction of physical trauma to oral mucosa (refer to the list of Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy below).

Routine Oral Hygiene Care

• Toothbrushing.  [Note: Electric and ultrasonic toothbrushes are acceptable if the patient is capable of using them without causing trauma.]



• Soft nylon-bristled brush (two to three rows).
  • Brush 2 to 3 times daily with Bass sulcular scrub method.
  • Rinse frequently.
  • Foam toothbrushes:
    • Use only when use of a regular toothbrush is not feasible.
    • Use with antimicrobial rinses when possible.
    • Brush teeth and mucosal surfaces 2 to 3 times a day.
    • Rinse frequently.



• Dentifrice:
  • Patient preference as tolerated.
  • Fluoride recommended.
  • Use 0.9% saline or water if toothpaste causes irritation.



• Flossing:
  • Once daily.
  • Atraumatic technique with modifications as needed.



• Bland Rinses:
  • Varieties:
    • 0.9% saline.
    • Sodium bicarbonate solution.
    • 0.9% saline plus sodium bicarbonate solution.
  • Use 8 to 12 oz of rinse, hold and expectorate; repeat every 2 to 4 hours or as needed for pain.



• Fluoride:
  • 1.1% neutral sodium fluoride gel.
  • 0.4% stannous fluoride gel.
  • Brush on gel for 2 to 3 minutes.
  • Expectorate and rinse mouth gently.
  • Apply once a day.



• Topical antimicrobial rinses:
  • 0.12% to 0.2% chlorhexidine oral rinse.
  • Povidone iodine oral rinse.
  • Rinse, hold 1 to 2 minutes, expectorate.
  • Repeat 2 to 4 times a day depending on severity of periodontal disease.

Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy [4]

• Minimize denture use during first 3 to 4 weeks posttransplant.
  • Wear dentures only when eating.
  • Discontinue use at all other times.
• Clean twice a day with a soft brush and rinse well.
• Soak in antimicrobial solutions when not being worn.
• Perform routine oral mucosal care procedures 3 to 4 times a day with the oral appliances out of the mouth.
• Leave appliances out of mouth when sleeping and during periods of significant mouth soreness.
• Dentures may be used to hold medications needed for oral care (e.g., antifungals).
• Discontinue use of removable appliances until oral mucositis has healed.
• Remove orthodontic appliances (e.g., brackets, wires, retainers) prior to conditioning.

Considerable variation exists across institutions relative to specific nonmedicated approaches to baseline oral care, given limited published evidence. Most nonmedicated oral care protocols utilize topical, frequent (every 4–6 hours) rinsing with 0.9% saline. Additional interventions include dental brushing with toothpaste, dental flossing, ice chips, and sodium bicarbonate rinses. Patient compliance with these agents can be maximized by comprehensive overseeing by the healthcare professional.

Patients utilizing removable dental prostheses or orthodontic appliances have risk of mucosal injury or infection. This risk can be eliminated or substantially reduced prior to high-dose cancer therapy (see the list of Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy above).

Dental brushing and flossing represent simple, cost-effective approaches to bacterial dental plaque control. This strategy is designed to reduce risk of oral soft tissue infection during myeloablation. Oncology teams at some centers promote their use, while teams at other centers have patients discontinue brushing and flossing when peripheral blood components decrease below defined thresholds (e.g., platelets <30,000/mm³).

Periodontal infection (gingivitis and periodontitis) causes risk for oral bleeding; healthy tissues should not bleed. Discontinuing dental brushing and flossing can increase risk for gingival bleeding, oral infection, and bacteremia. Risk for gingival bleeding and infection, therefore, is reduced by eliminating gingival infection prior to therapy and promoting oral health daily by removing bacterial plaque with gentle debridement with a soft or ultra-soft toothbrush during therapy. Mechanical plaque control not only promotes gingival health, but it also may decrease risk of exacerbation of oral mucositis secondary to microbial colonization of damaged mucosal surfaces.

Dental brushing and flossing should be performed daily under supervision of the professional staff. Patients should use a soft nylon-bristled toothbrush 2 to 3 times a day with techniques that specifically maintain the gingival portion of the tooth and periodontal sulcus keeping them free of bacterial plaque. Rinsing the toothbrush in hot water every 15 to 30 seconds during brushing will soften the brush and reduce risk for trauma. Oral rinsing with water or saline 3 to 4 times while brushing will further aid in removal of dental plaque dislodged by brushing. Rinses containing alcohol should be avoided. Since the flavoring agents in toothpaste can irritate oral soft tissues, a toothpaste with relatively neutral taste should be considered. Brushes should be air-dried between uses. While disinfectants have been suggested, their routine use to clean brushes has not been proven of value. Ultrasonic toothbrushes may be substituted for manual brushes if patients are properly trained in their use.

Patients skilled at flossing without traumatizing gingival tissues may continue flossing throughout the chemotherapy admission. Flossing allows for interproximal removal of dental bacterial plaque and thus promotes gingival health. As with dental brushing, this intervention should be performed in the context of daily monitoring by staff to assure its safe administration.

The oral cavity should be cleaned after meals. If xerostomia is present, plaque and food debris may accumulate secondary to reduced salivary function, and more frequent hygiene may be necessary. Dentures need to be cleaned with denture cleanser every day, and should be brushed and rinsed after meals. Rinsing the oral cavity may not be sufficient for thorough cleansing of the oral tissues; mechanical plaque removal is often necessary. Care must be exerted relative to use of the variety of mechanical hygiene aids that are available; for example, dental floss, interproximal brushes, and wooden wedges can injure oral tissues rendered fragile by chemotherapy. Toothettes have limited ability to cleanse the dentition. They may, however, be useful for cleaning maxillary/mandibular alveolar ridges of edentulous areas, palate, and tongue.

Preventing dryness of the lips to reduce risk for tissue injury is important. Mouth breathing and/or xerostomia secondary to anticholinergic medications used for nausea management can induce the condition. Lip care products containing petroleum-based oils and waxes can be useful. Lanolin-based creams and ointments may be more effective in protecting against trauma.

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 Surg Oral Med Oral Pathol 65 (1): 19-22, 1988.  [PUBMED Abstract]
   
   
2. Ezzone S, Jolly D, Replogle K, et al.: Survey of oral hygiene regimens among bone marrow transplant centers. Oncol Nurs Forum 20 (9): 1375-81, 1993.  [PUBMED Abstract]
   
   
3. Armstrong TS: Stomatitis in the bone marrow transplant patient. An overview and proposed oral care protocol. Cancer Nurs 17 (5): 403-10, 1994.  [PUBMED Abstract]
   
   
4. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   

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Oral Mucositis

The terms oral mucositis and stomatitis are often used interchangeably at the clinical level, but they do not reflect identical processes. Oral mucositis describes inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation.[1-5] Mucositis typically manifests as erythema or ulcerations. It may be exacerbated by local factors. Stomatitis refers to any inflammatory condition of oral tissue, including mucosa, dentition/periapices, and periodontium. Stomatitis thus includes infections of oral tissues, as well as mucositis as defined above.

Relationships between cancer therapy–induced compromise of systemic immune constituents and functionally distinct mucosal immune components are not well understood.[6-9] Additionally, the role of cytokines and oral mucosal lymphocyte subsets in mucositis has not been investigated systematically. Evidence now supports the impact of derangements in selected cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) as possible key contributors to development of oral mucositis.

As noted above, erythematous mucositis typically appears 7 to 10 days after initiation of high-dose cancer therapy. Clinicians should be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate gastrointestinal mucosal toxicity. High-dose chemotherapy, such as that utilized in the treatment of leukemia and hematopoietic stem cell transplant regimens, may produce severe mucositis. Mucositis is self-limited when uncomplicated by infection and typically heals within 2 to 4 weeks after cessation of cytotoxic chemotherapy.

Systematic assessment of the oral cavity following treatment permits early identification of lesions.[10-17] Oral hygiene and other supportive care measures are important to minimizing the severity of the lesion.

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 lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice.[12-14] Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of mucositis. These evaluative tools vary in complexity.

Oral mucositis in hematopoietic stem cell transplantation (HSCT) patients produces clinically significant toxicities that require multiprofessional interventions. The lesion can increase risk for systemic infection,[1] produce clinically significant pain,[18] and promote oral hemorrhage. It can also compromise the upper airway such that endotracheal intubation is required. Use of total parenteral nutrition is often necessary because of the patient’s inability to receive enteral nutrition.

Once mucositis has developed, its severity and the patient’s hematologic status govern appropriate oral management. Meticulous oral hygiene and palliation of symptoms are essential. 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 4 hours and at bedtime) that increases in frequency as the severity of mucositis increases.

Oral care protocols generally include atraumatically cleansing the oral mucosa, maintaining lubrication of the lips and oral tissues, and relieving pain and inflammation.

Palifermin (Kepivance), also known as keratinocyte growth factor-1, has been approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic cancers undergoing high-dose chemotherapy, with or without radiation therapy, followed by a bone marrow transplant.[19] Palifermin has also been shown in a randomized, placebo-controlled trial to reduce the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy.[20]

Mucositis Management

• Bland rinses:
  • 0.9% saline solution.
  
