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Oral Complications of Cancer Therapy

Oral Complications of Cancer Therapy

ABSTRACT: The mouth is a frequent site of complications arising from drug or radiation cancer therapy, with mucositis, xerostomia, osteoradionecrosis, and local infections being the most common. From the standpoint of dose limitation, treatment breaks, quality of life, and health economic outcomes, mucositis is the most significant acute oral toxicity. Xerostomia, a chronic side effect of radiation, involves the salivary gland tissue, and results in changes in taste, tissue resilience, and an increased risk of caries and periodontal disease. While the incidence of osteoradionecrosis seems to be decreasing, the chronicity and symptoms of this festering bony condition are especially difficult for patients. Local oral infections resulting from the overgrowth of opportunistic organisms or the activation of latent viruses are so common as to warrant a prophylactic approach in many cases. A surge of investigational interest has been directed at understanding the mechanisms of these stomatotoxicities and at developing treatment strategies to combat them. [ONCOLOGY 16:680-695, 2002]

The mouth is a frequent site of complications
associated with drug and radiation therapy for cancer,[1] and interest in these
complications has increased precipitously. For example, a 40% rise in literature
citations for mucositis was noted for 1996-2000 compared with 1991-1995. The
increased importance of oral complications is attributable to at least four
factors: First, the use of marrow-stimulating growth factors has made the
management of neutropenia readily available, and has successfully reduced its
impact as a dose-limiting toxicity.[2] Second, the use of increasingly
aggressive single-agent or multiagent drug therapy has resulted in increased
oral toxicity.[3] Third, the application of new radiation regimens, many
including concomitant chemotherapy, has contributed to a marked increase in oral
toxicity, such that optimal tumoricidal regimens are threatened.[4] Finally, a
series of studies have demonstrated that oral complications have a significant
impact on nonoral health and economic outcomes.[5,6]

Mucositis

Oral mucositis is probably the most significant oral toxicity associated with
cancer treatment. Its severity is often of such a magnitude as to require
parenteral narcotic intervention, reduced drug dosing, or altered radiation
schedules. The prevalence of clinically significant mucositis has become an
important limitation to the introduction of innovative forms of concomitant or
combination drug regimens. For many cancer patients, mucositis is the most
notable side effect of treatment.[7] However, the overall frequency of mucositis
is dependent on a variety of patient- and regimen-related variables.

Risk Factors

Certain populations are at exceptionally high risk, including patients
receiving conditioning regimens for bone marrow transplant, particularly those
including total-body irradiation; patients receiving induction therapy for
leukemia; and patients who are being treated with fluorouracil (5-FU) infusional
therapy for colorectal cancer. Patients who receive radiation therapy for tumors
of the head and neck also demonstrate a high rate of clinically significant
mucositis,[8] especially if they are receiving concomitant chemotherapy.

Although the drug or radiation treatment regimen is probably the most
noteworthy determinant of risk for mucositis, a number of other variables are
also important.[9] The presence of local mucosal irritation secondary to faulty
dental appliances or trauma, secondary infection, and xerostomia all increase
the risk of mucositis. Patients with hematologic malignancies develop more
severe and more frequent mucositis than do comparable patients with other types
of tumors. This observation is probably attributable to the tumor-induced
functional neutropenia that these individuals develop. The effect of age as a
risk factor is unresolved. It appears that younger populations are at increased
risk, perhaps because of a greater epithelial rate of proliferation.

Patients with poor oral hygiene tend to have more, and longer lasting
mucositis than do patients with clean mouths. The initiation of aggressive oral
hygiene protocols has been shown to favorably affect the course of mucositis,
probably by reducing the mouth’s bacterial load. Sloan et al recently reported
a female predilection for mucositis induced by 5-FU.[10] Finally, there could be
genetic factors that influence the risk of mucositis. For example, because
proinflammatory cytokines play a role in the pathogenesis of the condition,
patients who express these proteins at high levels may be more likely to develop
mucositis.

Clinical Features

Mucositis represents a clinical continuum. Mild mucositis produces mucosal
erythema that is accompanied by burning or soreness similar to that experienced
following a food burn. In patients receiving radiation, the condition is usually
first noted at cumulative doses of 20 Gy, after approximately 2 weeks of
treatment with conventional radiation protocols of 2 Gy/d (5 d/wk). Mucositis
worsens with accumulating radiation. By the time 30 Gy has been
administered, breakdown of the mucosal surface is apparent, manifesting as
pseudomembranes, or a fibrinous mass, overlying necrotic and ulcerated tissue.
Ultimately, full-thickness mucosal ulceration develops and may persist for
approximately 2 to 4 weeks after radiation ceases.[11]

