Oral Toxicity

Michael T. Brennan

Rajesh V. Lalla

Mark M. Schubert

Douglas E. Peterson

The oral cavity can be profoundly affected by cytotoxic chemotherapy used for the treatment of cancer. Resultant oral complications represent complex interactions among multiple factors. For example, normal oral labial and buccal mucosa has a range in turnover rate of approximately 5 to 16 days¹; this kinetic is one of the multiple contributors to risk of development of oral mucositis.²^,³^,⁴ In addition, many oral diseases are chronic and asymptomatic until late in their progression. Patients are often unaware of the diseases and do not seek dental care; therefore, oral disease is common and is frequently encountered in patients undergoing chemotherapy. Furthermore, the oral cavity in most adult patients harbors an extensive microbial flora that is commonly altered in the setting of prolonged neutropenia, especially when antibiotics that have a selective effect on oral microbes are administered.⁵ Opportunistic organisms, along with acquired pathogens, can cause systemic infection.

Therefore, oral lesions in patients undergoing chemotherapy can be classified into two subtypes (Table 12.1):

Direct stomatotoxicity (primary injury to oral tissues by the cytotoxic agents)
Indirect stomatotoxicity (nonoral toxicities that secondarily affect oral tissues)

Frequencies of these oral complications vary in patients undergoing chemotherapy; estimates include 10% (adjuvant chemotherapy), 40% (primary chemotherapy), and 80% (hematopoietic stem cell transplant [HSCT]).

Severe oral toxicities can compromise optimal dosing of cytotoxic therapy. For example, dose reduction or treatment schedule modifications may be necessary to permit resolution of oral lesions. Among patients undergoing chemotherapy for solid tumors or lymphomas, a reduction in the next dose of chemotherapy was twice as common after cycles with mucositis than after cycles without mucositis.⁶ These disruptions in cancer therapy due to oral complications can affect the treatment success and thereby patient survivorship. In the same study, episodes of infection were significantly more common during cycles with oral mucositis than during cycles without mucositis. Furthermore, cycles with oral mucositis resulted in a 50% increase in period of hospital stay as compared to cycles without mucositis.⁶ Severe grades of oral mucositis have also been shown to increase the days of total parenteral nutrition (TPN), parenteral narcotic use, number of days with fever, incidence of significant infection, and total inpatient charges.⁷^,⁸^,⁹^,¹⁰ Thus, oral toxicities of cancer therapy can have significant clinical and economic effects.

Management of oral complications of cancer therapy includes identification of high-risk populations, patient education, initiation of pretreatment interventions, and timely management of lesions and complications. Assessment of oral status and stabilization of oral disease before cancer therapy are critical to overall patient care.² This care should be both preventive and therapeutic as indicated to minimize the risk of oral and associated systemic complications. In general, cancer chemotherapy causes acute toxicities that resolve following discontinuation of therapy and recovery of damaged tissues. However, in selected cases, the injury may be lifelong.

Research continues to delineate mechanisms associated with these toxicities. In addition, clinical experience continues to support the importance of medically necessary oral care in many patients undergoing chemotherapy. For example, the frequency and severity of oral complications in cancer patients can be reduced by elimination of selected preexisting oral infections, institution of comprehensive oral hygiene protocols during therapy, and reduction of other factors that may compromise oral mucosal integrity (e.g., physical trauma to oral tissues).² In addition, mitigation of mucosal injury associated with ulcerative oral mucositis is emerging as a new therapeutic strategy. This has important clinical implications relative to quality of life, risk of sepsis in the myelosuppressed cancer patient, and in some cases, the likelihood of completing optimal chemotherapy dosing over time.¹⁰^,¹¹^,¹²

This chapter reviews the normal anatomy of oral structures most frequently affected by chemotherapy, followed by a discussion of the etiology, diagnosis, and management of relevant oral complications (Table 12.2). Because patients undergoing treatment for acute leukemia are typically at extreme risk of oral complications, they serve as the reference population unless otherwise noted.

