Oral Complications of Chemotherapy and Head/Neck Radiation

Summary Type: Supportive care
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about oral complications, such as mucositis and salivary gland dysfunction, that occur in cancer patients treated with chemotherapy or radiation therapy to the head and neck.

Oral Complications of Chemotherapy and Head/Neck Radiation

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.

¹ Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.

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.

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.

Chemotherapy-Induced Complications

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.

Oral Complications of Cancer Chemotherapy

Complication Direct Risk FactorIndirect Risk FactorsDIC = disseminated intravascular coagulation; HSV = herpes simplex virus.Oral mucositisMucosal cytotoxicityDecreased local/systemic immunity: local infections, reactivation of HSVPhysical/chemical traumaOral infections:ViralDecreased systemic immunityFungalDecreased systemic immunitySalivary gland dysfunctionAltered oral flora (decreased bacterial flora)BacterialInadequate oral hygieneDecreased systemic immunityMucosal breakdownSalivary gland dysfunctionAcquired pathogensTaste dysfunction Taste receptor toxicityXerostomiaSalivary gland toxicity Anticholinergic drugsNeuropathies Vinca alkaloid drug use; specific drug toxicityAnemia, dental hypersensitivity, temporomandibular dysfunction/myofascial painDental and skeletal growth and development (pediatric patients)Specific drug toxicityStage of dental and skeletal maturationGastrointestinal mucositis causing secondary changes in oral status including taste, hygiene, and dietary intakeMucosal cytotoxicity: radiation, chemotherapyNausea and vomitingHemorrhageOral mucositis ThrombocytopeniaPhysical trauma Decreased clotting factors (e.g., DIC) Infections (e.g., HSV)

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.^{5,6,7,8,9,10,11} 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.^{1,13,14,15,16,17,18,19,20,21} 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/Neck Radiation-Induced Complications

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.^{2,5,6,22,23,24} 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.

¹ Peterson DE: Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr (9): 61-71, 1990.

² Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.

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.

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.

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.

⁶ Peterson DE: Research advances in oral mucositis. Curr Opin Oncol 11 (4): 261-6, 1999.

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.

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.

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.

¹³ Donnelly JP: Infection in the neutropenic and haematopoietic stem cell transplant recipient. Curr Opin Infect Dis 13 (4): 337-342, 2000.

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.

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.

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.

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.

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.

²¹ Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.

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.

²³ Symonds RP: Treatment-induced mucositis: an old problem with new remedies. Br J Cancer 77 (10): 1689-95, 1998.

²⁴ Plevová P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: a review. Oral Oncol 35 (5): 453-70, 1999.

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.^1,2,3 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.^4,5,6 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.

Chemotherapy Patients

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.

Management Guidelines Relative to Invasive Dental Procedures

Medical Status Guideline CommentsCBC = complete blood cell count; IV = intravenous.*Assumes that all other coagulation parameters are within normal limits and that platelet counts will be maintained at or above the specified level until initial stabilization/healing has occurred.Patients with chronic indwelling venous access lines (e.g., Hickman). AHA prophylactic antibiotic recommendations (low risk). There is no clear scientific proof detailing infectious risk for these lines following dental procedures. This recommendation is empiric.Neutrophils Order CBC with differential. >2,000/mm3 No prophylactic antibiotics.1,000–2,000/mm3 AHA prophylactic antibiotic recommendations (low risk). Clinical judgment is critical. If infection is present or unclear, more aggressive antibiotic therapy may be indicated.<1,000/mm3 Amikacin 150 mg/m2 1 hour before surgery; ticarcillin 75 mg/kg IV ½ hour before surgery. Repeat both 6 hours postoperatively. If organisms are known or suspected, appropriate adjustments should be made based on sensitivities.Platelets* Order platelet count and coagulation tests.>75,000/mm3 No additional support needed.40,000–75,000/mm3 Platelet transfusions are optional; consider administering preoperatively and 24 hours later. Additional transfusions are based on clinical course. Utilize techniques to promote establishing and maintaining control of bleeding (i.e., sutures, pressure packs, minimize trauma).<40,000/mm3 Platelets should be transfused 1 hour before procedure, immediately obtain platelet count, transfuse regularly to maintain counts above 30,000–40,000/mm3 until initial healing has occurred. In addition to above, consider using hemostatic agents (i.e., microfibrillar collagen, topical thrombin). Monitor sites carefully.

