Purpose of This PDQ Summary
Overview
Etiopathogenesis

Chemotherapy-Induced Complications Head/Neck Radiation-Induced Complications

Oral and Dental Management Prior to Cancer Therapy

Chemotherapy Patients Assessment of Hematopoietic Stem Cell Transplant Patients

Management Following Cancer Therapy
Oral Mucositis

Chemotherapy and Hematopoietic Stem Cell Transplantation Patients         Management of mucositis

Infection

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

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

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

Head/Neck Radiation Patients

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

Conditions Affected By Both Chemotherapy and Head/Neck Radiation

Xerostomia         Topical oral antimicrobials Dysgeusia Fatigue Nutritional Compromise

Psychosocial Issues
Special Considerations in Pediatric Populations
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Changes to This Summary (03/13/2008)
Questions or Comments About This Summary
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Purpose of This PDQ Summary

This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of oral complications of chemotherapy and head/neck radiation. This summary is reviewed regularly and updated as necessary by the PDQ Supportive Care Editorial Board ¹.

Information about the following is included in this summary:

• Etiology.
• Management.
• Pediatric considerations.

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

This summary is also available in a patient version ², which is written in less technical language, and in Spanish ³.

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 ⁴ section for information on reduced-intensity regimens).
• 100% related to head and neck radiation therapy to fields involving the oral cavity.

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

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

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

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

References

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

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 ⁵ and the Management Following Cancer Therapy ⁶ sections for further information).[3,4]

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

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

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

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

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

Oral Complications of Radiation Therapy

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



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

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

References

1. Peterson DE: Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr (9): 61-71, 1990.  [PUBMED Abstract]
   
   
2. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.  [PUBMED Abstract]
   
   
3. Peters E, Monopoli M, Woo SB, et al.: Assessment of the need for treatment of postendodontic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 76 (1): 45-8, 1993.  [PUBMED Abstract]
   
   
4. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998.  [PUBMED Abstract]
   
   
5. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.  [PUBMED Abstract]
   
   
6. Peterson DE: Research advances in oral mucositis. Curr Opin Oncol 11 (4): 261-6, 1999.  [PUBMED Abstract]
   
   
7. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
8. Epstein JB, Chow AW: Oral complications associated with immunosuppression and cancer therapies. Infect Dis Clin North Am 13 (4): 901-23, 1999.  [PUBMED Abstract]
   
   
9. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
10. Toljanic JA, Bedard JF, Larson RA, et al.: A prospective pilot study to evaluate a new dental assessment and treatment paradigm for patients scheduled to undergo intensive chemotherapy for cancer. Cancer 85 (8): 1843-8, 1999.  [PUBMED Abstract]
    
    
11. De Pauw BE, Donnelly JP: Infections in the immunocompromised host: general principles. In: Mandell GL, Bennett JE, Dolin R, eds.: Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone, 2000, pp 3079-90. 
    
    
12. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72 (7): 2234-8, 1993.  [PUBMED Abstract]
    
    
13. Donnelly JP: Infection in the neutropenic and haematopoietic stem cell transplant recipient. Curr Opin Infect Dis 13 (4): 337-342, 2000.  [PUBMED Abstract]
    
    
14. Kennedy HF, Morrison D, Kaufmann ME, et al.: Origins of Staphylococcus epidermidis and Streptococcus oralis causing bacteraemia in a bone marrow transplant patient. J Med Microbiol 49 (4): 367-70, 2000.  [PUBMED Abstract]
    
    
15. Schubert MM: Oro-pharyngeal mucositis. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 812-20. 
    
    
16. Giamarellou H, Antoniadou A: Infectious complications of febrile leukopenia. Infect Dis Clin North Am 15 (2): 457-82, 2001.  [PUBMED Abstract]
    
    
17. Graber CJ, de Almeida KN, Atkinson JC, et al.: Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 27 (5): 537-42, 2001.  [PUBMED Abstract]
    
    
18. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001. 
    