NORMAL ANATOMY

The dentition and its supporting structures represent a complex, dynamic relationship. Teeth are suspended in a stroma of connective tissue that both supplies vasculature to the dental pulp and supports the teeth during function. This connective tissue, the periodontal ligament, extends chiefly from the cementum of teeth to alveolar bone. The space superior to the ligament between the tooth and the inner aspect of the free gingiva is called the periodontal sulcus; sulcular epithelium is normally nonkeratinized and nonulcerated.

Table 12-1 Oral Complications of Cancer Chemotherapy

Direct Toxicities		Indirect Toxicities
Oral mucositis		Myelosuppression
Salivary gland dysfunction		Neutropenia
Neurotoxicity		Immunosuppression
	Taste dysfunction		Anemia
	Dentinal hypersensitivity		Thrombocytopenia
Temporomandibular dysfunction		Infection
	Dental and skeletal growth and development (pediatric patients)		Viral (HSV, VZV, CMV, EBV, other) Fungal (Candida, Aspergillus, other)
	BON		Bacterial
HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalovirus; EBV, Epstein-Barr virus.
Modified from Schubert MM, Epstein JB, Peterson DE. Oral complications of cancer therapy. In: Yagelia JA, Neidle EA, Dowd FJ, eds. Pharmacology and Therapeutics in Dentistry. St. Louis, MO: Mosby-Year Book; 1998:644-655.

Dental pulp consists of a highly vascular connective tissue. Its components include a gelatinous ground substance, cellular elements, terminal blood vessels, nerves, and collagen. Its primary function is dentin formation during organogenesis; it normally retains its ability to sense hot and cold stimuli (usually interpreted as an uncomfortable sensation) throughout most of its life. The pulp communicates with the marrow spaces of the bone, chiefly through the apical foramen.

Gingival mucosa can be directly examined by the clinician. This mucosa terminates in a free edge surrounding the inferior margin of the clinical crowns of the teeth. The tissue is normally pale pink, with stippling evident. The alveolar mucosa covers the alveolar bony processes of both dental arches. In health, the junction of the gingival mucosa and alveolar mucosa is usually sharply delineated by a scalloped border, the mucogingival junction.

Mucosa lining the cheeks and lips of the oral cavity consists of nonkeratinized epithelium containing both minor salivary glands (chiefly mucous in character) and ectopic sebaceous glands in the anterior one-third of the mouth. Normally, the mucosa has a smooth, moist appearance, with a pink hue.

Chemotherapy can compromise the structure and function of these tissues such that clinically significant sequelae can ensue. The text that follows in this chapter is directed to prevention, assessment, and treatment of these toxicities.

MANAGEMENT BEFORE CHEMOTHERAPY

The incidence and severity of oral complications in patients scheduled to receive high-dose chemotherapy can be reduced significantly when an aggressive approach to stabilizing oral status is initiated before treatment.⁵^,¹³ The overall goal is to complete a comprehensive oral care plan that eliminates or stabilizes oral disease which could otherwise produce complications during or following chemotherapy. Achieving this goal can reduce the risk of oral toxicities with resultant reduced risk of systemic sequelae, lower the cost of patient care, and enhance quality of life.⁶^,¹⁰^,¹²^,¹³

An oral oncology team should become involved through either direct assessment and treatment of the patient or in consultation with the community-based dentist. Ideally, evaluation of oral status should be performed at least 1 month before chemotherapy; this timeframe is designed to permit adequate healing from any required invasive oral procedures targeted at reducing risk of acute complications during chemotherapy as well as ensure that optimal oral health, especially periodontal health, can be achieved. However, in practice, significantly less time is usually available for prechemotherapy oral assessment and treatment.

Effective communication between the oncology and dental teams is necessary to achieve an optimal clinical outcome. Elements of the consultation include the patient’s medical status and oncology treatment plan integrated with a plan for oral disease management before, during, and following cancer therapy (Table 12.3).

