Oral Complications of Cancer Therapies (PDQ®): Supportive care - Health Professional Information [NCI]

Overview

The field of oral complications caused by cancer therapies continues to evolve for a number of reasons, including:

• High-quality basic, translational, and clinical research.
• Translation of selected clinical interventions into systematic reviews and clinical practice guidelines based on this research.
• Advances in cancer treatment via precision medicine technology.
• Increased understanding of the value of integration of tumor treatment with evidence-based supportive care.

The oral cavity represents a unique anatomic and functional site. Clinical prevention and management of oral complications in patients with cancer should be based on state-of-the-science and implemented in an interprofessional practice setting. The interprofessional team includes, but is not limited to, oncologists, oncology nurses and nurse navigators, dental generalists and specialists, dental hygienists, social workers, and dieticians.

The type and severity of oral complications vary by classification, intensity, and duration of cancer therapy. Table 1 shows examples of these oral complications.

Table 1. Medically Necessary Oral Interventions, by Type of Cancer Therapy

Cancer Therapy	Before Cancer Therapy	During Cancer Therapy	After Cancer Therapy
GVHD = graft versus host disease; HPV = human papillomavirus; HSCT = hematopoietic stem cell transplant; WBC = white blood cell.
Chemotherapy, high dose (e.g., <1,000 WBC/µL for more than 5 days) and chemotherapy, moderate to low dose (e.g., nadir of 2,500 WBC/µL)	Advanced dental caries, with potential for pulpal involvement	Maintain effective oral hygiene	Implement preventive and treatment protocols to optimize oral health
	Dentition with moderate/severe periodontal disease
	Periapical lesions secondary to dental pulpal infection that have been symptomatic within the past 90 days
	Dental appliances (e.g., dentures, orthodontic appliances) that may traumatize oral mucosa
	Patient education	Assess for possible acute infection of oral origin
		Manage oral mucositis, including oral hygiene and pain management
HSCT, reduced intensity chemotherapy (e.g., nadir of 2,500 WBC/µL) and HSCT, myeloablative chemotherapy (e.g., <1,000 WBC/µL for more than 5 days)	Advanced dental caries, with potential for pulpal involvement	Maintain effective oral hygiene
	Dentition with moderate/severe periodontal disease
	Periapical lesions secondary to dental pulpal infection that have been symptomatic within the past 90 days	Assess for possible acute infection of oral origin
	Dental appliances (e.g., dentures, orthodontic appliances) that may traumatize oral mucosa
	Patient education	Manage oral mucositis, including oral hygiene and pain management
HSCT, GVHD	Determine likelihood of developing acute and/or chronic GVHD, depending on type of transplant	Differentiate oral mucosal injury caused by chemotherapy and acute oral GVHD	Monitor for emergence of chronic oral GVHD, potentially malignant mucosal disease, and/or oral squamous cell carcinoma
	Patient education	Provide supportive care, including oral hygiene and pain control
Head and neck radiation, high dose	Determine need for medically necessary dental extractions and potential change in occlusal vertical dimension, based on the following:	Maintain oral hygiene and nutritional support	Implement preventive and treatment protocols to optimize oral health
	• Advanced dental caries, with potential for pulpal involvement
	• Dentition involved with moderate/severe periodontal disease
	• Periapical lesions secondary to dental pulpal infection that have been symptomatic within the past 90 days
	• Dental appliances (e.g., dentures, orthodontic appliances) that may traumatize oral mucosa
	Patient education	Manage oral mucositis, including oral hygiene and pain management
		Prescribe jaw opening and closing exercises to reduce risk of trismus	Monitor for risk of osteoradionecrosis, recurrent or new oral mucosal malignancy
Head and neck radiation, deintensification (HPV + oropharyngeal squamous cell carcinoma)	Same as high-dose head and neck radiation; risk for late effects appears to be reduced	Same as high-dose head and neck radiation	Same as high dose head and neck radiation; risk for late effects appears to be reduced
	Patient education		Patient education
Immunotherapy and targeted cancer therapies	Document baseline oral mucosal status	Assess number and severity of oral mucosal lesions clinically documented to be caused by immunotherapy/targeted therapy	Monitor for possible late adverse oral effects
	Patient education	Provide topical, intralesional, or systemic steroid treatment if oral pain is sufficiently severe
Bone-stabilizing agents	Eliminate advanced dental caries that approaches the dental pulp	Perform periodic systematic dental evaluations for compliance with oral hygiene and assessment of dentition, periodontium, and oral mucosa	Perform periodic systematic dental evaluations for compliance with oral hygiene and assessment of dentition, periodontium, and oral mucosa
	Extract teeth with poor long-term prognosis due to periodontal disease and/or dental caries
	Correct ill-fitting, removable dental prostheses that cause or could cause mucosal trauma and potential bone exposure
	Patient education

Clinicians may consider many factors about oral interventions, including the following:

• Patient's immune status.
• Pending time to initiation of cancer therapy.
• Intensity and duration of cancer therapy.