    
19. Akintoye SO, Brennan MT, Graber CJ, et al.: A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (5): 581-8, 2002.  [PUBMED Abstract]
    
    
20. Raber-Durlacher JE, Epstein JB, Raber J, et al.: Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer 10 (6): 466-73, 2002.  [PUBMED Abstract]
    
    
21. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.  [PUBMED Abstract]
    
    
22. Jansma J, Vissink A, Bouma J, et al.: A survey of prevention and treatment regimens for oral sequelae resulting from head and neck radiotherapy used in Dutch radiotherapy institutes. Int J Radiat Oncol Biol Phys 24 (2): 359-67, 1992.  [PUBMED Abstract]
    
    
23. Symonds RP: Treatment-induced mucositis: an old problem with new remedies. Br J Cancer 77 (10): 1689-95, 1998.  [PUBMED Abstract]
    
    
24. Plevová P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: a review. Oral Oncol 35 (5): 453-70, 1999.  [PUBMED Abstract]
    
    

Oral and Dental Management Prior to Cancer Therapy

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

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

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

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

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



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

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

Specific interventions are directed to:

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

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

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

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

Phase I: Prior to Chemotherapy

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

Phase II: Neutropenic Phase

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

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

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

Phase III: Hematopoietic Recovery

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

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

Phase IV: Immune Reconstitution/Recovery from Systemic Toxicity

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

Phase V: Long-term Survival

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

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

References

1. Beck SL: Prevention and management of oral complications in the cancer patient. In: Hubbard SM, Greene PE, Knobf MT, eds.: Current Issues in Cancer Nursing Practice. Philadelphia, Pa: J.B. Lippincott Company, 1990, pp 27-38. 
   
   
2. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.  [PUBMED Abstract]
   
   
3. Epstein JB: Infection prevention in bone marrow transplantation and radiation patients. NCI Monogr (9): 73-85, 1990.  [PUBMED Abstract]
   
   
4. Woo SB, Matin K: Off-site dental evaluation program for prospective bone marrow transplant recipients. J Am Dent Assoc 128 (2): 189-93, 1997.  [PUBMED Abstract]
   
   
5. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
6. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds.: Hematopoietic Cell Transplantation. 2nd ed. Malden, Mass: Blackwell Science Inc, 1999, pp 751-63. 
   
   
7. Williford SK, Salisbury PL 3rd, Peacock JE Jr, et al.: The safety of dental extractions in patients with hematologic malignancies. J Clin Oncol 7 (6): 798-802, 1989.  [PUBMED Abstract]
   
   
8. Overholser CD, Peterson DE, Bergman SA, et al.: Dental extractions in patients with acute nonlymphocytic leukemia. J Oral Maxillofac Surg 40 (5): 296-8, 1982.  [PUBMED Abstract]
   
   

Management Following Cancer Therapy

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

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

Routine Oral Hygiene Care

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



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



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



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



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



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



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

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

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

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

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

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

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

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

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

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

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

References

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

Oral Mucositis

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

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

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

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

In an effort to standardize measurements of mucosal integrity, oral assessment scales have been developed to grade the level of stomatitis by characterizing alterations in lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice.[12-14] Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of mucositis. These evaluative tools vary in complexity.

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

Once mucositis has developed, its severity and the patient’s hematologic status govern appropriate oral management. Meticulous oral hygiene and palliation of symptoms are essential. In the absence of controlled clinical trials, many of the management recommendations are anecdotal. Some established guidelines for oral care include oral assessments twice daily for hospitalized patients and frequent oral care (minimum of every 4 hours and at bedtime) that increases in frequency as the severity of mucositis increases.