Guidelines for dental extractions, endodontic management, and related interventions can be utilized as necessary (Table 12.4).¹⁴^,¹⁵ Although controversial, antibiotic prophylaxis before invasive oral procedures may be recommended for patients with central venous catheters (e.g., Hickman catheters); the current American Heart Association protocol for prevention of infective endocarditis following oral procedures is frequently utilized for these patients.¹⁶

MANAGEMENT FOLLOWING CHEMOTHERAPY

A systematic approach to maintaining oral hygiene and lubrication of oral tissues is important for reducing the incidence and severity of oral sequelae in the neutropenic cancer patient. The rationale and specific procedures to be followed should be addressed to the patient and family caregivers in advance of initiation of the cytotoxic therapy. This approach also provides a setting in which anticipated oral toxicities of chemotherapy and their management can be discussed.

Both nonmedicated or medicated strategies can be utilized, depending on the degree of neutropenia and thrombocytopenia (Table 12.5). There is a considerable variation across institutions relative to specific nonmedicated approaches, given limited published evidence.¹⁷ Most nonmedicated oral care protocols utilize topical, frequent (every 4 to 6 hours) rinsing with 0.9% saline or sodium bicarbonate solutions, in conjunction with tooth brushing with a soft toothbrush and toothpaste (if tolerated), dental flossing, and oral cooling with ice chips. Irrigation with water or saline should be performed before administration of topical medication; removal of debris and thick, mucous saliva allows for enhanced tissue delivery of drug. Patient compliance with these agents can be maximized by comprehensive monitoring by the oncology team.¹⁸

Table 12-2 Common Complications of Chemotherapy

Problem	TimeSeen afterChemotherapy	Clinical Signs andSymptoms	LaboratoryFindings	Treatment Options	Course
Mucositis and ulceration	5-16 d after initiation of chemotherapy	Mucosal erythema Shallow or deep ulcerations on mucosa Poorly defined borders Usually on nonkeratinized tissue Very painful	Secondary infection may be present	Palliation: Topical and systemic analgesics Please see Table 12.7 for detailed management guidelines If secondary infection, systemic antibiotics to cover gram-negative organisms in addition to conventional gram-positive flora If hemorrhage, topical thrombin Soft bland diet as tolerated	Resolves after cessation of chemotherapy
Xerostomia	Variable	Dry mouth Thick ropy saliva Dysgeusia difficulty with speech and nutrition	Noncontributory	Sodium bicarbonate mouth rinse to decrease viscosity of oral environment Lemon drops (with artificial sweeteners; used only for acute management) Sugarless gum Saliva substitutes Sialogogues: Pilocarpine, cevimeline High-strength fluoride toothpaste prescription to prevent dental caries	Usually resolves after cessation of chemotherapy
Dysgeusia	Variable	Decreased taste or abnormal taste	Noncontributory	Maintain adequate nutritional intake while the condition is present Counseling for prevention of dysgeusia	Usually resolves after cessation of chemotherapy
“Odontogenic” pain of neurotoxic origin	During course of neurotoxic agent (e.g., vincristine and vinblastine)	Spontaneous, constant, dental pain often mimicking pulpitis Difficult to localize May be bilateral Afebrile No swelling, lymphadenopathy, significant caries, or periodontitis	Noncontributory	Gabapentin, carbamazepine Systemic analgesics	Resolves after discontinuation of neurotoxic agent