Assessment of Hematopoietic Stem Cell Transplant 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.

Oral Complications of Hematopoietic Stem Cell Transplantation

Transplant Phase Oral ComplicationGVHD = graft-versus-host disease.Phase I: Preconditioning Oral infections: dental caries, endodontic infections, periodontal disease (gingivitis, periodontitis), mucosal infections (i.e., viral, fungal, bacterial).Gingival leukemic infiltrates. Metastatic cancer. Oral bleeding. Oral ulceration: aphthous ulcers, erythema multiforme.Temporomandibular dysfunction. Phase II: Conditioning Neutropenic Phase Oropharyngeal mucositis.Oral infections: mucosal infections (i.e., viral, fungal, bacterial), periodontal infections.Hemorrhage. Xerostomia.Taste dysfunction.Neurotoxicity: dental pain, muscle tremor (e.g., jaws, tongue).Temporomandibular dysfunction: jaw pain, headache, joint pain.Phase III: Engraftment Hematopoietic RecoveryOral infections: mucosal infections (i.e., viral, fungal, bacterial). Acute GVHD. Xerostomia. Hemorrhage. Neurotoxicity: dental pain, muscle tremor (e.g., jaws, tongue). Temporomandibular dysfunction: jaw pain, headache, joint pain.Granulomas/papillomas.Phase IV: Immune Reconstitution Late Posttransplant Oral infections: mucosal infections (i.e., viral, fungal, bacterial).Chronic GVHD.Dental/skeletal growth and development alterations (pediatric patients). Xerostomia.Relapse-related oral lesions. Second malignancies.Phase V: Long-term Survival Relapse or second malignancies.Dental/skeletal growth and development alterations.

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.

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.

³ Epstein JB: Infection prevention in bone marrow transplantation and radiation patients. NCI Monogr (9): 73-85, 1990.

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.

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.

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.

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.^2,3,4,

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. 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.

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.

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.

³ Armstrong TS: Stomatitis in the bone marrow transplant patient. An overview and proposed oral care protocol. Cancer Nurs 17 (5): 403-10, 1994.

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.

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.^1,2,3,4,5 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.^6,7,8,9 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.^{10,11,12,13,14,15,16,17} 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.^12,13,14 Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of mucositis. These evaluative tools vary in complexity.

Chemotherapy and Hematopoietic Stem Cell Transplantation Patients

Management of mucositis

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.^{21,22,23,24,25,26,27} 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.^{30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54} 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.^51,52,53,54 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

²³ Bavier AR: Nursing management of acute oral complications of cancer. NCI Monogr (9): 123-8, 1990.

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.

²⁵ Takahashi A, Aoshiba K, Nagai A: Apoptosis of wound fibroblasts induced by oxidative stress. Exp Lung Res 28 (4): 275-84, 2002.

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.

²⁷ O'Toole EA, Goel M, Woodley DT: Hydrogen peroxide inhibits human keratinocyte migration. Dermatol Surg 22 (6): 525-9, 1996.

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.

³⁰ Elzawawy A: Treatment of 5-fluorouracil-induced stomatitis by allopurinol mouthwashes. Oncology 48 (4): 282-4, 1991.

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.

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.

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.

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.

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.

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.

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.

³⁹ Johnston EM, Crawford J: Hematopoietic growth factors in the reduction of chemotherapeutic toxicity. Semin Oncol 25 (5): 552-61, 1998.

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.

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.

⁴² Mills EE: The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 57 (4): 416-7, 1988.

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.

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.

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.

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.

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.

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.

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.

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.

⁵¹ Dray A: Mechanism of action of capsaicin-like molecules on sensory neurons. Life Sci 51 (23): 1759-65, 1992.

⁵² Green BG: Evidence that removal of capsaicin accelerates desensitization on the tongue. Neurosci Lett 150 (1): 44-8, 1993.

⁵³ Green BG: Temporal characteristics of capsaicin sensitization and desensitization on the tongue. Physiol Behav 49 (3): 501-5, 1991.

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.

