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October 16, 2007

Introduction

The immune response is the primary host defense against microorganisms, including bacteria, viruses, and fungi. The innate and acquired immune responses are synergistic, and play a vital role in the overall host defense mechanism.

Selected systemic diseases and conditions require medication for optimal management. However, both the clinician and the patient must assess the risks and benefits before proceeding with pharmacologic therapy. For example, anti-neoplastic agents are likely to cause mild, moderate, and/or severe side effects associated with various pharmacologic classes, doses, regimens, and mechanisms of action of these agents. Cancer chemotherapy should be managed by a qualified physician who is experienced in using such antineoplastic agents, and in a clinical facility that is appropriate to care for both the cancer and the potential medical complications that may result from chemotherapy.

We address three primary groups of medicationsⁱ that have the potential to either directly or indirectly influence the immune response:

• Antineoplastic agents
• Bisphosphonates
• Steroids

Concurrent immunosupportive therapies, such as antibiotics and antimicrobial rinses, are frequently used with these medications.

Antineoplastic agents primarily function to prevent or suppress the growth, development, or metastases of neoplastic cells. The ideal objective of cancer treatment is to reduce the cancer cell population to zero.¹ Many antineoplastic drugs are myelosuppressive, thus resulting in dramatic reduction of circulating leukocytes as measured by white blood cell count and/or total granulocyte count, and total platelet count. Contemporary oncology practice often uses combinations of antineoplastic agents in multiple cycles for patients collectively exhibiting a range of solid tumors. In addition, chemotherapy is increasingly administered concurrently with high-dose head and neck radiation for oral malignancies that have metastasized beyond the primary initial site of occurrence. This evolution of pharmacologic regimens for metastatic cancer continues to produce clinically significant side effects, including compromised oral, systemic, and tissue immunity, accompanied by compromised wound healing.

Bisphosphonates primarily function to enhance bone mineral density (generally measured with dual-energy x-ray absorptiometry (DEXA) and expressed as a “T score”), and reduce pathogenic fractures (e.g., as measured by hip fracture reduction). Pharmacologically, these agents reduce osteoclast function.² Bisphosphonates are associated with impaired angiogenesis³ and impaired wound healing,⁴ which impede delivery of immune cells to the site of microbial challenge, and therefore indirectly result in immunosuppression. Bisphosphonates are also associated with osteonecrosis of the jaw (BIONJ).^5,6

Steroids primarily function to suppress undesirable immune reactions. Pharmacologically, this is achieved through a number of mechanisms, including: (1) gene expression that leads to reduction in the synthesis of important mediators of the inflammatory process (such as prostaglandins and leukotrienes);⁷ (2) suppression of cyclooxygenase synthesis resulting in decreased neutrophil, monocyte, and eosinophil chemotaxis, as well as inhibition of vascular and inflammatory responses to prostaglandins;⁸ (3) inhibition of white blood cell production;⁸ (4) inhibition of adhesion molecule synthesis in endothelial cells, which impairs attachment of inflammatory cells and hinders their recruitment to sites of inflammation;⁸ (5) inhibition of macrophage-driven antigen phagocytosis, which is necessary for development of some immune responses;⁷ and, (6) suppression of antibody production.⁹ Topical or systemic steroid therapy is used for a wide variety of systemic and oral mucosal disorders. However, because of the profound and varied metabolic effects caused by steroids, they can exacerbate many systemic conditions including, but not limited to, hypertension, diabetes mellitus, gastrointestinal ulcers, cataracts, mental illness, tuberculosis, and fungal infections.¹⁰ The immune suppression that results from steroid use may also lead to infections by opportunistic or indigenous microorganisms.

Antineoplastic agents

High-dose chemotherapy can directly and indirectly result in oral toxicities, including impairment of both wound healing and immune response (Table 1).^11,12 The combination of these direct and indirect effects can compromise cancer patients’ quality of life.^13,14 In some cases, the oral lesions can result in the need to limit the dose of subsequent chemotherapy to allow the lesion to heal; in the neutropenic patient, this can contribute to mortality.¹²

Severe oral mucositis is characterized by extensive, painful ulcerations of non-keratinized mucosa (Figure 1). Chemotherapy-induced alimentary tract mucosal injury in cancer patients has been the subject of increasingly sophisticated research over the past decade.^11,12,16,17 This progress has included development of a pathobiologic model (Figure 2).¹⁸

Frequencies of oral mucositis vary in chemotherapy patients; estimates include 10% associated with adjuvant chemotherapy, 40% associated with primary chemotherapy, and 80% associated with hematopoietic stem cell transplant.^13,14 Incidence and severity of oral and gastrointestinal mucositis can be influenced by multiple variables, including drug class and mechanism of action of each chemotherapeutic agent (Figure 3), as well as dose intensity and frequency of administration.^13,14,19 While use of chemotherapy regimens is based on a number of cancer disease parameters including histologic type of the neoplasm, it is the chemotherapy, not the cancer itself, that directly governs risk for oral and gastrointestinal mucosal toxicity. Examples of this wide variation in mucositis incidence and severity have recently been reported across various cancer patient cohorts:¹⁹