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

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

Mucositis Management

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



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



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



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



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

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

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



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



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



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



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

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

A soft toothbrush that is replaced on a regular basis (see the 2005 Oral Mucositis Guidelines Update ¹⁰) should be used to maintain oral hygiene. Foam-swab brushes do not effectively clean teeth and should not be considered a routine substitute for a soft nylon-bristled toothbrush. Options for cleansing and debriding agents include salt and soda (½ tsp of salt and 2 tbsp of sodium bicarbonate in 32 oz of warm water), normal saline, sodium bicarbonate (1 tsp in 8 oz of water), and sterile water. Based on nonoral mucosa wound-healing studies, the repeated use of hydrogen peroxide rinses for daily preventive oral hygiene is not recommended, especially if mucositis is present. This is because of the potential for damage to fibroblasts and keratinocytes, which can cause delayed wound healing.[21-27] Using 3% hydrogen peroxide diluted 1:1 with water or normal saline to remove hemorrhagic debris may be helpful; however, this approach should only be used for 1 to 2 days since more extended use may impair timely healing of mucosal lesions associated with bleeding.[28]

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

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

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

Although mucositis continues to be one of the dose-limiting toxicities of fluorouracil (5-FU), cryotherapy may be an option in prevention of oral mucositis. Because 5-FU has a short half-life (5–20 minutes), patients are instructed to swish ice chips in their mouths for 30 minutes, beginning 5 minutes prior to 5-FU administration.[29]

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

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

References

1. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.  [PUBMED Abstract]
   
   
2. Schubert MM, Epstein JB, Peterson DE: Oral complications of cancer therapy. In: Yagiela JA, Neidle EA, Dowd FJ: Pharmacology and Therapeutics for Dentistry. 4th ed. St. Louis, Mo: Mosby-Year Book Inc, 1998, pp 644-55. 
   
   
3. Peterson DE: Research advances in oral mucositis. Curr Opin Oncol 11 (4): 261-6, 1999.  [PUBMED Abstract]
   
   
4. Sonis ST, Elting LS, Keefe D, et al.: Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100 (9 Suppl): 1995-2025, 2004.  [PUBMED Abstract]
   
   
5. Rubenstein EB, Peterson DE, Schubert M, et al.: Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100 (9 Suppl): 2026-46, 2004.  [PUBMED Abstract]
   
   
6. Sonis ST, Costa JW Jr, Evitts SM, et al.: Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Oral Surg Oral Med Oral Pathol 74 (6): 749-55, 1992.  [PUBMED Abstract]
   
   
7. Sonis ST, Lindquist L, Van Vugt A, et al.: Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3. Cancer Res 54 (5): 1135-8, 1994.  [PUBMED Abstract]
   
   
8. Sonis S, Muska A, O'Brien J, et al.: Alteration in the frequency, severity and duration of chemotherapy-induced mucositis in hamsters by interleukin-11. Eur J Cancer B Oral Oncol 31B (4): 261-6, 1995.  [PUBMED Abstract]
   
   
9. Keith JC Jr, Albert L, Sonis ST, et al.: IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells 12 (Suppl 1): 79-89; discussion 89-90, 1994.  [PUBMED Abstract]
   
   
10. Jansma J, Vissink A, Spijkervet FK, et al.: Protocol for the prevention and treatment of oral sequelae resulting from head and neck radiation therapy. Cancer 70 (8): 2171-80, 1992.  [PUBMED Abstract]
    
    
11. Beck SL: Prevention and management of oral complications in the cancer patient. In: Hubbard SM, Greene PE, Knobf MT, eds.: Current Issues in Cancer Nursing Practice. Philadelphia, Pa: J.B. Lippincott Company, 1990, pp 27-38. 
    
    
12. Schubert MM, Williams BE, Lloid ME, et al.: Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 69 (10): 2469-77, 1992.  [PUBMED Abstract]
    
    
13. Sonis ST, Eilers JP, Epstein JB, et al.: Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer 85 (10): 2103-13, 1999.  [PUBMED Abstract]
    
    
14. McGuire DB, Peterson DE, Muller S, et al.: The 20 item oral mucositis index: reliability and validity in bone marrow and stem cell transplant patients. Cancer Invest 20 (7-8): 893-903, 2002.  [PUBMED Abstract]
    
    
15. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998.  [PUBMED Abstract]
    
