Oral Complications of Cancer Therapy
Oral Complications of Cancer Therapy
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, 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. Second, the use of increasingly aggressive single-agent or multiagent drug therapy has resulted in increased oral toxicity. 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. Finally, a series of studies have demonstrated that oral complications have a significant impact on nonoral health and economic outcomes.[5,6]
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. However, the overall frequency of mucositis is dependent on a variety of patient- and regimen-related variables.
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, 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. 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. 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.
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.
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.
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. 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. 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.
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. 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.
The pathogenesis of mucositis is more complex than was first envisioned. 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.
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. 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. A correlation between plasma levels of TNF-alpha and IL-6 and the severity of mucositis has been reported.
It also seems that the local oral environment and, in particular, the oral microbiota and saliva influence the course and severity of mucositis. 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. 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. Thus, one intervention strategy has been directed at lowering the local bacterial load.
Xerostomia appears to predispose for the development of mucositis. 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.