  
  
  • Sodium bicarbonate solution.
  
  
  
  • 0.9% saline/sodium bicarbonate solution.
  
  
  



• Topical anesthetics:
  • Lidocaine: viscous, ointments, sprays.
  
  
  
  • Benzocaine: sprays, gels.
  
  
  
  • 0.5% or 1.0% dyclonine hydrochloride (HCl).
  
  
  
  • Diphenhydramine solution.
  
  
  



• Mucosal coating agents:
  • Amphojel.
  
  
  
  • Kaopectate.
  
  
  
  • Hydroxypropyl methylcellulose film-forming agents (e.g., Zilactin).
  
  
  
  • Cyanoacrylate mucoadherent film.
  
  
  
  • Gelclair (approved by the FDA as a device). This gel soothes oral mucositis pain by forming a protective coating that shields exposed and overstimulated nerve endings.
  
  
  



• Analgesics:
  • Benzydamine HCl topical rinse (not approved in the United States).
  
  
  
  • Opioid drugs: oral, intravenous (e.g., bolus, continuous infusion, patient-controlled analgesia [PCA]), patches, transmucosal.
  
  
  



• Growth factor (keratinocyte growth factor-1):
  • Palifermin (approved by the FDA in December 2004 to decrease the incidence and duration of severe oral mucositis in patients undergoing high-dose chemotherapy with or without radiation therapy followed by bone marrow transplant for hematologic cancers).

Management of oral mucositis via topical approaches should address efficacy, patient acceptance, and appropriate dosing. A stepped approach is typically utilized, with progression from one level to the next as follows:

• Bland rinses (e.g., 0.9% normal saline and/or sodium bicarbonate solutions).



• Mucosal coating agents (e.g., antacid solutions, kaolin solutions).



• Water-soluble lubricating agents, including artificial saliva for xerostomia.



• Topical anesthetics (e.g., viscous lidocaine, benzocaine sprays/gels, dyclonine rinses, diphenhydramine solutions).



• Cellulose film-forming agents for covering localized ulcerative lesions (e.g., hydroxypropyl cellulose).

Normal saline solution is prepared by adding approximately 1 tsp of table salt to 32 oz of water. The solution can be administered at room or refrigerated temperatures, depending on patient preference. The patient should rinse and swish approximately 1 tbsp, followed by expectoration; this can be repeated as often as necessary to maintain oral comfort. Sodium bicarbonate (1–2 tbsp/qt) can be added, if viscous saliva is present. Saline solution can enhance oral lubrication directly as well as by stimulating salivary glands to increase salivary flow.

A soft toothbrush that is replaced on a regular basis (see the 2005 Oral Mucositis Guidelines Update) should be used to maintain oral hygiene. Foam-swab brushes do not effectively clean teeth and should not be considered a routine substitute for a soft nylon-bristled toothbrush. Options for cleansing and debriding agents include salt and soda (½ tsp of salt and 2 tbsp of sodium bicarbonate in 32 oz of warm water), normal saline, sodium bicarbonate (1 tsp in 8 oz of water), and sterile water. Based on nonoral mucosa wound-healing studies, the repeated use of hydrogen peroxide rinses for daily preventive oral hygiene is not recommended, especially if mucositis is present. This is because of the potential for damage to fibroblasts and keratinocytes, which can cause delayed wound healing.[21-27] Using 3% hydrogen peroxide diluted 1:1 with water or normal saline to remove hemorrhagic debris may be helpful; however, this approach should only be used for 1 to 2 days since more extended use may impair timely healing of mucosal lesions associated with bleeding.[28]

Focal topical application of anesthetic agents is preferred over widespread oral topical administration, until the patient requires more extensive pain relief. Products such as 2% viscous lidocaine, diphenhydramine solution, or one of the many extemporaneously prepared mixtures incorporating coating agents such as milk of magnesia, kaolin with pectin suspension, mixtures of aluminum, and/or magnesium hydroxide suspensions (many antacids) combined with topical anesthetic agents may provide relief.

Irrigation should be performed prior to topical medication because removal of debris and saliva allows for better coating of oral tissues and prevents material from accumulating. Frequent rinsing cleans and lubricates tissues, prevents crusting, and palliates painful gingiva and mucosa.

Systemic analgesics should be administered when topical anesthetic strategies are not sufficient for clinical relief. Opiates are typically used;[18] the combination of chronic indwelling venous catheters and computerized drug administration pumps to provide PCA has significantly increased the effectiveness of controlling severe mucositis pain while lowering the dose and side effects of narcotic analgesics. Nonsteroidal anti-inflammatory drugs that affect platelet adhesion and damage gastric mucosa are contraindicated, especially if thrombocytopenia is present.

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. Because 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.[29]

Many agents and protocols have been promoted for management or prevention of mucositis.[30-54] Although not adequately supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that decrease the severity of mucositis. Prostaglandin E2 was not effective as a prophylaxis of oral mucositis following bone marrow transplant,[45] although more recent studies indicate possible efficacy when administered via a different dosing protocol.[34]

Capsaicin preparations may be effective in controlling oral mucositis pain.[51-54] Capsaicin and its analogues are the active ingredients in chili peppers that produce burning pain by stimulating polymodal nociceptors, which are the predominant pain receptors found in skin and mucous membranes. It has been demonstrated experimentally that after ingesting capsaicin-containing foods or after capsaicin application to the oral mucosa, severity of pain is directly proportional to concentration of capsaicin present. Capsaicin’s clinical potential derives from the fact that it elevates the threshold for pain in areas to which it is applied. The pain threshold can be further elevated by gradually increasing the capsaicin concentration in a series of repeated applications. This approach to mucositis pain control is not convenient, and some patients are clearly not candidates for its use. Thus far, evidence that capsaicin produces symptomatic relief for mucositis pain is encouraging but limited to anecdotal reports and a small case series. It is not yet known what effects capsaicin may have on compromised human gastrointestinal mucosa at doses and durations that may be useful in treating mucositis. Further evaluation is warranted.

References

1. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.  [PUBMED Abstract]
   
   
2. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
3. Peterson DE: Research advances in oral mucositis. Curr Opin Oncol 11 (4): 261-6, 1999.  [PUBMED Abstract]
   
   
4. Sonis ST, Elting LS, Keefe D, et al.: Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100 (9 Suppl): 1995-2025, 2004.  [PUBMED Abstract]
   
   
5. Rubenstein EB, Peterson DE, Schubert M, et al.: Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100 (9 Suppl): 2026-46, 2004.  [PUBMED Abstract]
   
   
6. Sonis ST, Costa JW Jr, Evitts SM, et al.: Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Oral Surg Oral Med Oral Pathol 74 (6): 749-55, 1992.  [PUBMED Abstract]
   
   
7. Sonis ST, Lindquist L, Van Vugt A, et al.: Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3. Cancer Res 54 (5): 1135-8, 1994.  [PUBMED Abstract]
   
   
8. Sonis S, Muska A, O'Brien J, et al.: Alteration in the frequency, severity and duration of chemotherapy-induced mucositis in hamsters by interleukin-11. Eur J Cancer B Oral Oncol 31B (4): 261-6, 1995.  [PUBMED Abstract]
   
   
9. Keith JC Jr, Albert L, Sonis ST, et al.: IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells 12 (Suppl 1): 79-89; discussion 89-90, 1994.  [PUBMED Abstract]
   
   
10. 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): 2171-80, 1992.  [PUBMED Abstract]
    
    
11. 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. 
    
    
12. Schubert MM, Williams BE, Lloid ME, et al.: Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 69 (10): 2469-77, 1992.  [PUBMED Abstract]
    
    
13. Sonis ST, Eilers JP, Epstein JB, et al.: Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer 85 (10): 2103-13, 1999.  [PUBMED Abstract]
    
    
14. McGuire DB, Peterson DE, Muller S, et al.: The 20 item oral mucositis index: reliability and validity in bone marrow and stem cell transplant patients. Cancer Invest 20 (7-8): 893-903, 2002.  [PUBMED Abstract]
    
    
15. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998.  [PUBMED Abstract]
    
    
16. Schubert MM: Oro-pharyngeal mucositis. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 812-20. 
    
    
17. Plevová P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: a review. Oral Oncol 35 (5): 453-70, 1999.  [PUBMED Abstract]
    
    
18. Pillitteri LC, Clark RE: Comparison of a patient-controlled analgesia system with continuous infusion for administration of diamorphine for mucositis. Bone Marrow Transplant 22 (5): 495-8, 1998.  [PUBMED Abstract]
    
    
19. Spielberger R, Stiff P, Bensinger W, et al.: Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351 (25): 2590-8, 2004.  [PUBMED Abstract]
    
    
20. Rosen LS, Abdi E, Davis ID, et al.: Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol 24 (33): 5194-200, 2006.  [PUBMED Abstract]
    
    
21. National Institutes of Health Consensus Development Conference on Oral Complications of Cancer Therapies: Diagnosis, Prevention, and Treatment. Bethesda, Maryland, April 17-19, 1989. NCI Monogr (9): 1-184, 1990.  [PUBMED Abstract]
    