Chemotherapy-induced mucositis is more acute and is generally observed within
2 weeks of drug administration (usually between 1 to 2 weeks). In the case of chemotherapy-induced mucositis, a distinct erythematous
stage may not be seen. Rather, after a brief, 1- or 2-day period of atrophy,
superficial sloughing, and redness, the tissue becomes ulcerated and covered by
necrotic tissue. This breakdown often precedes the nadir of neutropenia by 2 to
3 days. Ulceration persists for approximately 1 or 2 weeks, during which
neutropenic patients are most susceptible to bacteremia and sepsis through
mucosal breaks. In the absence of secondary infection, lesions resolve
spontaneously.[12]

Health and Economic Significance

It is becoming increasingly apparent that mucositis drives a number of health
and economic outcomes. The strong relationship between mucositis, bacteremias,
and sepsis is well established.[13] Similarly, the trend toward an increasing
frequency of viridans streptococcal infections in myeloablated patients is
largely attributable to mucositis; the presence of mucositis confers a three- to
fourfold greater probability of viridans streptococcal infection.[14] Thus, the
finding that mucositis is associated with increased use of health resources is
not surprising. Reuscher et al found that among autologous bone marrow
transplant recipients, mucositis was associated with a significant increase in
the length of hospital stay.[15]

In one recent study of hematopoietic stem-cell transplant recipients, Sonis,
Oster, and colleagues explored the relationship between mucositis and selected
clinical and economic outcomes.[6] They found that the extent and severity of
mucositis significantly contributed to the use of analgesics, total parenteral
nutrition, injectable antibiotics, and to the risk of significant infection,
prolonged hospital stay, and increased hospital charges. In the cohort studied,
severe ulcerative mucositis resulted in hospital charges that were $43,000
greater than those for patients without the condition.

Biological Factors

The pathogenesis of mucositis is more complex than was first envisioned.[16]
Challenge to mucosal tissue with stomatotoxic forms and doses of chemotherapy or
radiation initiates a parallel and sequential series of events that result in
injury. The generation of oxygen-free radicals and DNA damage are primary events
in the process, triggering a variety of signal pathways that result in
downstream events.

Although mucositis is generally considered an epithelial process, electron
microscopic evidence suggests that early changes occur in both the endothelium
of submucosal blood vessels and connective tissue. The nature of these changes
is currently being defined, but they may stimulate additional molecular
activity. For example, it seems probable that damage to connective tissue leads
to a disruption of fibronectin. This breakup can result in stimulation of
proinflammatory cytokines and production of potentially destructive
metalloproteinases.

Up-regulated Genes

It appears that a number of genes in mucosal tissue
are up-regulated almost immediately following exposure to radiation. Many of
these genes, such as p53, are associated with the response of epithelial cells
to injury. Others reflect an almost immediate attempt by the tissue to initiate
healing. Of particular interest is the finding that genes controlling certain
proinflammatory cytokines—in particular, tumor necrosis factor (TNF)-alpha and
interleukin (IL)-6—are up-regulated at a rate that parallels the development
of mucositis.[17] In contrast, no increase in the expression of genes for
transforming growth factor (TGF)-beta or IL-2 has been demonstrated. Like TNF,
submucosal cellular expression of IL-1b also increases during, and correlates
with, the development of mucositis.[17] A correlation between plasma levels of
TNF-alpha and IL-6 and the severity of mucositis has been reported.[18]

Oral Environment

It also seems that the local oral environment and, in
particular, the oral microbiota and saliva influence the course and severity of
mucositis.[19] The mouth’s microflora consists of bacteria, fungi, and
viruses. The bacterial load of the mouth is among the greatest of any site in
the body. Consequently, breaks in mucosal integrity caused by mucositis serve as
a conduit for systemic influxes of bacteria, especially in neutropenic patients.
Although the predominant bacteria in the mouths of healthy individuals are
gram-positive streptococci, an increase in gram-negative organisms occurs during
periods of myelosuppression.

During the 1970s, the frequency and sequelae of gram-negative sepsis led to
the development and prophylactic use of quinolone antibiotics.[20] The advent of
these agents reduced the incidence of gram-negative infections but caused an
increase in gram-positive infections, many of which were derived from the mouth.
In addition to causing bacteremias and sepsis, the bacteria that secondarily
colonize ulcerative lesions of mucositis spew out cell wall products and
endotoxins into the underlying submucosa. These materials serve to amplify the
production of proinflammatory cytokines with the consequence of producing
worsening lesions of increased duration.[21] Thus, one intervention strategy has
been directed at lowering the local bacterial load.

Xerostomia

Xerostomia appears to predispose for the development of
mucositis.[22] Desiccated tissue is more likely to break down than normal, moist
mucosa. In addition, saliva plays an important role in controlling the level of
local bacteria. Not only does saliva perform a washing function to clear
microorganisms, but it is also rich in bactericidal enzymes and immunoglobulin A
(IgA). The latter binds to bacteria and prevents their adherence to tissue.

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