Oral complications associated with cancer chemotherapy and radiation result from complex interactions among multiple factors. 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 the following:
- Loss of tissue-based immune cells.
- 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 preexisting 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).
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 (see Table 2) 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.Table 2. Oral Complications of Cancer Chemotherapy
|Complication||Direct Risk Factor||Indirect Risk Factors|
|DIC = disseminated intravascular coagulation; HSV = herpes simplex virus.|
|Oral mucositis||Mucosal cytotoxicity||Decreased local/systemic immunity: local infections, reactivation of HSV|
|Viral||Decreased systemic immunity|
|Fungal||Decreased oral mucosal and/or systemic immunity|
|Salivary gland dysfunction|
|Altered oral flora (decreased bacterial flora)|
|Bacterial||Inadequate oral hygiene||Decreased oral mucosal and/or systemic immunity|
|Mucosal breakdown||Salivary gland dysfunction|
|Taste dysfunction||Taste receptor toxicity|
|Xerostomia||Salivary gland toxicity||Anticholinergic drugs|
|Neuropathies||Vinca alkaloid, thalidomide, bortezomib drug use; risk for specific drug toxicity varies||Anemia, dental hypersensitivity, temporomandibular dysfunction/myofascial pain|
|Dental and skeletal growth and development (pediatric patients)||Specific drug toxicity||Stage of dental and skeletal maturation|
|Gastrointestinal mucositis causing secondary changes in oral status including taste, hygiene, and dietary intake||Mucosal cytotoxicity: radiation, chemotherapy||Nausea and vomiting|
|Physical 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.[2-4]
Chemotherapy directly impairs replication of basal epithelial cells; other factors, including proinflammatory cytokines and metabolic products of bacteria, may also play a role. The labial mucosa, buccal mucosa, tongue, floor of mouth, and soft palate are more severely affected by chemotherapy than are the attached, heavily keratinized tissues such as the hard palate and gingiva; this may be caused by relative rate of epithelial cell turnover among high-risk versus low-risk oral mucosal tissues. 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.
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 a propensity to damage oral mucosa:
- The platinum coordination complexes, including cisplatin and carboplatin.
- Mammalian target of rapamycin (mTOR) inhibitors (a new class of targeted cancer therapeutic agents).[6,7]
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.[8-11] Specific criteria for determining risk of infectious flare during myelosuppression have not been developed. Guidelines for assessment primarily address both degree of severity of the chronic lesion and whether acute symptoms have recently (i.e., <90 days) developed. However, chronic asymptomatic periodontitis may also represent a focus for systemic infectious complications since bacteria, bacterial cell wall substances, and inflammatory cytokines may translocate into the circulation via ulcerated pocket epithelium. In addition, poor oral hygiene and periodontitis seem to increase the prevalence of pulmonary infections in high-risk patients.
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.Head/Neck Radiation–induced Complications
Head and neck radiation 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. In addition, oral mucosal toxicity can be increased by use of head and neck radiation together with concurrent chemotherapy.
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 injury to osteocytes, osteoblasts, and osteoclasts.
- 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.
Oral Complications of Radiation Therapy
- Acute complications:
- Oral mucositis.
- Salivary gland dysfunction:
- Taste dysfunction.
- Chronic complications:
- Mucosal fibrosis and atrophy.
- Dental caries.
- Soft tissue necrosis.
- Taste dysfunction:
- Muscular/cutaneous fibrosis.
Unlike chemotherapy, however, radiation damage is anatomically site-specific; toxicity is localized to irradiated tissue volumes. Degree of damage depends on treatment regimen-related factors, including type of radiation utilized, 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
- 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]
- 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]
- Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis, Mo: Mosby Elsevier, 2011, pp 782-98.
- Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.
- 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]
- Pilotte AP, Hohos MB, Polson KM, et al.: Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs 15 (5): E83-9, 2011. [PUBMED Abstract]
- de Oliveira MA, Martins E Martins F, Wang Q, et al.: Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol 47 (10): 998-1003, 2011. [PUBMED Abstract]
- 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.
- 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]
- 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]
- Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990. [PUBMED Abstract]
- Paju S, Scannapieco FA: Oral biofilms, periodontitis, and pulmonary infections. Oral Dis 13 (6): 508-12, 2007. [PUBMED Abstract]