• Conventional chemotherapeutic regimens for non-Hodgkin’s lymphoma are associated with 3-10% incidence of severe oral mucositis. However, most (>90%) comparable patients do not develop severe oral mucosal injury.
• Multi-cycle platinum-based regimens, with or without concurrent radiotherapy, are associated with a low incidence of severe oral mucositis in lung cancer patients. However, radiotherapy in these patients is associated with >15% incidence of severe esophageal (versus oral) mucositis.
• Conventional chemotherapy in advanced colorectal cancer patients is not likely to be associated with producing severe oral mucositis. In contrast, however, the overall incidence of diarrhea in these patients is high (16%), increasing to approximately 25% when both irinotecan and oxaliplatin are incorporated into the cancer treatment regimens.

Current research includes pursuit of possible mechanistic-based factors that are principally responsible for this variable expression of oral and gastrointestinal mucositis across cancer patients.

In some cases, oral mucositis necessitates chemotherapy dose reduction or schedule modifications in order to reduce severity of future oral mucosal injury. For example, among patients undergoing chemotherapy for solid tumors or lymphomas, dose reduction was twice as common after treatment cycles for patients with mucositis than for those without mucositis.¹⁶ This compromise in optimal dosing schedule can affect tumor response and thus patient survival. In addition, oral mucositis can contribute to increased healthcare costs associated with (a) extended hospital stays, (b) need for total parenteral nutrition, (c) infection management, and (d) nutritional support.¹³

Dental management of patients taking antineoplastic agents. It is important that the oncologist and dentist maintain clear communication in order to provide maximum preventive and therapeutic management. Elements of the health professional consultation include both the patient’s medical status and an integrated oncology/dental management plan (relative to oral disease before, during, and after cancer treatment).¹⁴ Management suggestions relative to invasive dental procedures in patients currently receiving antineoplastic therapy are outlined in Table 2.

A limited number of studies address guidelines for dental extractions, endodontic management, and related interventions in patients scheduled to receive high-dose chemotherapy. However, procedures associated with dental extractions have been used by clinicians for many years, based on historical retrospective studies.^22,23 Guidelines for dental extractions in patients scheduled to undergo myelosuppressive chemotherapy are outlined in Table 3.

New trends in oncology practice based on “targeted” therapies. Targeted cancer therapies, including monoclonal antibodies, are being utilized with increasing frequency in clinical oncology practice.²⁴ For example, potential targets of monoclonal antibodies are growth factor receptors, signaling kinases, and transcription factors.²⁴ These novel molecular approaches are in turn causing a change in expression of toxicities among various cancer cohorts, including diarrhea and oral mucosal ulceration.²⁴ The potential impact on immune response and wound healing relative to oral toxicities requires additional study.

Bisphosphonates

Management of cancer patients may also include bisphosphonates to control metastatic bone lesions through impairment of osteoclast function.⁶ A severe complicating factor is BIONJ with associated osteomyelitis, although most BIONJ patients exhibit osteonecrosis without osteomyelitis.^5,6 Maxillary, mandibular, and soft-tissue lesions, secondary to long-term bisphosphonate use in patients with cancer, have been increasingly reported in the literature.^25-28 Over time, the accumulation of compromised bone matrix can lead to pain and clinically evident bone exposure that can be difficult to manage clinically (Figure 4).²⁸ Since there are currently no evidence-based guidelines for treatment of BIONJ, prevention may be the best approach to managing this complication.²⁶

Steroids

Topical or systemic steroid therapy is indicated for a wide variety of systemic and oral mucosal disorders. Common uses for systemic steroids include endocrine disorders (primary or secondary adrenal insufficiency), rheumatic disorders (rheumatoid arthritis), collagen diseases (systemic lupus erythematosus), dermatologic diseases (pemphigus, pemphigoid, lichen planus, erythema multiforme), respiratory diseases (sarcoidosis, chronic obstructive pulmonary disease), hematologic diseases (idiopathic or secondary thrombocytopenia, acquired hemolytic anemia), gastrointestinal diseases (ulcerative colitis, regional enteritis) and edematous states.¹⁰ Intraoral disorders for which steroids are indicated include recurrent aphthous stomatitis,²⁹ lichen planus,^30-32 pemphigus,³³ and pemphigoid.^30,33