    
22. Solomon CS, Shaikh AB, Arendorf TM: An efficacious oral health care protocol for immunocompromised patients. Spec Care Dentist 15 (6): 228-33, 1995 Nov-Dec.  [PUBMED Abstract]
    
    
23. Bavier AR: Nursing management of acute oral complications of cancer. NCI Monogr (9): 123-8, 1990.  [PUBMED Abstract]
    
    
24. Tombes MB, Gallucci B: The effects of hydrogen peroxide rinses on the normal oral mucosa. Nurs Res 42 (6): 332-7, 1993 Nov-Dec.  [PUBMED Abstract]
    
    
25. Takahashi A, Aoshiba K, Nagai A: Apoptosis of wound fibroblasts induced by oxidative stress. Exp Lung Res 28 (4): 275-84, 2002.  [PUBMED Abstract]
    
    
26. Bennett LL, Rosenblum RS, Perlov C, et al.: An in vivo comparison of topical agents on wound repair. Plast Reconstr Surg 108 (3): 675-87, 2001.  [PUBMED Abstract]
    
    
27. O'Toole EA, Goel M, Woodley DT: Hydrogen peroxide inhibits human keratinocyte migration. Dermatol Surg 22 (6): 525-9, 1996.  [PUBMED Abstract]
    
    
28. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Blume KG, Forman SJ, Applebaum FR, eds.: Thomas' Hematopoietic Cell Transplantation. 3rd ed. Malden, Mass: Blackwell Science Inc, 2004, pp 911-28. 
    
    
29. 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): 2234-8, 1993.  [PUBMED Abstract]
    
    
30. Elzawawy A: Treatment of 5-fluorouracil-induced stomatitis by allopurinol mouthwashes. Oncology 48 (4): 282-4, 1991.  [PUBMED Abstract]
    
    
31. Wadleigh RG, Redman RS, Graham ML, et al.: Vitamin E in the treatment of chemotherapy-induced mucositis. Am J Med 92 (5): 481-4, 1992.  [PUBMED Abstract]
    
    
32. Labar B, Mrsić M, Pavletić Z, et al.: Prostaglandin E2 for prophylaxis of oral mucositis following BMT. Bone Marrow Transplant 11 (5): 379-82, 1993.  [PUBMED Abstract]
    
    
33. 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 Surg Oral Med Oral Pathol 71 (2): 172-8, 1991.  [PUBMED Abstract]
    
    
34. Peterson DE: Effect of misoprostol in reducing oral mucositis in stem cell transplant patients. [Abstract] Proceedings of the 11th Multinational Association of Supportive Care Cancer 67, 1999. 
    
    
35. Cowen D, Tardieu C, Schubert M, et al.: Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial. Int J Radiat Oncol Biol Phys 38 (4): 697-703, 1997.  [PUBMED Abstract]
    
    
36. LeVeque FG, Parzuchowski JB, Farinacci GC, et al.: Clinical evaluation of MGI 209, an anesthetic, film-forming agent for relief from painful oral ulcers associated with chemotherapy. J Clin Oncol 10 (12): 1963-8, 1992.  [PUBMED Abstract]
    
    
37. Karthaus M, Rosenthal C, Huebner G, et al.: Effect of topical oral G-CSF on oral mucositis: a randomised placebo-controlled trial. Bone Marrow Transplant 22 (8): 781-5, 1998.  [PUBMED Abstract]
    
    
38. Nicolatou O, Sotiropoulou-Lontou A, Skarlatos J, et al.: A pilot study of the effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients during X-radiation therapy: a preliminary report. Int J Radiat Oncol Biol Phys 42 (3): 551-6, 1998.  [PUBMED Abstract]
    
    
39. Johnston EM, Crawford J: Hematopoietic growth factors in the reduction of chemotherapeutic toxicity. Semin Oncol 25 (5): 552-61, 1998.  [PUBMED Abstract]
    
    
40. Oguchi M, Shikama N, Sasaki S, et al.: Mucosa-adhesive water-soluble polymer film for treatment of acute radiation-induced oral mucositis. Int J Radiat Oncol Biol Phys 40 (5): 1033-7, 1998.  [PUBMED Abstract]
    
    
41. Matejka M, Nell A, Kment G, et al.: Local benefit of prostaglandin E2 in radiochemotherapy-induced oral mucositis. Br J Oral Maxillofac Surg 28 (2): 89-91, 1990.  [PUBMED Abstract]
    
    
42. Mills EE: The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 57 (4): 416-7, 1988.  [PUBMED Abstract]
    
    
43. Osaki T, Ueta E, Yoneda K, et al.: Prophylaxis of oral mucositis associated with chemoradiotherapy for oral carcinoma by Azelastine hydrochloride (Azelastine) with other antioxidants. Head Neck 16 (4): 331-9, 1994 Jul-Aug.  [PUBMED Abstract]
    
    
44. Pretnar J, Glazar D, Mlakar U, et al.: Prostaglandin E2 in the treatment of oral mucositis due to radiochemotherapy in patients with haematological malignancies. Bone Marrow Transplant 4 (Suppl 3): 106, 1989.  [PUBMED Abstract]
    
    
45. Dueñas-Gonzalez A, Sobrevilla-Calvo P, Frias-Mendivil M, et al.: Misoprostol prophylaxis for high-dose chemotherapy-induced mucositis: a randomized double-blind study. Bone Marrow Transplant 17 (5): 809-12, 1996.  [PUBMED Abstract]
    
    
46. Anderson PM, Schroeder G, Skubitz KM: Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 83 (7): 1433-9, 1998.  [PUBMED Abstract]
    
    
47. Oblon DJ, Paul SR, Oblon MB, et al.: Propantheline protects the oral mucosa after high-dose ifosfamide, carboplatin, etoposide and autologous stem cell transplantation. Bone Marrow Transplant 20 (11): 961-3, 1997.  [PUBMED Abstract]
    
    
48. Lugliè PF, Mura G, Mura A, et al.: [Prevention of periodontopathy and oral mucositis during antineoplastic chemotherapy. Clinical study] Minerva Stomatol 51 (6): 231-9, 2002.  [PUBMED Abstract]
    
    
49. Cheng KK, Molassiotis A, Chang AM, et al.: Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients. Eur J Cancer 37 (16): 2056-63, 2001.  [PUBMED Abstract]
    
    
50. Wardley AM, Jayson GC, Swindell R, et al.: Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 110 (2): 292-9, 2000.  [PUBMED Abstract]
    
    
51. Dray A: Mechanism of action of capsaicin-like molecules on sensory neurons. Life Sci 51 (23): 1759-65, 1992.  [PUBMED Abstract]
    
    
52. Green BG: Evidence that removal of capsaicin accelerates desensitization on the tongue. Neurosci Lett 150 (1): 44-8, 1993.  [PUBMED Abstract]
    
    
53. Green BG: Temporal characteristics of capsaicin sensitization and desensitization on the tongue. Physiol Behav 49 (3): 501-5, 1991.  [PUBMED Abstract]
    
    
54. Berger A, Henderson M, Nadoolman W, et al.: Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J Pain Symptom Manage 10 (3): 243-8, 1995.  [PUBMED Abstract]
    
    

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Infection

The multiple protective-barrier functions associated with normal oral mucosa directly affect risk for acute infection. Normal oral mucosa functions to reduce levels of oral microorganisms colonizing the mucosa by means of shedding of the surface layer and to limit penetration of many compounds into the epithelium by maintaining a chemical barrier.[1] Normal salivary gland function promotes mucosal health.

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]

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:

• 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).

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:

• 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.

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.

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), varicella-zoster 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.

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. Recurrent oral 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.

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]

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]

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-cell–depleted 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.

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.

References

1. Squier CA, Kremer MJ: Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr (29): 7-15, 2001.  [PUBMED Abstract]
   
   
2. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
3. Epstein JB, Chow AW: Oral complications associated with immunosuppression and cancer therapies. Infect Dis Clin North Am 13 (4): 901-23, 1999.  [PUBMED Abstract]
   
   
4. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
5. Silverman S Jr: Oral cancer: complications of therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88 (2): 122-6, 1999.  [PUBMED Abstract]
   
   
6. De Pauw BE, Donnelly JP: Infections in the immunocompromised host: general principles. In: Mandell GL, Bennett JE, Dolin R, eds.: Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone, 2000, pp 3079-90. 
   
   
7. Donnelly JP: Infection in the neutropenic and haematopoietic stem cell transplant recipient. Curr Opin Infect Dis 13 (4): 337-342, 2000.  [PUBMED Abstract]
   
   
8. Kennedy HF, Morrison D, Kaufmann ME, et al.: Origins of Staphylococcus epidermidis and Streptococcus oralis causing bacteraemia in a bone marrow transplant patient. J Med Microbiol 49 (4): 367-70, 2000.  [PUBMED Abstract]
   
   
9. Rolston KV, Bodey GP: Infections in patients with cancer. In: Holland JF, Frei E III, Bast RC Jr, et al., eds.: Cancer Medicine. 3rd ed. Philadelphia, Pa: Lea & Febiger, 1993, pp 2416-41. 
   