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.^{2,3,4,5,6,7,8} 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.^12,13,14,15 Dental management prior to initiation of the cytoreductive therapy can substantially reduce the risk of acute infectious flares.^16,17,18,19

Bacterial Infection

Changes in infection profiles in myelosuppressed cancer patients have occurred over the past 3 decades. This evolving epidemiology has been caused by multiple factors, including use of prophylactic and therapeutic antimicrobial regimens, as well as decreased depth and duration of myelosuppression via growth factor therapy.²⁰ Gram-positive organisms including viridans streptococci and enterococci species are currently associated with systemic infection of oral origin. In addition, gram-negative pathogens including Pseudomonas aeruginosa, Neisseria species, and Escherichia coli remain of concern.

Myeloablated cancer patients with chronic periodontal disease may develop acute periodontal infections with associated systemic sequelae.^{4,12,13,14,15} 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).

Fungal Infection

Candidiasis

Candidiasis is typically caused by opportunistic overgrowth of C. albicans.^21,22 A number of variables contribute to its clinical expression, including myelosuppression, mucosal injury, and salivary compromise.⁴ In addition, antibiotics used during prolonged neutropenia and/or concurrent steroid therapy typically alter oral flora, thereby creating a favorable environment for fungal overgrowth. Final diagnosis must be based on the collective relevant features of the history, risk factor analysis, and physical examination.

Protocols utilizing topical oral antifungal agents appear to have variable efficacy in preventing or treating fungal infection in immunocompromised patients.^{21,23,24,25,26,27,28,29} 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.

Noncandidal fungal infections

An increasing number of different fungal organisms are being associated with oral infection in immunocompromised cancer patients in recent years, and includes infection by species of Aspergillus, Mucormycosis, and Rhizopus.⁴ The clinical presentation is not pathognomonic; lesions may appear similar to other oral toxicities. Microbiologic documentation is essential. Systemic therapy must be instituted promptly due to high risk for morbidity and mortality.

Viral Infections

Herpes virus

Herpes group viral infections, including those caused by oral lesions, can cause a variety of diseases that range from mild to serious conditions in patients receiving cancer therapy.^{30,31,32,33,34,35,36,37,38} 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.

Herpes simplex virus

Oral herpetic lesions can range from routine herpes labialis to severe stomatitis causing large painful ulcerations throughout the mouth. The severity of lesions dramatically increases with increasing degrees of immunosuppression. The incidence of recurrent oral HSV lesions in myelosuppressed cancer patients has been considerably reduced with the use of prophylactic acyclovir and more recently, valacyclovir regimens.^39,40,41 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.

Varicella-zoster virus

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

Cytomegalovirus

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

Epstein-Barr virus

EBV is linked with tumor development.⁴⁵ In addition, oral hairy leukoplakia has been attributed to EBV infection in immunocompromised patients, including those with AIDS and renal transplant. The lesion does not appear to be clinically significant in chemotherapy recipients, however. In contrast, hematopoietic stem cell transplant patients who are immunocompromised for a prolonged period may be at risk for development of EBV-related lymphomas of the head and neck region, especially when T-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.

Nonherpes group virus infections

Infections caused by nonherpes viruses are more common in immunocompromised patients, with the risk of infection apparently increasing with the depth and duration of immunosuppression. Oral lesions caused by adenovirus and oral human papilloma virus (HPV) have been described. Often, patients with increased cutaneous HPV lesions will demonstrate oral lesions. These lesions can present as hyperkeratotic verrucoid lesions or as flat acuminata-like lesions. Restoration of immune function will often result in a digression and possibly, disappearance of the oral mucosal lesions. Laser surgery or cryotherapy are typically utilized to remove oral HPV lesions when medically or cosmetically necessitated; intralesional injections of interferon alfa may prove effective for recurrent lesions.

¹ Squier CA, Kremer MJ: Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr (29): 7-15, 2001.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

¹⁶ Peterson DE: Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr (9): 61-71, 1990.

¹⁷ Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.

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.

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.

²⁰ Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.

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.

²² Böhme A, Karthaus M, Hoelzer D: Antifungal prophylaxis in neutropenic patients with hematologic malignancies. Antibiot Chemother 50: 69-78, 2000.

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.

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.

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.

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.

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.

²⁸ Gøtzsche PC, Johansen HK: Nystatin prophylaxis and treatment in severely immunodepressed patients. Cochrane Database Syst Rev (4): CD002033, 2002.

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.

³⁰ Schubert MM: Oral manifestations of viral infections in immunocompromised patients. Curr Opin Dent 1 (4): 384-97, 1991.