    
16. Schubert MM: Oro-pharyngeal mucositis. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 812-20. 
    
    
17. Plevová P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: a review. Oral Oncol 35 (5): 453-70, 1999.  [PUBMED Abstract]
    
    
18. Pillitteri LC, Clark RE: Comparison of a patient-controlled analgesia system with continuous infusion for administration of diamorphine for mucositis. Bone Marrow Transplant 22 (5): 495-8, 1998.  [PUBMED Abstract]
    
    
19. Spielberger R, Stiff P, Bensinger W, et al.: Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351 (25): 2590-8, 2004.  [PUBMED Abstract]
    
    
20. Rosen LS, Abdi E, Davis ID, et al.: Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol 24 (33): 5194-200, 2006.  [PUBMED Abstract]
    
    
21. National Institutes of Health Consensus Development Conference on Oral Complications of Cancer Therapies: Diagnosis, Prevention, and Treatment. Bethesda, Maryland, April 17-19, 1989. NCI Monogr (9): 1-184, 1990.  [PUBMED Abstract]
    
    
22. Solomon CS, Shaikh AB, Arendorf TM: An efficacious oral health care protocol for immunocompromised patients. Spec Care Dentist 15 (6): 228-33, 1995 Nov-Dec.  [PUBMED Abstract]
    
    
23. Bavier AR: Nursing management of acute oral complications of cancer. NCI Monogr (9): 123-8, 1990.  [PUBMED Abstract]
    
    
24. Tombes MB, Gallucci B: The effects of hydrogen peroxide rinses on the normal oral mucosa. Nurs Res 42 (6): 332-7, 1993 Nov-Dec.  [PUBMED Abstract]
    
    
25. Takahashi A, Aoshiba K, Nagai A: Apoptosis of wound fibroblasts induced by oxidative stress. Exp Lung Res 28 (4): 275-84, 2002.  [PUBMED Abstract]
    
    
26. Bennett LL, Rosenblum RS, Perlov C, et al.: An in vivo comparison of topical agents on wound repair. Plast Reconstr Surg 108 (3): 675-87, 2001.  [PUBMED Abstract]
    
    
27. O'Toole EA, Goel M, Woodley DT: Hydrogen peroxide inhibits human keratinocyte migration. Dermatol Surg 22 (6): 525-9, 1996.  [PUBMED Abstract]
    
    
28. Schubert MM, Peterson DE, Lloid ME: Oral complications. In: Blume KG, Forman SJ, Applebaum FR, eds.: Thomas' Hematopoietic Cell Transplantation. 3rd ed. Malden, Mass: Blackwell Science Inc, 2004, pp 911-28. 
    
    
29. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72 (7): 2234-8, 1993.  [PUBMED Abstract]
    
    
30. Elzawawy A: Treatment of 5-fluorouracil-induced stomatitis by allopurinol mouthwashes. Oncology 48 (4): 282-4, 1991.  [PUBMED Abstract]
    
    
31. Wadleigh RG, Redman RS, Graham ML, et al.: Vitamin E in the treatment of chemotherapy-induced mucositis. Am J Med 92 (5): 481-4, 1992.  [PUBMED Abstract]
    
    
32. Labar B, Mrsić M, Pavletić Z, et al.: Prostaglandin E2 for prophylaxis of oral mucositis following BMT. Bone Marrow Transplant 11 (5): 379-82, 1993.  [PUBMED Abstract]
    
    
33. Epstein JB, McBride BC, Stevenson-Moore P, et al.: The efficacy of chlorhexidine gel in reduction of Streptococcus mutans and Lactobacillus species in patients treated with radiation therapy. Oral Surg Oral Med Oral Pathol 71 (2): 172-8, 1991.  [PUBMED Abstract]
    
    
34. Peterson DE: Effect of misoprostol in reducing oral mucositis in stem cell transplant patients. [Abstract] Proceedings of the 11th Multinational Association of Supportive Care Cancer 67, 1999. 
    