   
10. Giamarellou H, Antoniadou A: Infectious complications of febrile leukopenia. Infect Dis Clin North Am 15 (2): 457-82, 2001.  [PUBMED Abstract]
    
    
11. Zambelli A, Montagna D, Da Prada GA, et al.: Evaluation of infectious complications and immune recovery following high-dose chemotherapy (HDC) and autologous peripheral blood progenitor cell transplantation (PBPC-T) in 148 breast cancer patients. Anticancer Res 22 (6B): 3701-8, 2002 Nov-Dec.  [PUBMED Abstract]
    
    
12. Peterson DE, Minah GE, Overholser CD, et al.: Microbiology of acute periodontal infection in myelosuppressed cancer patients. J Clin Oncol 5 (9): 1461-8, 1987.  [PUBMED Abstract]
    
    
13. Graber CJ, de Almeida KN, Atkinson JC, et al.: Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 27 (5): 537-42, 2001.  [PUBMED Abstract]
    
    
14. Akintoye SO, Brennan MT, Graber CJ, et al.: A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (5): 581-8, 2002.  [PUBMED Abstract]
    
    
15. Raber-Durlacher JE, Epstein JB, Raber J, et al.: Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer 10 (6): 466-73, 2002.  [PUBMED Abstract]
    
    
16. Peterson DE: Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr (9): 61-71, 1990.  [PUBMED Abstract]
    
    
17. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.  [PUBMED Abstract]
    
    
18. Peters E, Monopoli M, Woo SB, et al.: Assessment of the need for treatment of postendodontic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 76 (1): 45-8, 1993.  [PUBMED Abstract]
    
    
19. Toljanic JA, Bedard JF, Larson RA, et al.: A prospective pilot study to evaluate a new dental assessment and treatment paradigm for patients scheduled to undergo intensive chemotherapy for cancer. Cancer 85 (8): 1843-8, 1999.  [PUBMED Abstract]
    
    
20. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.  [PUBMED Abstract]
    
    
21. Meunier F, Paesmans M, Autier P: Value of antifungal prophylaxis with antifungal drugs against oropharyngeal candidiasis in cancer patients. Eur J Cancer B Oral Oncol 30B (3): 196-9, 1994.  [PUBMED Abstract]
    
    
22. Böhme A, Karthaus M, Hoelzer D: Antifungal prophylaxis in neutropenic patients with hematologic malignancies. Antibiot Chemother 50: 69-78, 2000.  [PUBMED Abstract]
    
    
23. Cuttner J, Troy KM, Funaro L, et al.: Clotrimazole treatment for prevention of oral candidiasis in patients with acute leukemia undergoing chemotherapy. Results of a double-blind study. Am J Med 81 (5): 771-4, 1986.  [PUBMED Abstract]
    
    
24. Slavin MA, Osborne B, Adams R, et al.: Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation--a prospective, randomized, double-blind study. J Infect Dis 171 (6): 1545-52, 1995.  [PUBMED Abstract]
    
    
25. Epstein JB, Vickars L, Spinelli J, et al.: Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol 73 (6): 682-9, 1992.  [PUBMED Abstract]
    
    
26. Ferretti GA, Ash RC, Brown AT, et al.: Control of oral mucositis and candidiasis in marrow transplantation: a prospective, double-blind trial of chlorhexidine digluconate oral rinse. Bone Marrow Transplant 3 (5): 483-93, 1988.  [PUBMED Abstract]
    
    
27. Goodman JL, Winston DJ, Greenfield RA, et al.: A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 326 (13): 845-51, 1992.  [PUBMED Abstract]
    
    
28. Gøtzsche PC, Johansen HK: Nystatin prophylaxis and treatment in severely immunodepressed patients. Cochrane Database Syst Rev (4): CD002033, 2002.  [PUBMED Abstract]
    
    
29. Kami M, Machida U, Okuzumi K, et al.: Effect of fluconazole prophylaxis on fungal blood cultures: an autopsy-based study involving 720 patients with haematological malignancy. Br J Haematol 117 (1): 40-6, 2002.  [PUBMED Abstract]
    
    
30. Schubert MM: Oral manifestations of viral infections in immunocompromised patients. Curr Opin Dent 1 (4): 384-97, 1991.  [PUBMED Abstract]
    
    
31. Schubert MM, Peterson DE, Flournoy N, et al.: Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection. Oral Surg Oral Med Oral Pathol 70 (3): 286-93, 1990.  [PUBMED Abstract]
    
    
32. Kawasaki H, Takayama J, Ohira M: Herpes zoster infection after bone marrow transplantation in children. J Pediatr 128 (3): 353-6, 1996.  [PUBMED Abstract]
    
    
33. Lloid ME, Schubert MM, Myerson D, et al.: Cytomegalovirus infection of the tongue following marrow transplantation. Bone Marrow Transplant 14 (1): 99-104, 1994.  [PUBMED Abstract]
    
    
34. Schubert MM, Epstein JB, Lloid ME, et al.: Oral infections due to cytomegalovirus in immunocompromised patients. J Oral Pathol Med 22 (6): 268-73, 1993.  [PUBMED Abstract]
    
    
35. Devine SM, Wingard JR: Viral infections in severely immunocompromised cancer patients. Support Care Cancer 2 (6): 355-68, 1994.  [PUBMED Abstract]
    
    
36. Reusser P: Current concepts and challenges in the prevention and treatment of viral infections in immunocompromised cancer patients. Support Care Cancer 6 (1): 39-45, 1998.  [PUBMED Abstract]
    
    
37. Samonis G, Mantadakis E, Maraki S: Orofacial viral infections in the immunocompromised host. Oncol Rep 7 (6): 1389-94, 2000 Nov-Dec.  [PUBMED Abstract]
    
    
38. Vancíková Z, Dvorák P: Cytomegalovirus infection in immunocompetent and immunocompromised individuals--a review. Curr Drug Targets Immune Endocr Metabol Disord 1 (2): 179-87, 2001.  [PUBMED Abstract]
    
    
39. Leflore S, Anderson PL, Fletcher CV: A risk-benefit evaluation of aciclovir for the treatment and prophylaxis of herpes simplex virus infections. Drug Saf 23 (2): 131-42, 2000.  [PUBMED Abstract]
    
    
40. Reusser P: Management of viral infections in immunocompromised cancer patients. Swiss Med Wkly 132 (27-28): 374-8, 2002.  [PUBMED Abstract]
    
    
41. Naesens L, De Clercq E: Recent developments in herpesvirus therapy. Herpes 8 (1): 12-6, 2001.  [PUBMED Abstract]
    
    
42. Jubelt B: Valacyclovir and famciclovir therapy in herpes zoster. Curr Neurol Neurosci Rep 2 (6): 477-8, 2002.  [PUBMED Abstract]
    
    
43. Burns LJ, Miller W, Kandaswamy C, et al.: Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation. Bone Marrow Transplant 30 (12): 945-51, 2002.  [PUBMED Abstract]
    
    
44. Zaia JA: Prevention of cytomegalovirus disease in hematopoietic stem cell transplantation. Clin Infect Dis 35 (8): 999-1004, 2002.  [PUBMED Abstract]
    
    
45. Kanegane H, Nomura K, Miyawaki T, et al.: Biological aspects of Epstein-Barr virus (EBV)-infected lymphocytes in chronic active EBV infection and associated malignancies. Crit Rev Oncol Hematol 44 (3): 239-49, 2002.  [PUBMED Abstract]
    
    
46. Kumar S, Wairagkar NS, Mahanta J: Demonstration of Epstein-Barr virus antibodies in serum of patients with nasopharyngeal carcinoma. Indian J Cancer 38 (2-4): 72-5, 2001 Jun-Dec.  [PUBMED Abstract]
    
    

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Hemorrhage

Hemorrhage may occur during treatment-induced thrombocytopenia and/or coagulopathy and is a concern for patients receiving high-dose chemotherapy or undergoing hematopoietic stem cell transplantation.[1] Spontaneous gingival oozing may occur when platelet counts diminish to less than 30,000/mm³, especially when there is preexisting gingivitis or periodontitis. Even normal function or routine oral hygiene (brushing and flossing) can induce gingival oozing in the face of preexisting gingivitis and periodontitis. Although rarely serious, oral bleeds can be of concern to nonexperienced individuals such as the patient and family. Oral bleeding may be mild (e.g., petechiae located on the lips, soft palate, or floor of the mouth) or severe (e.g., persistent gingival hemorrhage or bleeding from herpes simplex virus (HSV) ulcers in the face of severe thrombocytopenia).

