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Cancer patients commonly suffer from oral complications during and following cancer therapy. These include oral/pharyngeal mucositis (OM), infection, pain, bleeding, and hyposalivation. In addition, rampant dental caries may develop in patients treated with radiation in the head and neck region (H&N RT). Patients treated with hematopoietic stem cell transplant (HCT) may develop oral graft versus host disease (GVHD).
Approximately 1.2 million Americans receive cancer therapy each year, of whom approximately a third develop OM. It is the most common debilitating acute complication of cancer chemotherapy1 and H&N RT2 reported by patients, and is among the most significant major dose-limiting toxicities of cancer therapy.3-6
Severe OM may result in dose reduction, dose delay, and even in termination of planned therapy.In addition, OM is associated with considerable cost implications, ranging from US$12,000 in patients with solid tumors 7,8 to US$42,000 in HCT patients.9
In radiation-induced OM, initial mucosal whitening may occur prior to erythema and mucosal ulceration. Mucosal lesions that extend beyond the field of radiation often represent infection due to candidiasis or herpes simplex virus (HSV) reactivation. In contrast, chemotherapy-associated OM typically presents bilaterally. Myelosuppression increases the risk of bacterial and fungal invasion and systemic infection. Generally, three to five weeks are required for oral tissues to heal following completion of H&N RT, whereas healing typically occurs in two to three weeks after cancer chemotherapy.
The pathogenesis of OM is complex, involving cells of connective tissue and epithelium.10,11 Bacterial colonization of mucosal lesions and exposure of submucosal tissues to lipopolysaccharide may contribute to the severity of mucositis. It is important to further identify the sequence of the cellular and tissue events involved because this may provide a key to adequate prevention and treatment.
The risk factors for OM have not been well established, although high-risk cancer treatment protocols are defined.A number of variables have been suggested to increase the risk of mucositis, which include poor oral hygiene, trauma, tobacco use, hyposalivation, lower baseline neutrophil counts, impaired renal function, genetic polymorphisms, body mass, gender, and old age.12-15 However, study design deficiencies have hampered mucositis prevention trials and affected acceptance of the results of these studies.
The protective and homeostatic role of saliva has been documented. Important salivary functions include physical cleansing of the oral cavity, facilitation of deglutition and speech, antimicrobial activities, and buffering of acidic bacterial metabolic by-products. H&N RT leads to irreversible damage to salivary glands that are in the high-dose volume.16,76 Dry mouth (xerostomia) is a common complaint in patients on chemotherapy.17 In HCT patients, total body irradiation (TBI), as well as chronic GVHD, may contribute to hyposalivation. Hyposalivation predisposes to dental caries, periodontal diseases, mucosal infection, mucosal trauma (e.g. denture irritation), reduced denture retention, altered speech and taste, and inability to take certain foods by mouth.
Loss of barrier function and salivary dysfunction enhances the risk for oral and systemic infection, particularly in myelo- and immunosuppressed patients. Malignant disease, antibiotic regimens, and cancer treatment may impair the equilibrium between the oral microflora and the host.This leads to an increased risk for infection by micro-organisms that are part of the normal flora, and also promotes a shift in favor of pathogenic gram-negative bacteria.18 The most common oral bacterial infection in neutropenic patients is caused by streptococci, which often translocate into the bloodstream particularly in the presence of ulcerative OM.19-21 Although the majority of patients with viridans streptococcal bacteremia have no other manifestation of infection than fever, some patients develop an acute respiratory distress syndrome (ARDS) and septic shock, especially following bacteremia with S. mitis.22,23 In addition, systemic and invasive fungal infection is of concern.21 Whereas oropharyngeal candidiasis is associated with symptomatic infection, diagnosis of systemic candidiasis is difficult.
Oral infection is also a common cause of oral symptoms. Reactivation of latent viruses such as herpes simplex (HSV) and varicella zoster is often painful. In addition, acute necrotizing gingivitis and exacerbation of chronic dental infections are associated with pain. Furthermore, solid oral tumors, leukemia, multiple myeloma, or metastatic breast cancer may be associated with oral and facial numbness and pain.
Topical approaches to prevention and management of oral complications offer the potential advantages of high local concentration with limited or no systemic penetration and with reduced risk of drug interactions and toxicity.A number of the conditions of concern in cancer patients occur on the mucosal surface (e.g. candidiasis), and in the epithelium and immediately adjacent connective tissue (e.g. mucositis), and therefore are amenable to topical therapies.
Topical therapy requires a means of delivery of the medication to the site, retention, and release of the medication. Different forms of delivery include rinses, topical gels or creams, lozenges, and chewing gum. Selected currently used topical treatment approaches, and the need to develop products in formulations acceptable to cancer patients and to conduct studies in these patient populations, will be discussed.