    
35. Cowen D, Tardieu C, Schubert M, et al.: Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial. Int J Radiat Oncol Biol Phys 38 (4): 697-703, 1997.  [PUBMED Abstract]
    
    
36. LeVeque FG, Parzuchowski JB, Farinacci GC, et al.: Clinical evaluation of MGI 209, an anesthetic, film-forming agent for relief from painful oral ulcers associated with chemotherapy. J Clin Oncol 10 (12): 1963-8, 1992.  [PUBMED Abstract]
    
    
37. Karthaus M, Rosenthal C, Huebner G, et al.: Effect of topical oral G-CSF on oral mucositis: a randomised placebo-controlled trial. Bone Marrow Transplant 22 (8): 781-5, 1998.  [PUBMED Abstract]
    
    
38. Nicolatou O, Sotiropoulou-Lontou A, Skarlatos J, et al.: A pilot study of the effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients during X-radiation therapy: a preliminary report. Int J Radiat Oncol Biol Phys 42 (3): 551-6, 1998.  [PUBMED Abstract]
    
    
39. Johnston EM, Crawford J: Hematopoietic growth factors in the reduction of chemotherapeutic toxicity. Semin Oncol 25 (5): 552-61, 1998.  [PUBMED Abstract]
    
    
40. Oguchi M, Shikama N, Sasaki S, et al.: Mucosa-adhesive water-soluble polymer film for treatment of acute radiation-induced oral mucositis. Int J Radiat Oncol Biol Phys 40 (5): 1033-7, 1998.  [PUBMED Abstract]
    
    
41. Matejka M, Nell A, Kment G, et al.: Local benefit of prostaglandin E2 in radiochemotherapy-induced oral mucositis. Br J Oral Maxillofac Surg 28 (2): 89-91, 1990.  [PUBMED Abstract]
    
    
42. Mills EE: The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 57 (4): 416-7, 1988.  [PUBMED Abstract]
    
    
43. Osaki T, Ueta E, Yoneda K, et al.: Prophylaxis of oral mucositis associated with chemoradiotherapy for oral carcinoma by Azelastine hydrochloride (Azelastine) with other antioxidants. Head Neck 16 (4): 331-9, 1994 Jul-Aug.  [PUBMED Abstract]
    
    
44. Pretnar J, Glazar D, Mlakar U, et al.: Prostaglandin E2 in the treatment of oral mucositis due to radiochemotherapy in patients with haematological malignancies. Bone Marrow Transplant 4 (Suppl 3): 106, 1989.  [PUBMED Abstract]
    
    
45. Dueñas-Gonzalez A, Sobrevilla-Calvo P, Frias-Mendivil M, et al.: Misoprostol prophylaxis for high-dose chemotherapy-induced mucositis: a randomized double-blind study. Bone Marrow Transplant 17 (5): 809-12, 1996.  [PUBMED Abstract]
    
    
46. Anderson PM, Schroeder G, Skubitz KM: Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 83 (7): 1433-9, 1998.  [PUBMED Abstract]
    
    
47. Oblon DJ, Paul SR, Oblon MB, et al.: Propantheline protects the oral mucosa after high-dose ifosfamide, carboplatin, etoposide and autologous stem cell transplantation. Bone Marrow Transplant 20 (11): 961-3, 1997.  [PUBMED Abstract]
    
    
48. Lugliè PF, Mura G, Mura A, et al.: [Prevention of periodontopathy and oral mucositis during antineoplastic chemotherapy. Clinical study] Minerva Stomatol 51 (6): 231-9, 2002.  [PUBMED Abstract]
    
    
49. Cheng KK, Molassiotis A, Chang AM, et al.: Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients. Eur J Cancer 37 (16): 2056-63, 2001.  [PUBMED Abstract]
    
    
50. Wardley AM, Jayson GC, Swindell R, et al.: Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 110 (2): 292-9, 2000.  [PUBMED Abstract]
    
    
51. Dray A: Mechanism of action of capsaicin-like molecules on sensory neurons. Life Sci 51 (23): 1759-