It is not uncommon for oncology patients to be told specifically to not use toothbrushes and dental floss when platelet counts drop below 40,000/mm³. This is generally poorly advised unless there are extenuating circumstances. Healthy gingival tissues do not bleed unless traumatized. Discontinuation of routine oral hygiene can increase the risk of infection that could not only promote bleeding, but also increase the risk of local and systemic infection due to accumulation of bacterial plaque, leading to periodontal infections and tissue breakdown. This further supports the utility of precancer therapy dental treatments to reduce or eliminate gingival or periodontal conditions. The degree of health professional oversight of thrombocytopenic patients is an important consideration relative to risk of mechanical hygiene procedures; with comprehensive monitoring, patients can often safely use dental brushing and flossing throughout the thrombocytopenic episode. While the use of foam brushes is often promoted to reduce the risk of bleeding, this is usually ill-advised. Studies have shown that foam brushes cannot adequately remove dental plaque along gingival margins, thus promoting gingival infection and bleeding.

Management of oral bleeds revolves around the use of vasoconstrictors, clot forming agents, and tissue protectants. Epinephrine or cocaine can be used topically to reduce blood flow rates through bleeding vessels. Topical thrombin and/or hemostatic collagen agents can be used to organize and stabilize clots. Application of mucosal adherent products (including cyanoacrylate products) help seal bleeding sites and protect organized clots. Patients who tend to form friable and easily dislodged clots will benefit from topical application of aminocaproic acid; in some instances, intravenous administration can be considered to improve coagulation and the formation of stable clots.

Application of 3% hydrogen peroxide and 0.9% saline (1:2 to 1:3 by volume) can aid in wound cleansing and removal of superficial blood debris. Care must be taken not to disturb clots, which might promote bleeding.[2]

References

1. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
2. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Blume KG, Forman SJ, Applebaum FR, eds.: Thomas' Hematopoietic Cell Transplantation. 3rd ed. Malden, Mass: Blackwell Science Inc, 2004, pp 911-28. 
   
   

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Neurotoxicity

Selected classes of chemotherapy, including the vinca alkaloids, vincristine, and vinblastine, can cause direct neurotoxicity. Deep-seated, throbbing mandibular pain can occur. Since this symptom is also consistent with acute dental pulpal disease, it is important that a thorough history and oral physical examination be performed when oral pain is present; radiographs and vitality testing of the dental pulp are typically necessary. After neurotoxicity is appropriately diagnosed, management includes pain support and patient counseling. The symptom generally resolves within a week following cessation of the causative chemotherapy.

Dental hypersensitivity may occasionally arise in patients weeks or months after discontinuation of chemotherapy. Additionally, it has been observed that patients being treated with cyclosporine for treatment of graft-versus-host disease will report increased thermal sensitivity. The mechanisms of this response are not known. Fortunately, thermal stimuli are self-resolving after discontinuation or withdrawal of therapy, though they can persist for several months. Topical application of fluorides and/or desensitizing toothpaste may ameliorate the discomfort.

Patients may experience temporomandibular dysfunction pain involving muscles of mastication, temporomandibular joints, or teeth. This condition is not unique to cancer patients, and it correlates with stress and dysfunctional habits including bruxism and clenching of the jaws. Stress and sleep dysfunction appear to be the most frequent etiologic factors. Judicious use of muscle relaxants or anxiety-reducing agents plus physical therapy (moist heat applications, massage, and gentle stretching) are standard approaches for management. For patients who have propensity for clenching or bruxism during sleep, customized occlusal splints for use while sleeping may be of value.

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Graft-versus-Host Disease

Patients who have received allogeneic or matched unrelated transplants are at risk for graft-versus-host disease (GVHD).[1-3] A related condition referred to as pseudo-GVHD is occasionally reported in autologous hematopoietic stem cell transplant recipients. The lesion can affect oral tissues and often mimics naturally occurring autoimmune diseases such as erosive lichen planus, lupus erythematosus, scleroderma, and Sjögren syndrome. Oral GVHD has also been linked with oral precancerous and malignant lesions.[4]

Acute GVHD can occur as early as 2 to 3 weeks posttransplant; mucosal erythema and erosion/ulceration are typical manifestations. Chronic oral GVHD changes can be recognized as early as day 70 posttransplant.[5] The pattern and types of lesions seen in acute GVHD are also seen in chronic GVHD, but manifestations can also include raised white plaques and striae and persistent reduced salivary function. Oral symptoms of oral GVHD include xerostomia and increased sensitivity and pain with spices, alcohols, and flavoring agents (especially mint flavors in toothpaste and oral care products).

Biopsy of oral mucosa including both surface epithelium and minor labial salivary glands may be of value in establishing a final diagnosis.[6,7] Presence of a lymphocytic infiltrate (grade I) with epithelial cell necrosis (grade II) provides the diagnostic basis for oral GVHD. As clinical criteria for recognition of oral signs and symptoms of GVHD have become more established, dependance on the oral biopsy to diagnose oral involvement has lessened. In cases of equivocal examination findings, the biopsy can improve the recognition of oral evolvement.

Topical management of mucosal lesions may include steroids, azathioprine, and/or oral psoralen and ultraviolet A (PUVA) (refer to the list on Management of Oral Chronic GVHD below).[5,8] While topical cyclosporin has been suggested as being therapeutically beneficial, its effectiveness is less than other treatments, which when coupled with increased cost of care, usually decreases its utility. The use of FK506 and mycophenolate mofetil to topically treat oral GVHD remains anecdotal and of uncertain efficacy. Systemic therapy (e.g., prednisone, cyclosporine, and other immunosuppressive agents) is routinely necessary primarily to treat the condition. Patients with clinically significant xerostomia may benefit from pilocarpine (5 mg 3 or 4 times a day) or cevimeline (10 mg 4 times a day) if native salivary gland function remains partially intact.

Management of Oral Chronic GVHD

• Topical steroids:
  • Rinses: dexamethasone elixir (Decadron).
  • Gels, creams:
    • fluocinonide (Fluonex)
    • clobetasol (Temovate)
    • halobetasol (Ultravate)
    • betamethasone (Celestone)
  • Powders: beclomethasone (Beclovent) (inhalers applied to mucosa).



• Other topical immunosuppressants:
  • azathioprine rinse (Imuran; 5–8 mg/mL)
  • cyclosporin (Neoral)



• Antifungals:
  • Topical preparations:
    • nystatin (Mycostatin)
    • clotrimazole (Mycelex)
    • amphotericin (Amphocin)
  • Systemic agents:
    • fluconazole (Diflucan)
    • itraconazole (Sporanox)



• PUVA: Psoralen and ultraviolet irradiation.



• Sialogogues:
  • pilocarpine (Salagen)
  • bethanechol
  • cevimeline (Evoxac)



• Topical anesthetics:
  • lidocaine (Xylocaine)
  • dyclonine (Dyclone)
  • diphenhydramine (Benadryl)
  • doxepin (Zonalon)



• Dental caries prevention:
  • Oral hygiene (dental plaque removal)
  • Fluorides:
    • Adult patients: brush-on, rinses, home-use trays
    • Pediatric patients: brush-on

     [Note: If drinking water does not have adequate fluoride content to prevent tooth decay, oral fluoride (e.g., drops, vitamins) should be provided to children younger than 12 years.]

  • Remineralizing solution.

References

1. Schubert MM, Sullivan KM: Recognition, incidence, and management of oral graft-versus-host disease. NCI Monogr (9): 135-43, 1990.  [PUBMED Abstract]
   
   
2. Woo SB, Lee SJ, Schubert MM: Graft-vs.-host disease. Crit Rev Oral Biol Med 8 (2): 201-16, 1997.  [PUBMED Abstract]
   
   
3. Demarosi F, Bez C, Sardella A, et al.: Oral involvement in chronic graft-vs-host disease following allogenic bone marrow transplantation. Arch Dermatol 138 (6): 842-3, 2002.  [PUBMED Abstract]
   
   
4. Abdelsayed RA, Sumner T, Allen CM, et al.: Oral precancerous and malignant lesions associated with graft-versus-host disease: report of 2 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93 (1): 75-80, 2002.  [PUBMED Abstract]
   
   
5. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
6. Loughran TP Jr, Sullivan K, Morton T, et al.: Value of day 100 screening studies for predicting the development of chronic graft-versus-host disease after allogeneic bone marrow transplantation. Blood 76 (1): 228-34, 1990.  [PUBMED Abstract]
   
   
7. Yamada H, Chihara J, Hamada K, et al.: Immunohistology of skin and oral biopsies in graft-versus-host disease after bone marrow transplantation and cytokine therapy. J Allergy Clin Immunol 100 (6 Pt 2): S73-6, 1997.  [PUBMED Abstract]
   
   
8. Epstein JB, Nantel S, Sheoltch SM: Topical azathioprine in the combined treatment of chronic oral graft-versus-host disease. Bone Marrow Transplant 25 (6): 683-7, 2000.  [PUBMED Abstract]
   
   

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Posttransplantation Dental Treatment

Caution should be given relative to oral treatment for transplant patients for at least the first year posttransplant. Even though hematologic parameters including complete blood count and differential may be documented as within normal limits, functional abnormalities may still be present. Patients should not resume routine dental treatment, including dental scaling and polishing, until adequate immunologic reconstitution has occurred; this includes recovery from graft-versus-host disease. The aerosolization of debris and bacteria during the use of ultrasonic or high-speed rotary cutting instruments can put the patient at risk for aspiration pneumonia; additionally, bacteremias often occur as a result of dental treatment and their impact can be noticeable. Appropriate supportive care including antibiotics, immunoglobulin G administration, adjustment of steroid doses, and/or platelet transfusions should be comprehensively considered prior to invasive oral procedures.