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.

³² Kawasaki H, Takayama J, Ohira M: Herpes zoster infection after bone marrow transplantation in children. J Pediatr 128 (3): 353-6, 1996.

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.

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.

³⁵ Devine SM, Wingard JR: Viral infections in severely immunocompromised cancer patients. Support Care Cancer 2 (6): 355-68, 1994.

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.

³⁷ Samonis G, Mantadakis E, Maraki S: Orofacial viral infections in the immunocompromised host. Oncol Rep 7 (6): 1389-94, 2000 Nov-Dec.

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.

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.

⁴⁰ Reusser P: Management of viral infections in immunocompromised cancer patients. Swiss Med Wkly 132 (27-28): 374-8, 2002.

⁴¹ Naesens L, De Clercq E: Recent developments in herpesvirus therapy. Herpes 8 (1): 12-6, 2001.

⁴² Jubelt B: Valacyclovir and famciclovir therapy in herpes zoster. Curr Neurol Neurosci Rep 2 (6): 477-8, 2002.

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.

⁴⁴ Zaia JA: Prevention of cytomegalovirus disease in hematopoietic stem cell transplantation. Clin Infect Dis 35 (8): 999-1004, 2002.

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.

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.

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,

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.

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. Once appropriately diagnosed, management of neurotoxicity includes pain support and counseling of the patient. 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.

Graft-versus-Host Disease

Patients who have received allogeneic or matched unrelated transplants are at risk for graft-versus-host disease (GVHD).^1,2,3 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’s 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

    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.

¹ Schubert MM, Sullivan KM: Recognition, incidence, and management of oral graft-versus-host disease. NCI Monogr (9): 135-43, 1990.

² Woo SB, Lee SJ, Schubert MM: Graft-vs.-host disease. Crit Rev Oral Biol Med 8 (2): 201-16, 1997.

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.

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.

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.

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.

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.

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.

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.

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.

Preradiation Evaluation and Disease Stabilization

Elimination of oral disease and implementation of oral care protocols designed to maintain maximum oral health must be a component of patient assessment and care prior to radiation therapy. During and after radiation therapy, oral management will be dictated by the specific needs of the patient, the specifics of the radiation therapy, and presence of chronic complications caused by radiation therapy. Ongoing oral assessment and treatment of complications are essential, because radiation to oral tissues typically renders patients at lifelong risk for oral complications. In addition, invasive oral procedures can cause additional sequelae. Dental care typically needs to be altered due to underlying chronic radiation-induced tissue damage.

Patients should receive a comprehensive oral evaluation several weeks prior to initiation of 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.

Oral Complications of Head and Neck Radiation

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

Management of oral mucositis

The etiopathogenesis of head and neck radiation mucositis appears to be similar but not identical to mucositis caused by high-dose chemotherapy.^2,3,4,5 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).^6,7,8 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,

Early infections

Candidiasis is the most common clinical infection of the oropharynx in irradiated patients. Patients receiving head and neck radiation are frequently colonized with Candida, as demonstrated by an increase in quantitative counts and rates for clinical infection.¹¹ 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.^12,13,

Taste dysfunction

As oral and pharyngeal mucosa is exposed to radiation, taste receptors become damaged and taste discrimination becomes increasingly compromised.^14,15 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.^16,17,18,

Late reactions

Late oral complications of radiation therapy are chiefly a result of chronic injury to vasculature, salivary glands, mucosa, connective tissue, and bone.^16,19,20 Types and severity of these changes are directly related to radiation dosimetry, including total dose, fraction size, and duration of treatment. Mucosal changes include epithelial atrophy, reduced vascularization, and submucosal fibrosis. These changes lead to an atrophic, friable barrier. Fibrosis involving muscle, dermis, and the temporomandibular joint results in compromised oral function. Salivary tissue changes include loss of acinar cells, alteration in duct epithelium, fibrosis, and fatty degeneration. Compromised vascularization and remodeling capacity of bone leads to risk for osteonecrosis.

Caries

Dental-caries risk increases secondary to a number of factors including shifts to a cariogenic flora, reduced concentrations of salivary antimicrobial proteins, and loss of mineralizing components (refer to the Conditions Affected By Both Chemotherapy and Head/Neck Radiation section for further information).¹⁶ 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 sh