Chemotherapy-Induced Complications
Head/Neck Radiation-Induced Complications

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

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

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

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

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

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

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

Oral Complications of Radiation Therapy

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



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

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

References

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

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