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Relapse and Second Malignancy

Gingival infiltrates, oral infection, and/or bleeding disproportionate to local etiology can indicate possible relapsed disease. Painless unilateral lymphadenopathy can also represent relapse in patients with previously treated lymphoma.

Incidence of second malignancy can increase as cancer patients live longer. Previous exposure to chemotherapy and radiation and alterations in immune function, graft-versus-host disease (GVHD), and GVHD therapy collectively contribute to risk for second malignancy. Oral squamous cell carcinoma is the most frequently occurring secondary oral malignancy in transplant patients, with the lips and tongue being the most frequently reported sites.

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Oral Toxicities Not Related to Chemotherapy or Radiation Therapy

Bisphosphonate-associated Osteonecrosis (BON)

Osteonecrosis of the mandible and maxilla can result from radiation therapy of the head and neck, chronic corticosteroid therapy, and herpes zoster virus infection in immunocompromised patients. Terminology associated with the lesions is based on the etiologic agent (e.g., radiation osteonecrosis, steroid osteonecrosis, or viral osteonecrosis). The term BON is based on a comparable approach.

BON is an oral complication of bisphosphonate therapy in cancer patients.[1] First reported in 2003,[2,3] BON is defined as the unexpected appearance of exposed necrotic bone anywhere in the oral cavity of an individual who is receiving a bisphosphonate and who has not received radiation therapy to the head and neck. The exposed bone persists for 6 to 8 weeks after standard dental care is provided. It is also possible that symptoms of dental and/or periodontal disease may be present, without visible exposed bone.[4] The occurrence of BON is based on cases reported in the literature, and occurrence ranges between 1% and 10% for patients receiving the intravenous formulation (pamidronate and zoledronic acid) and less than 1% for patients taking oral bisphosphonate.[5,6] The mandible is affected in approximately 68% of cases, the maxilla in about 28% of cases, and both jawbones in approximately 4% of cases.[7] This complication is exclusively seen in the head and neck area.

Bisphosphonates are potent inhibitors of osteoclasts. They are utilized in cancer patients with skeletal metastasis, including breast, prostate, or lung cancer; and in patients with multiple myeloma. They are also used to treat hypercalcemia of malignancy. (Refer to the PDQ summary on Hypercalcemia for more information.) Bisphosphonates reduce the risk for fracture and skeletal pain, improving the quality of life of patients with malignant bone disease.[8] (Refer to the PDQ summary on Pain for more information.)

Diagnosis of BON can be clinically challenging. The two most common clinical presentations are as follows:

• Classical: a cancer patient with skeletal metastasis who is receiving intravenous bisphosphonate therapy and who presents with visible necrotic bone in the oral cavity. The site may be infected and painful; these conditions are the typical reason for referral to a dentist. Pain results from both inflammation of the soft tissues contiguous to the necrotic bone as well as from infection. Other symptoms typically occur in more advanced cases (e.g., paresthesia secondary to local neurologic involvement). Purulent secretion at the exposed area indicates active infection. Radiographic examination may demonstrate typical radiolucent and radiopaque areas associated with a bone sequestrum. Bone trabeculation may present with a “mothlike” appearance, suggesting ongoing bone destruction.



• Less common: a cancer patient receiving intravenous bisphosphonate therapy who complains of pain that mimics periodontal or pulpal pathology. There is no clinically visible exposed necrotic bone, but a draining fistula or purulent secretion from the periodontal sulcus may exist. The involved teeth will typically be symptomatic upon palpation and percussion.

Confirmed BON with exposed bone in the oral cavity should initially be managed conservatively with local debridement and removal of sharp margins of bone. This reduces risk of trauma to the soft tissues, including the tongue. Systemic antibiotics should be administered when active infection with purulent secretion, swelling and inflammation of the surrounding soft tissues, and pain are present. Initial therapy can be implemented with only one antibiotic, but there is no agreement regarding drug of first choice. Options include the following:

• Amoxicillin, 500 mg 4 times a day for at least 14 days.
• Metronidazole, 250 mg 3 times a day for at least 14 days.
• Clindamycin, 300 mg 4 times a day for at least 14 days.
• Augmentin, 500 mg 4 times a day for at least 14 days.

In addition, topical oral therapy can be implemented via 0.12% chlorhexidine mouth rinses twice a day. The need for oral hygiene with meticulous brushing and flossing after meals should be emphasized.[5-10]

The patient should be reevaluated in 2 weeks. Systemic antibiotics can be discontinued when clinical signs and symptoms improve. The local measures should be maintained, however, as part of the routine oral hygiene procedures consisting of brushing and flossing.

In BON cases refractory to therapy, patients may need to be maintained on long-term antibiotic therapy. With these patients, a combination of different antibiotic agents such as penicillin and metronidazole can be considered. Another possibility is to use clindamycin or augmentin in the place of amoxicillin. When the infectious process extends to more critical areas of the head and neck, the patient may need hospitalization and intravenous antibiotic therapy, culminating in the need for extensive surgical resection of the affected areas.[10]

Occasionally, cancer patients complain of oral pain and discomfort, and a definitive diagnosis of BON cannot be made because no clinically exposed bone is evident. In these cases, the most likely clinical diagnosis should be addressed first. Routine clinical pulp testing and procurement of signs and symptoms of periodontal disease (e.g., pocket depths, bone loss, and bleeding on probing) should be performed. Radiographic examination should also be conducted. Although not yet definitively confirmed in the literature, the radiographic finding of sclerosing or absence of the lamina dura of the involved teeth may indicate early presence of BON.[7] Endodontic and periodontal therapy should be performed first. The patient should be advised about the possibility of BON and should be educated about oral hygiene procedures. If dental extraction is indicated, the possibility of subclinical BON should be considered and explained to the patient. Thus, delay or absence of healing postextraction must be considered. Before the invasive procedure is performed, the risk of excessive bleeding and/or infection due to bone marrow suppression must be discussed with the patient’s physician, and proper preventive measures should be formulated.

The use of hyperbaric oxygen therapy (HBO) to treat cases of established BON does not appear to be effective.[7-10] However, evidence indicates that HBO in addition to discontinuation of bisphosphonate therapy may benefit patients with BON.[11] Research in this area is ongoing.

The literature does not support discontinuing bisphosphonate therapy as a means to enhance the healing process. Bisphosphonates accumulate in the patient’s skeleton and could remain active for several years, especially in patients who have been treated with an intravenous bisphosphonate for longer than a year. There is anecdotal evidence that even with discontinuation of zoledronic acid therapy in patients who developed BON, the osteonecrotic process clinically progresses and can extend to contiguous sites. However, discontinuation of bisphosphonate therapy is advocated by some authors, especially when a procedure is planned to treat BON.[5,7] Some clinicians believe that there may be beneficial effects from discontinuation of the drug in patients who will receive surgery to treat the necrotic area, although this belief is not supported by scientific study. It is recommended that such a drug holiday be maintained until clinical evidence of healing is observed.[5] However, controversy surrounds this issue [6] and will only be resolved with scientific investigation. It is advisable to discuss with the patient’s physician whether discontinuing bisphosphonate therapy will not put the patient’s general health status at risk. Obtaining an informed consent from the patient before execution of the proposed drug discontinuation and therapy is important.

Patients may present with asymptomatic exposed necrotic bone anywhere in the oral cavity, although the mylohyoid plate on the posterior mandible is the most frequently affected area. In this case, only local measures and effective oral hygiene will typically be necessary, in addition to periodic patient recall and evaluation.

The number of patients who develop BON is small compared to the large number of people taking bisphosphonates. However, some lesions can progress to large sizes and cause severe changes in the patient’s quality of life.[1,8] Advanced mandibular lesions, for instance, can cause necrosis of the cortical bone, increasing the risk for fractures.[8] Advanced and nonresponsive infections may require hospitalization and intravenous antibiotic therapy.[8] Advanced cases of BON may require extensive jawbone resection.[12] Therefore, this adverse event of bisphosphonate therapy may negatively affect quality of life.

The use of new and potent nitrogen-containing bisphosphonates such as oral ibandronate in Europe is under investigation in the United States. These compounds could have a relative bone resorption capacity similar to that of zoledronic acid.[13] Studies have indicated important safety profiles for such medications [14-16] and cost-effectiveness when compared with zoledronic acid and pamidronate.[17] However, initial reports have demonstrated that these compounds can also induce BON.[6,18]

The discontinuation of tobacco use to favor the healing process has been recommended in other studies.[19] However, the role of tobacco and other comorbidities in the process of BON formation requires further investigation.[7]

References

1. Migliorati CA, Siegel MA, Elting LS: Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 7 (6): 508-14, 2006.  [PUBMED Abstract]
   
   
2. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61 (9): 1115-7, 2003.  [PUBMED Abstract]
   
   
3. Migliorati CA: Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 21 (22): 4253-4, 2003.  [PUBMED Abstract]
   
   
4. American Association of Oral and Maxillofacial Surgeons: Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws. Rosemont, Ill: AAOMS, 2006. Available online. Last accessed November 6, 2008. 
   