Acute necrotizing ulcerative gingivitis	Variable. May be unrelated to chemotherapy, but incidence increases with neutropenia	Gingival pain and bleeding Fever Lymphadenopathy Gingival necrosis with punched-out papillae Oral malodor	May see leukocytosis if no myelosuppression Fusospirochetal smear (positive)	Systemic antibiotics, penicillin drug of choice; oral debridement	Resolves after appropriate therapy in 10 d
Candidiasis	Variable, more likely with prolonged neutropenia, antibiotics, or steroid use	White curd-like lesions or erythematous atrophic areas Mild pain or burning, often asymptomatic Affects dorsal tongue and buccal and palatal mucosa Corners of mouth may be affected, especially in edentulous patients (see angular cheilitis)	Neutropenia, (positive) smear for Candida spp.	Clotrimazole troches Systemic antifungals, for example, fluconazole	Resolves with antifungal therapy or with marrow recovery
Angular cheilitis	Variable, incidence increases with xerostomia	Cracking, bleeding, possible exudate and pain in corner of mouth	Smear will likely demonstrate fungi	Nystatin ointment Nystatin/triamcinolone combination ointment Check occlusal vertical dimension	Usually resolves with antifungal therapy
Herpes simplex infection	Variable	Commonly on lip near the mucocutaneous junction (herpes labialis); in immunocompromised patients intraoral ulcerative lesions can occur	Seropositive Increased nuclearcytoplasmic ratio Viral inclusion bodies	Prevention: Keep lips lubricated; this is often a secondary infection in a neutropenic host Treatment: Topical or systemic antivirals, for example, acyclovir	10-14 d, depending on immune status
Salivary gland infection	Variable, most common in debilitated patients with diminished oral intake and dehydration	Swelling (may be unilateral or bilateral) Pain Suppuration from salivary duct Xerostomia Fever	Variable, (positive) bacterial or viral cultures, CMV common	Antibiotics (systemic) to cover Staphylococcus spp. if bacterial Rehydrate Watch for possible airway obstruction	Resolution depends on host status and treatment
Odontogenic infection	Variable	May present with fever of unknown origin, pain, lymphadenopathy Swelling not a consistent finding with neutropenia May be subclinical until neutropenia develops	Neutropenia Blood culture may be positive	Pulpal therapy or extraction in presence of adequate cell counts (e.g., platelets >40,000/mm³) In immunosuppressed patients, consider systemic broad-spectrum antibiotics to cover for opportunistic organisms and normal flora	Variable; depends on organism, hematologic status, extent of infection
Mucosal bleeding	10-14 d after initiation of chemotherapy	Hematoma or bleeding, especially from mucosal sites commonly traumatized In case of neutropenic patient, likely chance of secondary infection Possible airway obstruction due to sublingual or pharyngeal extension	Thrombo cytopenia Blast crisis with functional decrease in platelets	Remove partial and full dentures Remove orthodontic bands or retainers Cover for secondary infection Topical/systemic aminocaproic acid Topically applied: Thrombin, microfibrillar collagen, epinephrine	Resolves with increased platelets Resolving hematoma may extrude a granulation plug from the healing base; this should not be disturbed
Gingival bleeding	Variable, typically 10-14 d after initiation of chemotherapy	Marginal hemorrhage from gingiva May be spontaneous if platelets <40,000/mm³	Thrombo cytopenia	Platelet transfusion Topical thrombin, microfibrillar collagen, epinephrine Topical thrombin, microfibrillar collagen, epinephrine Aminocaproic acid Pressure therapy Undisturbed clot Avoid trauma to site	Resolves as platelet count increases
Modified from Natl Cancer Inst 2010 PDQ website: Oral complications of chemotherapy and head/neck radiation.
http://www.cancer.gov/cancertopics/pdq/supportivecare/oralcomplications/healthprofessional.