Dental management of patients receiving steroid therapy. The mainstay of pharmacologic immunomodulation depends on the proper incorporation of steroid therapy into the management of many intraoral mucosal disorders such as recurrent aphthous ulcerations and lichen planus. This class of medications can be used either topically or systemically, but care must be exercised to minimize steroid-induced side effects. The medical history must be used to identify patients on chronic steroid therapy to manage systemic illness, to ensure that they can respond to the pain and anxiety of the dental procedure. The primary endogenously secreted glucocorticoid is cortisol. Cortisol and its exogenous analogues are responsible for a wide variety of functions and physiologic effects, which include the inhibition of inflammation. The anti-inflammatory action of cortisol is modulated by its inhibitory action on lysosome release, prostaglandin production, eicosanoid and cytokine release, endothelial cell expression of intracellular and extracellular adhesion molecules that attract neutrophils and the function of leukocytes.³⁴ Inappropriate management of patients on chronic steroid therapy could result in unusual but documented acute adrenal insufficiency (Addisonian crisis), which is potentially life threatening.^35,36 Because of the profound and varied metabolic effects caused by steroids, care must be taken in their administration.

Most adverse reactions to corticosteroids occur after a 2-week period.³⁷ Therefore, if systemic steroids are prescribed by the dentist, whenever possible, the general rule is to prescribe a higher dose for a short period of time (burst therapy) rather than a lower dose over a protracted period of time. Topical steroid therapy for oral mucosal disorders has been reported to be quite safe for a short-term course of therapy. Table 4 identifies systemic equivalent doses for steroids to assist the clinician in the prescription of these medications. If ultra-potency topical steroids are used (Table 5), there is a potential for systemic absorption. Custom trays and adhesive vehicles can be used to enhance the topical effect of intraorally applied topical steroids.³⁸

There are no uniformly accepted or absolute guidelines for steroid supplementation in the dental setting. Current evidence suggests that most patients who are managed with chronic corticosteroids and undergoing routine dental therapy do not require supplementation as long as pain and anxiety are well controlled (Table 6).^35,40 However, patients on chronic corticosteroid therapy may remain at risk for adrenal suppression. Medical consultation with the patient’s physician will assist the dental practitioner in determining if a need for steroid supplementation exists.

Conclusion

High-dose cytotoxic agents continue to be a key component of cancer treatment regimens directed to metastatic cancer. Despite development of medications that have shown impressive clinical outcomes in recent years, many of these products can directly impair immune function as well as wound healing. In addition, novel molecularly targeted therapies are being used with increasing frequency in oncology practice, with associated changes in toxicity profiles for many patients. Further research is needed in order to more fully define the adverse events associated with these molecules.

It is essential that the dentist collaborate with the rest of the oncology team in order to prevent or ameliorate acute and chronic oral sequelae of antineoplastic therapies. This collaboration is warranted by compelling evidence in the literature, which suggests that high-risk oral lesions - of the dentition, periodontium, periradicular region, and mucosa - should be eliminated prior to initiation of myelosuppressive chemotherapy. In addition, chemotherapy can cause acute oral complications that in selected cases require several months following cessation of the drugs for clinical resolution. Multiprofessional approaches to management of these medically complex cancer patients can directly improve quality of life and, in some cases, patient survival.

Bisphosphonates (intravenous and oral) are used in management of osteoporosis, and osteoporosis-related sequelae of selected medications (e.g., anti-cancer, anti-psychotic, antacids). Dental management should proceed with caution in patients currently taking this family of medications.

The mainstay of pharmacologic immunomodulation depends on the proper incorporation of steroid therapy into the management of many intraoral mucosal disorders such as recurrent aphthous ulcerations and lichen planus. This class of medications can be used either topically or systemically, but care must be exercised to minimize steroid-induced side effects. Proper use of this class of medications can significantly improve the morbitity of vesiculubullous and ulcerative oral mucosal disorders.

Disclosures

Douglas E. Peterson, DMD, PhD serves as consultant to Endo Pharmaceuticals, Genzyme Corporation, MGI Pharma, and Nuvelo.

Jon B. Suzuki, DDS, PhD, MBA serves on the scientific advisory boards of Biohorizons and Philips Oral HealthCare.

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Douglas E. Peterson, DMD, PhD Professor, Department of Oral Health and Diagnostic Sciences, School of Dental Medicine; Chair, Head & Neck/Oral Oncology Program, Neag Comprehensive Cancer Center, University of Connecticut Health Center; Farmington, CT

Michael A. Siegel, DDS, MS Professor and Chair, Department of Diagnostic Sciences, Nova Southeastern University, College of Dental Medicine, Fort Lauderdale, FL

Jon B. Suzuki, DDS, PhD, MBA Professor of Microbiology-Immunology, School of Medicine; Professor of Periodontology and Oral Implantology, School of Dentistry; Associate Dean for Graduate Education, Research, and International Affairs; Director, Graduate Periodontology and Oral Implantology; Temple University, Philadelphia, PA

1. The group of medications used to permit “acceptance” of a transplanted organ is discussed in another article in this issue of Grand Rounds; please see “Dental Implications for the Immunocompromised Organ Transplant Patient.”