Etiopathogenesis
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.
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 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 |
Physical/chemical trauma |
Oral infections: |
|
|
Viral |
|
Decreased systemic immunity |
Fungal |
|
Decreased systemic immunity |
Salivary gland dysfunction |
Altered oral flora (decreased
bacterial flora) |
Bacterial |
Inadequate oral hygiene |
Decreased systemic immunity |
Mucosal breakdown |
Salivary gland dysfunction |
Acquired pathogens |
Taste dysfunction |
Taste receptor toxicity |
|
Xerostomia |
Salivary gland toxicity |
Anticholinergic drugs |
Neuropathies |
Vinca alkaloid drug use; specific drug toxicity |
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 |
Hemorrhage |
Oral mucositis
|
Thrombocytopenia |
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.[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/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.[2,22,5,6,23,24] 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:
- Salivary gland dysfunction:
- Taste dysfunction.
- Chronic complications:
- Mucosal fibrosis and atrophy.
- Xerostomia.
- Dental caries.
- Soft tissue necrosis.
- Osteonecrosis.
- Taste dysfunction:
- Muscular/cutaneous fibrosis.
- Infections:
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.
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