Table 12-3 Oral Disease Stabilization Before High-Dose Chemotherapy and/or Stem Cell Rescue

Data Provided by Oncology to Dental Medicine
	Underlying disease
		Cancer: Type, stage, prognosis
		Aplastic anemia
		Other
	Type of transplant
		Autologous
		Allogeneic
			Matched
			Mismatched related
			Mismatched unrelated
		Syngeneic
	Planned date of transplant
	Conditioning regimen
		Chemotherapy
		Total body irradiation
	Current hematologic status including neutrophil and platelet counts
	Comorbidities
	Present medications
	Potential need for antibiotic prophylaxis before invasive procedures, for example, infective endocarditis, artificial joints, central venous catheter
Data Provided by Dental Medicine to Oncology
	Dental caries
	Number of teeth requiring restorations
	Endodontic disease
		Teeth with pulpal infection
		Teeth requiring endodontic treatment
	Periodontal disease status
	Number of teeth requiring extraction
	Other urgent care required
	Time necessary to complete stabilization of oral disease
Modified from Schubert MM, Peterson DE, Lloid ME. Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation. 2nd ed. Malden, MA: Blackwell Science; 1999:751-763.

Table 12-4 Management Suggestions Relative to Invasive Dental Procedures

Medical Status	Guideline	Comments
Patients with chronic indwelling venous access catheters (Hickman, etc.)	Regimens recommended by the American Heart Association for infective endocarditis prophylaxis are often used	There is no clear scientific proof detailing infectious risk of these lines following dental procedures; this recommendation is empiric
Neutrophils		Order CBC with differential
1,500/mm³ or greater	Prophylactic antibiotics for neutropenia are usually not necessary	Other indications for prophylaxis may be present
<1,500/mm³	Antibiotic prophylaxis should be considered; regimens recommended by the American Heart Association for infective endocarditis prophylaxis are often used; however, clinical judgment is critical: if infection is present or neutropenia is severe, more aggressive antibiotic therapy may be indicated, based on consultation with an infectious diseases specialist	If organisms are known or suspected, appropriate adjustments to antibiotic regimens should be made based on sensitivities
Platelets^a		Order platelet count and coagulation tests
>75,000/mm³	No additional support needed
40,000-75,000/mm³	Platelet transfusions are optional; consider administering preoperatively and 24 h later; additional transfusions are based on clinical course	Utilize techniques to promote establishing and maintaining control of bleeding (sutures, pressure packs, minimize trauma, etc.)
<40,000/mm³	Platelets should be transfused 30 min before surgical procedure, obtain STAT platelet count, transfuse regularly to maintain counts above 30,000-40,000/mm³ until initial healing has occurred	In addition to above, consider using hemostatic agents (microfibrillar collagen, topical thrombin, fibrin glues, etc.); monitor sites carefully
^aAssumes that all other coagulation parameters are within normal limits and that platelet counts will be maintained at or above the specified level until initial stabilization/healing has occurred.
CBC, complete blood count.
Modified from Schubert MM, Epstein JB, Peterson DE. Oral complications of cancer therapy. In: Yagelia JA, Neidle EA, Dowd FJ, eds. Pharmacology and Therapeutics in Dentistry. St. Louis, MO: Mosby-Year Book; 1998:644-655.

Table 12-5 Baseline Oral Hygiene in the Neutropenic Cancer Patient

Toothbrushing
	Soft or ultrasoft bristled brush
	Brush two to three times daily with Bass sulcular scrub method
	Rinse frequently
Dentifrice
	Patient preference/tolerated
	Should contain fluoride
	Avoid strong flavoring (e.g., cinnamon) or whitening toothpastes; may irritate oral tissues.
Flossing
	Once daily
	Atraumatic technique with modifications as needed
Foam toothettes
	Use only when use of regular toothbrush not feasible
	Use with antimicrobial rinse
	Use on teeth two to three times a day
	Rinse frequently
Bland rinses
	0.9% saline
	Sodium bicarbonate solution
	0.9% saline plus sodium bicarbonate solution
	8-12 oz (236.5-354.8 ml) rinsed, held, and spat out
	Repeat q2-4 h or p.r.n.
Fluoride
	1.1% neutral sodium fluoride gel
	0.4% stannous fluoride gel
	Brush on for 2-3 min
	Expectorate thoroughly
	Apply once a day
Topical antimicrobial rinses
	0.12%-0.2% chlorhexidine oral rinse
	Povidone iodine oral rinse
	Minocycline rinse (25 mg/oz)
	Rinse, hold 1-2 min, expectorate
	Repeat two to four times a day depending on severity of periodontal disease and patient tolerance (alcohol in rinse may cause burning especially if mucositis present).
Modified from Schubert MM, Peterson DE, Lloid ME. Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation. 2nd ed. Malden, MA: Blackwell Science; 1999:751-763.

Dental brushing and flossing after meals represent simple, cost-effective approaches to bacterial dental plaque control. This strategy is designed to reduce the risk of oral infection (especially gingival infection) and its systemic spread during neutropenia. Discontinuing dental brushing and flossing can increase the risk of local oral infections and associated bacteremia unless other approaches (e.g., antibacterial mouth rinses) are utilized. The presence of poor hygiene—measured by higher levels of plaque and calculus and generalized bleeding following tooth brushing—has been shown to increase bacteremia associated with oral bacteria.¹⁹ Oncology teams at some centers incorporate dental brushing and flossing into daily patient management, whereas patients treated at other institutions are instructed to discontinue brushing and flossing when peripheral blood components decrease below defined thresholds (e.g., platelets <30,000 per mm³),¹⁷ because of the misconception that it is the oral hygiene efforts that cause bleeding. It is important to recognize that discontinuation of effective dental plaque control measures will increase risk of periodontal infection and subsequent risk of bleeding; conversely, healthy gingival tissue does not spontaneously bleed. Studies have demonstrated that soft sponge toothettes are not effective in maintaining adequate oral hygiene over time.²⁰

