Commentary (Sonis): Minimizing Oral Complications of Cancer Treatment

Toth and his colleagues present an increasingly important subject in their review; not only do oral complications adversely affect patients' quality of life, but also, as nonsurgical antineoplastic therapy becomes more aggressive, they represent an increasingly more common source of sepsis and local and distant-site infection.

In a recent review, Martin and van Saene [1] note a number of negative changes in the defense mechanisms of the oral cavity that may occur following antineoplastic therapy. These include alterations in the composition and flow of saliva, a reduction in salivary immunoglobulin A, and modifications of mucosal renewal with consequent mucosal ulceration. Changes in the local oral environment often lead to the mouth serving as a microbial reservoir at a time when local mucosal barriers are disrupted. Moreover, the patient's vulnerability to infection is enhanced as a consequence of therapy-induced myelosuppression. It stands to reason that any intervention that reduces the likelihood of local oral infection or mucosal disruption would be of tremendous advantage to the patient.

As Toth et al aptly discuss, preventive measures for oral disease tend to be easily performed, are of low cost, and have a high rate of success [2]. Identification and elimination of existing oral disease prior to the initiation of cancer therapy should be readily incorporated into treatment protocols that pose a high risk of oral complications. Communication between the oncologist or radiation therapist and the dentist is a key element for ensuring that appropriately aggressive dental intervention is pursued. In order for the dentist to prescribe effective prophylaxis, he or she should know the anticipated duration of anticancer therapy, the extent of myelosuppression associated with the regimen to be used, and the anticipated stomatotoxicity relative to mucositis. For patients undergoing radiation therapy, the dentist should be made aware of the total dose and fields to be irradiated.

Stomatitis vs Mucositis

The authors spend some time discussing the difference between the terms "stomatitis" and "mucositis." In practice, these terms are often used interchangeably, although stomatitis has usually been connected with non-cancer- related oral conditions, especially viral infections. Mucositis applies to the oral changes that result from direct stomatotoxicity [3]. Although it may occur spontaneously, mucositis is exaggerated by functional or mechanical trauma. Consequently, the identification and elimination of potential sources of mucosal irritation will reduce the likelihood of mucositis.

The lack of a standardized scoring system for mucositis poses a major barrier to effective comparisons of drug toxicity or therapy for oral complications. A recent review of the literature revealed at least 15 different schemes that are being used to assess mucositis [4]. Some are descriptive, many are subjective, others are functionally based, and the remainder focus on objective clinical findings. Scoring systems tend to be modified by the institutions in which they are used, and therefore, are often parochial and hinder scientific assessment of oral toxicity. A priority of individuals interested in oral complications should be the development of an easy-to-use, standardized assessment tool for mucositis that can satisfy the needs of both caregivers and researchers.

Biologic Manipulation of the Oral Epithelium

Current preventive and treatment regimens for mucositis rely heavily on folklore. However, as neutropenia is more readily controlled with colony-stimulating growth factors, the importance of mucositis as a dose-limiting toxicity has escalated. Consequently, a more objective and scientific approach to this problem has emerged over the past 5 years.

As noted by Toth et al, there is little in the way of predictive, effective therapy for mucositis. However, it seems likely that active biologic manipulation of the oral epithelium will result in significant reductions in the frequency, severity, and duration of the condition. Both transforming growth factor beta 3 and interleukin-11 have demonstrated promising efficacy in an animal model of chemotherapy-induced mucositis [5,6]. In addition, cytokine-stimulated neutrophil recovery reduces the likelihood of local secondary infection or delayed healing, thereby reducing the duration of ulcerative mucositis [7].

Radiation-Induced Oral Problems

In addition to the oral complications resulting from chemotherapy, patients receiving radiation to the head and neck are also prone to problems in their mouths. The M.D. Anderson group has been among the leaders in describing these complications.

Perhaps the major objective of preventive treatment in this patient population is minimization of the risk of osteoradionecrosis. Patients with teeth are at higher risk for osteoradionecrosis than edentulous patients. Identification and elimination of latent dental infection prior to the initiation of radiation therapy are likely to constitute the single most effective intervention for preventing osteoradionecrosis.

As reported by Toth et al, once radiation treatment has commenced, consequent xerostomia places patients at risk for caries. Aggressive use of topical fluorides markedly reduces this likelihood.

Chronic xerostomia is a common, bothersome side effect of radiation that includes the tissues of the major salivary glands, particularly the parotids. In addition to the topical rinses suggested in the Toth article, there is strong evidence that pilocarpine is effective in stimulating residual salivary gland function [8].

Complexity of the Problem

The mouth is unique in many ways. It is the only anatomic site in which calcified tissue is exposed to the external environment. It has its own secretory system, as well as histologically and functionally different mucosal membranes. Cell turnover time of the oral mucosa is among the most rapid in the body. The oral microflora is complex and changes in response to external conditions and the patient's systemic status. Consequently, the oral cavity's response to cancer therapy represents an intricate series of interactions between the antineoplastic agent and each compartment within the mouth. The variation in oral complications reflects this complexity and provides a vast array of research opportunities.

References:

1. Martin MV, van Saene HK: The role of oral microorganisms in cancer therapy. Curr Opin Dent 2:81, 1992

2. Sonis ST, Kunz A: Impact of improved dental services on the frequency or oral complications for patients with non-head and neck malignancies. Oral Surg, Oral Med, Oral Pathol 65:19, 1988.

3. Sonis ST: Oral complications of cancer therapy, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 4th Ed, pp 2385-2394. Philadelphia, JB Lippincott, 1993.

4. Sonis ST, Costello KA: A database for mucositis induced by cancer chemotherapy. Oral Oncol, Eur J Cancer vol 31, 1995.

5. Sonis ST, Lindquist L, VanVugt A, et al: Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3. Cancer Res 54:1135, 1994.

6. Keith JC Jr, Albert L, Sonis ST, et al: IL-11, a pleiotropic cytokine: Exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells 12(suppl 1):79, 1994

7. Gordon B, Spadinger A, Hodges E, et al: Effect of granulocyte-macrophage stimulating factor on oral mucositis after hematopoietic stem-cell transplantation. J Clin Oncol 12:1917, 1994.

8. Johnson JT, Ferretti GA, Nethery WJ, et al: Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 329:390, 1993.