   
5. Woo SB, Hellstein JW, Kalmar JR: Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144 (10): 753-61, 2006.  [PUBMED Abstract]
   
   
6. Khosla S, Burr D, Cauley J, et al.: Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22 (10): 1479-91, 2007.  [PUBMED Abstract]
   
   
7. Marx RE, Sawatari Y, Fortin M, et al.: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63 (11): 1567-75, 2005.  [PUBMED Abstract]
   
   
8. Migliorati CA, Casiglia J, Epstein J, et al.: Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 136 (12): 1658-68, 2005.  [PUBMED Abstract]
   
   
9. Migliorati CA, Schubert MM, Peterson DE, et al.: Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 104 (1): 83-93, 2005.  [PUBMED Abstract]
   
   
10. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102 (4): 433-41, 2006.  [PUBMED Abstract]
    
    
11. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, et al.: Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 65 (7): 1321-7, 2007.  [PUBMED Abstract]
    
    
12. Chaudhry AN, Ruggiero SL: Osteonecrosis and bisphosphonates in oral and maxillofacial surgery. Oral Maxillofac Surg Clin North Am 19 (2): 199-206, vi, 2007.  [PUBMED Abstract]
    
    
13. Licata AA: Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 39 (4): 668-77, 2005.  [PUBMED Abstract]
    
    
14. Body JJ, Diel IJ, Lichinitser MR, et al.: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14 (9): 1399-405, 2003.  [PUBMED Abstract]
    
    
15. Body JJ, Coleman R, Clezardin P, et al.: International Society of Geriatric Oncology (SIOG) clinical practice recommendations for the use of bisphosphonates in elderly patients. Eur J Cancer 43 (5): 852-8, 2007.  [PUBMED Abstract]
    
    
16. Bergner R, Henrich DM, Hoffmann M, et al.: Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function. J Clin Pharmacol 47 (8): 942-50, 2007.  [PUBMED Abstract]
    
    
17. De Cock E, Hutton J, Canney P, et al.: Cost-effectiveness of oral ibandronate versus IV zoledronic acid or IV pamidronate for bone metastases in patients receiving oral hormonal therapy for breast cancer in the United Kingdom. Clin Ther 27 (8): 1295-310, 2005.  [PUBMED Abstract]
    
    
18. Malden NJ, Pai AY: Oral bisphosphonate associated osteonecrosis of the jaws: three case reports. Br Dent J 203 (2): 93-7, 2007.  [PUBMED Abstract]
    
    
19. Yarom N, Yahalom R, Shoshani Y, et al.: Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 18 (10): 1363-70, 2007.  [PUBMED Abstract]
    
    

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Head/Neck Radiation Patients

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.

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 high-dose 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 patient’s 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. Radiation injury is oral tissue-specific and is dependent on dosage and portals of therapy.



2. 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.



3. 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.)
   • 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.
   
   
   

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), and muscular and cutaneous fibrosis.[1]

The etiopathogenesis of head and neck radiation mucositis appears to be similar but not identical to mucositis caused by high-dose chemotherapy.[2-5] Management strategies described for chemotherapy/hematopoietic stem cell transplantation are generally applicable to the head/neck radiation patient (refer to the Management of mucositis section).[6-8] The extensive duration and severity of radiation mucositis combined with most radiation patients being treated as outpatients results in pain management challenges. 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.[9] 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. Doses for NSAIDs are titrated up to their recommended dosing ceiling; on the other hand, opioids are titrated to effective pain relief. 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.[10] The use of alcohol-free povidone-iodine mouthwash can reduce the severity and delay the onset of oral mucositis due to antineoplastic radiation therapy.[11]

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.[12] 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.[13,14]

As oral and pharyngeal mucosa are exposed to radiation, taste receptors become damaged and taste discrimination becomes increasingly compromised.[15,16] 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.[17-19]

Late oral complications of radiation therapy are chiefly a result of chronic injury to vasculature, salivary glands, mucosa, connective tissue, and bone.[20,21,17] 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.

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).[17] 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.

Necrosis and secondary infection of previously irradiated tissue is a serious complication for patients who have undergone radiation for head and neck tumors.[17] 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.

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.

References

1. Vera-Llonch M, Oster G, Hagiwara M, et al.: Oral mucositis in patients undergoing radiation treatment for head and neck carcinoma. Cancer 106 (2): 329-36, 2006.  [PUBMED Abstract]
   
   
2. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.  [PUBMED Abstract]
   
   
3. Peterson DE: Research advances in oral mucositis. Curr Opin Oncol 11 (4): 261-6, 1999.  [PUBMED Abstract]
   
   
4. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001. 
   
   
5. Barasch A, Peterson DE: Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol 39 (2): 91-100, 2003.  [PUBMED Abstract]
   
   
6. Dose AM: The symptom experience of mucositis, stomatitis, and xerostomia. Semin Oncol Nurs 11 (4): 248-55, 1995.  [PUBMED Abstract]
   
   
7. Demarosi F, Bez C, Carrassi A: Prevention and treatment of chemo- and radiotherapy-induced oral mucositis. Minerva Stomatol 51 (5): 173-86, 2002.  [PUBMED Abstract]
   
   
8. Shih A, Miaskowski C, Dodd MJ, et al.: A research review of the current treatments for radiation-induced oral mucositis in patients with head and neck cancer. Oncol Nurs Forum 29 (7): 1063-80, 2002.  [PUBMED Abstract]
   
   
9. Wong PC, Dodd MJ, Miaskowski C, et al.: Mucositis pain induced by radiation therapy: prevalence, severity, and use of self-care behaviors. J Pain Symptom Manage 32 (1): 27-37, 2006.  [PUBMED Abstract]
   
   
10. Lin LC, Que J, Lin LK, et al.: Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. Int J Radiat Oncol Biol Phys 65 (3): 745-50, 2006.  [PUBMED Abstract]
    
    
11. Madan PD, Sequeira PS, Shenoy K, et al.: The effect of three mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies: a randomized control trial. J Cancer Res Ther 4 (1): 3-8, 2008 Jan-Mar.  [PUBMED Abstract]
    
    
12. Epstein JB, Freilich MM, Le ND: Risk factors for oropharyngeal candidiasis in patients who receive radiation therapy for malignant conditions of the head and neck. Oral Surg Oral Med Oral Pathol 76 (2): 169-74, 1993.  [PUBMED Abstract]
    
    
13. Oakley C, Epstein JB, Sherlock CH: Reactivation of oral herpes simplex virus: implications for clinical management of herpes simplex virus recurrence during radiotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84 (3): 272-8, 1997.  [PUBMED Abstract]
    
    
14. Epstein JB, Gorsky M, Hancock P, et al.: The prevalence of herpes simplex virus shedding and infection in the oral cavity of seropositive patients undergoing head and neck radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (6): 712-6, 2002.  [PUBMED Abstract]
    
    
15. Nelson GM: Biology of taste buds and the clinical problem of taste loss. Anat Rec 253 (3): 70-8, 1998.  [PUBMED Abstract]
    
    
16. Zheng WK, Inokuchi A, Yamamoto T, et al.: Taste dysfunction in irradiated patients with head and neck cancer. Fukuoka Igaku Zasshi 93 (4): 64-76, 2002.  [PUBMED Abstract]
    
    
17. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. Hamilton, Canada: BC Decker Inc, 2003, pp 113-28. 
    
    
18. Ripamonti C, Zecca E, Brunelli C, et al.: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 82 (10): 1938-45, 1998.  [PUBMED Abstract]
    
    
19. Silverman JE, Weber CW, Silverman S Jr, et al.: Zinc supplementation and taste in head and neck cancer patients undergoing radiation therapy. J Oral Med 38 (1): 14-6, 1983 Jan-Mar.  [PUBMED Abstract]
    
    
20. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.  [PUBMED Abstract]
    
    
21. Epstein JB, Wong FL, Stevenson-Moore P: Osteoradionecrosis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 45 (2): 104-10, 1987.  [PUBMED Abstract]
    
    

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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 mouth’s 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 = 0.3–0.5 mL/minute). Xerostomia produces the following changes in the mouth that collectively cause patient discomfort and increased risk for oral lesions:

• 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 patient’s 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):

• 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 (½ tsp salt and ½ 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]

• Plaque removal:
  • 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:
  • 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 patient’s evening dose may be increased to 10 mg within 1 week after starting pilocarpine. Subsequently, morning and afternoon doses may also be increased to a maximum 10 mg per dose (30 mg/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 Sjögren 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]

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 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]

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.)