Daily professional oversight of dental brushing and flossing is important, to ensure nontraumatic oral care by the patient. Patients should utilize a soft nylon bristled toothbrush two to three times a day with techniques that specifically maintain the gingival one-third of the tooth and periodontal sulcus free of bacterial plaque (e.g., Bass sulcular scrub technique).²¹ The brush can be softened by rinsing it in warm water every 15 to 30 seconds during use. Oral rinsing with water or saline three to four times while brushing will further aid in removal of dental plaque dislodged by brushing. Dentrifices containing flavoring agents, especially mint flavors, can irritate oral soft tissues when mucositis is present. Therefore, toothpaste with relatively neutral taste should be considered for these patients with oral mucositis. Dental flossing can generally be continued during mild-moderate neutropenia and/or thrombocytopenia, if the patient has exhibited previous acceptable flossing technique. As with dental brushing, daily professional oversight remains important to minimizing risk of mechanical injury. Mouth rinses containing alcohol should be avoided, because they can cause dryness and discomfort of oral tissues.

Historically, reports of the effect of chemotherapy on salivary gland function do not consistently demonstrate a cause-and-effect relationship. However, many medications, including antinausea agents, exert a profound anticholinergic effect and can result in salivary gland dysfunction.²² A patient with decreased saliva is more prone to mucosal injury and infection due to a reduction in the protection normally provided by saliva. Therefore, more frequent dental brushing, flossing, and oral rinses with saline may be indicated. In addition, standard lip care products containing petroleum-based oils and waxes can be useful. However, lanolinbased creams and ointments may be more effective in moisturizing and softening lips with moderate to severe chapping.

Table 12-6 Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Chemotherapy

Dentures
Minimize use during first 3-4 wk posttransplant or postchemotherapy
	Wear only when eating
	Discontinue use at all other times
Clean twice a day with a soft brush and rinse well
Soak in antimicrobial solution when not being worn
Perform routine oral mucosal care procedures without the oral appliance three to four times a day
Leave appliance out of mouth when sleeping and during periods of significant mouth soreness
Dentures may be used to hold medications needed for oral care (e.g., antifungals)
Orthodontic Appliances (Brackets, Wires, Retainers, etc.)
Remove before conditioning
Discontinue use of removable appliances until oral mucositis has healed
Modified from Schubert MM, Peterson DE, Lloid ME. Oral complications. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation. 2nd ed. Malden, MA: Blackwell Science; 1999:751-763.

Patients utilizing removable dental prostheses or orthodontic appliances are at risk of mucosal injury or appliance-related infection, especially oral candidiasis. Management guidelines for these patients are listed in Table 12.6. In general, orthodontic appliances should be removed before high-dose chemotherapy. Oral tissues of patients wearing dentures should be inspected before the initiation of chemotherapy. Denture-related soft tissue injury should be prevented by careful adjustment of the prosthesis. Patients may utilize dentures during the chemotherapy admission, if no evidence of oral injury exists. Dentures should be cleaned daily, using a commercially available denture cleanser. The prostheses should be brushed and rinsed after meals. During profound myelosuppression, denture use should be restricted to periods of eating. Otherwise, the dentures should be stored in denture-cleansing solution in a labeled, closed container; the denture solution should be changed daily.

DIRECT STOMATOTOXIC EFFECTS

Mucositis

In a clinical setting, “oral mucositis” and “stomatitis” are often used synonymously. However, distinctions exist between the two lesions that are important in both clinical and research contexts.

Oral mucositis describes inflammation of oral mucosa resulting from cytotoxic cancer therapy, including chemotherapeutic agents or ionizing head/neck radiation. The lesion typically manifests as mucosal atrophy and erythema, and, in severe cases, ulceration. Oral mucositis may be worsened by local factors, including trauma and infection.
Stomatitis refers to any inflammatory condition of oral tissue, including mucosa, dentition, and periodontium. Stomatitis, therefore, includes infections of oral tissues as well as mucositis as defined earlier.

Mucositis remains the preferred term when describing the direct and indirect injury mediated by chemotherapy on oral mucosa. This term was recently added as a Medical Subject Heading (MeSH) term by the U.S. Library of Medicine and is now utilized for indexing articles for MEDLINE/PubMed related to mucosal injury associated with cancer therapies.

Pathogenesis

An interplay of multiple factors appears to contribute to the trajectory of oral mucositis observed clinically. Although the cytotoxic effects of chemotherapy upon replicating oral epithelium do contribute to oral mucositis,²³ studies have indicated that the mechanisms involved are much more complex.²⁴^,²⁵^,²⁶^,²⁷

The currently accepted model for the pathogenesis of oral mucositis postulates the following five stages (Fig. 12.1).³^,²⁸

Initiation phase. Cells injured by chemotherapy can release chemotherapy and radiation-associated molecular pattern molecules called CRAMPs. These bind to receptors, leading to the generation of damaging reactive oxygen species (ROS).²⁸
Primary damage response phase. This phase is characterized by activation of transcription factors such as nuclear factor-κ B (NF-κB) and other pathways such as the ceramide pathway. Collectively, activation of these molecules can lead to injury and death of basal epithelial cells.
Signal amplification. Molecules induced by the primary response can further amplify the tissue response. For example, upregulation of proinflammatory cytokines, such as tumor necrosis factor κ (TNF-κ), can result in activation of pathways which would amplify mucosal injury, in addition to direct injurious effects on mucosal cells.
Ulceration with inflammation. During the ulcerative phase of mucositis, there is a significant inflammatory cell infiltrate in the affected tissue. The production of proinflammatory cytokines is further increased.²⁹ Microbial colonization of the disrupted mucosa can further aggravate mucosal injury.
Healing. This stage involves a renewal of epithelial proliferation and differentiation.³⁰

Figure 12.1 Five-phase model for the pathogenesis of oral mucositis. (Figure courtesy of Stephen T. Sonis, DMD, DMSc. From Sonis ST. A biological approach to mucositis. J Supp Oncol. 2004;2:21-32.)

Although these steps are presented in a linear manner, it is important to recognize that the damage actually occurs with both simultaneous and sequential patterns of damage. Furthermore, the whole process will be repeated with each successive administration of chemotherapy.

Clinical Presentation

In the initial clinical stages of mucositis, the patient experiences a mucosal burning sensation within 1 week of administration of the drugs; the mucosa may appear erythematous. The lesion then typically ulcerates within 5 days, with ulcerations subsequently becoming confluent (Fig. 12.2A). Labial/buccal mucosa, lateral and ventral tongue, and floor of mouth and soft palate are more severely affected by chemotherapy than attached, more heavily keratinized tissues such as hard palate and gingival.³¹^,³²

Histologic changes associated with these clinical findings most commonly include vascular inflammation, collagen degeneration, and epithelial atrophy. Ulcerations in this setting are usually covered by a fibrin exudate pseudomembrane and become rapidly colonized by the oral flora. Thus, drug-induced mucositis represents a potential portal of entry for systemic infection.¹¹^,³³

Single agent chemotherapeutic drugs that frequently cause oral mucositis include methotrexate, doxorubicin, 5-fluorouracil (5-FU), busulfan, and bleomycin. Multidrug regimens can cause increased risk of clinically significant mucositis as compared to single-agent regimens. For example, 5-FU, with or without leucovorin, is associated with a 22% incidence of oral mucositis only, 8% incidence of gastrointestinal (GI) mucositis only, and a 16% incidence of both oral and GI mucositis.⁶ Most anthracycline-based regimens are associated with an approximately 10% risk of clinically significant oral mucositis, except when the regimen includes 5-FU. Thus, the combination of docetaxel with 5-FU is associated with a much higher risk of clinically significant oral mucositis, in the range³^,³⁴ of 58% to 74%.

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