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 patient’s 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.[21,22]

References

1. 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. J Clin Oncol 11 (6): 1124-31, 1993.  [PUBMED Abstract]
   
   
2. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
3. Jellema AP, Slotman BJ, Doornaert P, et al.: Impact of radiation-induced xerostomia on quality of life after primary radiotherapy among patients with head and neck cancer. Int J Radiat Oncol Biol Phys 69 (3): 751-60, 2007.  [PUBMED Abstract]
   
   
4. Seikaly H, Jha N, McGaw T, et al.: Submandibular gland transfer: a new method of preventing radiation-induced xerostomia. Laryngoscope 111 (2): 347-52, 2001.  [PUBMED Abstract]
   
   
5. Epstein JB, Burchell JL, Emerton S, et al.: A clinical trial of bethanechol in patients with xerostomia after radiation therapy. A pilot study. Oral Surg Oral Med Oral Pathol 77 (6): 610-4, 1994.  [PUBMED Abstract]
   
   
6. Rieger J, Seikaly H, Jha N, et al.: Submandibular gland transfer for prevention of xerostomia after radiation therapy: swallowing outcomes. Arch Otolaryngol Head Neck Surg 131 (2): 140-5, 2005.  [PUBMED Abstract]
   
   
7. Scarantino C, LeVeque F, Swann RS, et al.: Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients. J Support Oncol 4 (5): 252-8, 2006.  [PUBMED Abstract]
   
   
8. Buentzel J, Micke O, Adamietz IA, et al.: Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled phase III study. Int J Radiat Oncol Biol Phys 64 (3): 684-91, 2006.  [PUBMED Abstract]
   
   
9. Sasse AD, Clark LG, Sasse EC, et al.: Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys 64 (3): 784-91, 2006.  [PUBMED Abstract]
   
   
10. Wasserman TH, Brizel DM, Henke M, et al.: Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial. Int J Radiat Oncol Biol Phys 63 (4): 985-90, 2005.  [PUBMED Abstract]
    
    
11. Bartoshuk LM: Chemosensory alterations and cancer therapies. NCI Monogr (9): 179-84, 1990.  [PUBMED Abstract]
    
    
12. State FA, Hamed MS, Bondok AA: Effect of vincristine on the histological structure of taste buds. Acta Anat (Basel) 99 (4): 445-9, 1977.  [PUBMED Abstract]
    
    
13. Garrick R: Neurologic complications. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 958-79. 
    
    
14. Fetting JH, Wilcox PM, Sheidler VR, et al.: Tastes associated with parenteral chemotherapy for breast cancer. Cancer Treat Rep 69 (11): 1249-51, 1985.  [PUBMED Abstract]
    
    
15. Marinone MG, Rizzoni D, Ferremi P, et al.: Late taste disorders in bone marrow transplantation: clinical evaluation with taste solutions in autologous and allogeneic bone marrow recipients. Haematologica 76 (6): 519-22, 1991 Nov-Dec.  [PUBMED Abstract]
    
    
16. Mattsson T, Arvidson K, Heimdahl A, et al.: Alterations in taste acuity associated with allogeneic bone marrow transplantation. J Oral Pathol Med 21 (1): 33-7, 1992.  [PUBMED Abstract]
    
    
17. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. Hamilton, Canada: BC Decker Inc, 2003, pp 113-28. 
    
    
18. Ripamonti C, Zecca E, Brunelli C, et al.: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 82 (10): 1938-45, 1998.  [PUBMED Abstract]
    
    
19. Silverman JE, Weber CW, Silverman S Jr, et al.: Zinc supplementation and taste in head and neck cancer patients undergoing radiation therapy. J Oral Med 38 (1): 14-6, 1983 Jan-Mar.  [PUBMED Abstract]
    
    
20. Visser MR, Smets EM: Fatigue, depression and quality of life in cancer patients: how are they related? Support Care Cancer 6 (2): 101-8, 1998.  [PUBMED Abstract]
    
    
21. Robinson CA: Enteral nutrition in adult oncology. In: Elliott L, Molseed LL, McCallum PD, eds.: The Clinical Guide to Oncology Nutrition. 2nd ed. Chicago, Ill: American Dietetic Association, 2006, pp 138-55. 
    
    
22. Kagan SH, Sweeney-Cordes E: Head and neck cancers. In: Kogut VJ, Luthringer SL, eds.: Nutritional Issues in Cancer Care. Pittsburgh, Pa: Oncology Nursing Society, 2005, pp 103-16. 
    
    
23. Beer KT, Krause KB, Zuercher T, et al.: Early percutaneous endoscopic gastrostomy insertion maintains nutritional state in patients with aerodigestive tract cancer. Nutr Cancer 52 (1): 29-34, 2005.  [PUBMED Abstract]
    
    
24. Tyldesley S, Sheehan F, Munk P, et al.: The use of radiologically placed gastrostomy tubes in head and neck cancer patients receiving radiotherapy. Int J Radiat Oncol Biol Phys 36 (5): 1205-9, 1996.  [PUBMED Abstract]
    
    

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Psychosocial Issues

Oral complications of cancer, including oral mucositis,[1] are among the most devastating of both short- and long-term problems encountered by people with cancer because they affect eating and communication, the most basic of human activities. Patients with these problems can become withdrawn, socially avoidant, and even clinically depressed as a result of the difficulties and frustrations they encounter living with oral complications. When employing psychotropic drug interventions in treatment of such patients, it is important to choose them with an eye toward improving or at least not worsening their oral complications. For example, in the treatment of depression in such patients, highly anticholinergic drugs should be avoided in patients with xerostomia and salivary problems. (Refer to the PDQ summaries on Anxiety Disorder and Depression for more information.)

Supportive care including education and symptom management are important for patients experiencing oral complications related to cancer therapy. It is important to closely monitor each patient’s level of distress, ability to cope, and response to treatment. This approach provides a setting for the health professional to demonstrate concern for the patient’s complications and to educate the patient and family caregivers. Comprehensive supportive care from staff and family can enhance the patient’s ability to cope with cancer and its complications.

References

1. Dodd MJ, Dibble S, Miaskowski C, et al.: A comparison of the affective state and quality of life of chemotherapy patients who do and do not develop chemotherapy-induced oral mucositis. J Pain Symptom Manage 21 (6): 498-505, 2001.  [PUBMED Abstract]
   
   

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Special Considerations in Pediatric Populations

Altered dental growth and development is a frequent complication for long-term cancer survivors who received high-dose chemotherapy and/or head/neck radiation for childhood malignancies.[1-8] Developmental disturbances in children treated at younger than 12 years generally affect size, shape, and eruption of teeth as well as craniofacial development. Abnormal tooth formation manifests as decreased crown size, shortened and conical shaped roots, and microdontia; on occasion, complete agenesis may occur. Eruption of teeth can be delayed, including increased frequency of impacted maxillary canines. Shortened root length is associated with diminished alveolar processes which in turn leads to decreased occlusal vertical dimension. Additionally, conditioning-induced injury to maxillary and mandibular growth centers can compromise full maturation of the craniofacial complex. Because the changes tend to be symmetric, the effect is not always clinically evident; cephalometric analysis is typically necessary to delineate the scope of the condition.

The role and timing of orthodontic treatment for patients who have had transplant-related malocclusions or other alterations of dental growth and development is not fully established. The number of successfully managed orthodontic interventions appears to be increasing; however, specific guidelines for management, including optimal force and pace with which teeth should be moved, remains undefined. Influence of growth hormone relative to improved development of maxillary and mandibular structures is yet to be comprehensively studied. Such studies may well influence recommendations for orthodontic treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for further information.)

References

1. Cohen A, Rovelli R, Zecca S, et al.: Endocrine late effects in children who underwent bone marrow transplantation: review. Bone Marrow Transplant 21 (Suppl 2): S64-7, 1998.  [PUBMED Abstract]
   
   
2. Dahllöf G, Barr M, Bolme P, et al.: Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 65 (1): 41-4, 1988.  [PUBMED Abstract]
   
   
3. Dahllöf G: Craniofacial growth in children treated for malignant diseases. Acta Odontol Scand 56 (6): 378-82, 1998.  [PUBMED Abstract]
   
   
4. Dahllöf G, Forsberg CM, Ringdén O, et al.: Facial growth and morphology in long-term survivors after bone marrow transplantation. Eur J Orthod 11 (4): 332-40, 1989.  [PUBMED Abstract]
   
   
5. Uderzo C, Fraschini D, Balduzzi A, et al.: Long-term effects of bone marrow transplantation on dental status in children with leukaemia. Bone Marrow Transplant 20 (10): 865-9, 1997.  [PUBMED Abstract]
   
   
6. Lucas VS, Roberts GJ, Beighton D: Oral health of children undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 22 (8): 801-8, 1998.  [PUBMED Abstract]
   
   
7. Dahllöf G, Heimdahl A, Bolme P, et al.: Oral condition in children treated with bone marrow transplantation. Bone Marrow Transplant 3 (1): 43-51, 1988.  [PUBMED Abstract]
   
   
8. Rosenberg SW, Kolodney H, Wong GY, et al.: Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia. A review of 17 cases. Cancer 59 (9): 1640-8, 1987.  [PUBMED Abstract]
   
   

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Changes to This Summary (11/06/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Head/Neck Radiation Patients

Added text on the use of alcohol-free povidone-iodine mouthwash (cited Madan et al. as reference 11).

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• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

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  Treatment options for childhood cancers.

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