Many of the oral complications that develop in oncology patients are characterized by considerable biological and clinical complexity.[1,2,3,4,5,6,7,8,9,10,11,12]

References:

1. Mougeot JC, Stevens CB, Morton DS, et al.: Oral Microbiome and Cancer Therapy-Induced Oral Mucositis. J Natl Cancer Inst Monogr 2019 (53): , 2019.
2. Lalla RV, Brennan MT, Gordon SM, et al.: Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy. J Natl Cancer Inst Monogr 2019 (53): , 2019.
3. Keefe DMK, Bateman EH: Potential Successes and Challenges of Targeted Cancer Therapies. J Natl Cancer Inst Monogr 2019 (53): , 2019.
4. Carrozzo M, Eriksen JG, Bensadoun RJ, et al.: Oral Mucosal Injury Caused by Targeted Cancer Therapies. J Natl Cancer Inst Monogr 2019 (53): , 2019.
5. Epstein JB, Miaskowski C: Oral Pain in the Cancer Patient. J Natl Cancer Inst Monogr 2019 (53): , 2019.
6. Fall-Dickson JM, Pavletic SZ, Mays JW, et al.: Oral Complications of Chronic Graft-Versus-Host Disease. J Natl Cancer Inst Monogr 2019 (53): , 2019.
7. Deng J, Wulff-Burchfield EM, Murphy BA: Late Soft Tissue Complications of Head and Neck Cancer Therapy: Lymphedema and Fibrosis. J Natl Cancer Inst Monogr 2019 (53): , 2019.
8. Murphy BA, Wulff-Burchfield E, Ghiam M, et al.: Chronic Systemic Symptoms in Head and Neck Cancer Patients. J Natl Cancer Inst Monogr 2019 (53): , 2019.
9. Spijkervet FKL, Brennan MT, Peterson DE, et al.: Research Frontiers in Oral Toxicities of Cancer Therapies: Osteoradionecrosis of the Jaws. J Natl Cancer Inst Monogr 2019 (53): , 2019.
10. Jensen SB, Vissink A, Limesand KH, et al.: Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients. J Natl Cancer Inst Monogr 2019 (53): , 2019.
11. Migliorati CA, Brennan MT, Peterson DE: Medication-Related Osteonecrosis of the Jaws. J Natl Cancer Inst Monogr 2019 (53): , 2019.
12. Elting LS, Chang YC: Costs of Oral Complications of Cancer Therapies: Estimates and a Blueprint for Future Study. J Natl Cancer Inst Monogr 2019 (53): , 2019.

Oral Management of Patients Receiving Chemotherapy

Before Chemotherapy

Oral evaluation and management of patients scheduled to undergo myeloablative chemotherapy should occur as early as possible before initiation of therapy (see the list in Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplant [HSCT] and Table 1). The overall goal is to complete a comprehensive oral care plan that eliminates or stabilizes oral disease that could otherwise produce complications during or after chemotherapy. To maximize positive outcomes, the oncology team should inform the dentist about the patient's medical status and oncology treatment plan. In turn, the dental team should delineate and communicate a plan for oral disease management before, during, and after chemotherapy.[1]

Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplant (HSCT)

• Data provided by the oncology team to dental providers includes the following:
  • Underlying disease:
    • Cancer type, stage, and prognosis.
    • Hematologic status and metabolic panel.
    • Additional data based on clinical status.
  • Type of chemotherapy:
    • High/moderate/low dose (without HSCT).
  • Type of transplant:
    • Autologous.
    • Allogeneic donor types:
      • Matched related and unrelated.
      • Mismatched related.
      • Mismatched unrelated.
    • Syngeneic.
  • Hematopoietic stem cell source:
    • Bone marrow.
    • Peripheral stem cells.
    • Cord blood stem cells.
  • Conditioning regimen:
    • Myeloablative.
    • Reduced-intensity conditioning (including nonmyeloablative regimens).
  • Planned date of transplant.
  • Conditioning regimen:
    • Chemotherapy.
    • Total-body irradiation.
    • Radioactive antibodies.
  • Current hematologic and immunologic status.
  • Current medications.
  • Other medical considerations:
    • Cardiac disease.
    • Pulmonary disease.
    • Indwelling venous access line.
    • Coagulation status.
    • Splenectomy.
• Data provided by dental providers to the oncology team includes the following:
  • Dental caries (number of teeth and severity, including number of teeth that should be treated before cancer treatment begins).
  • Endodontic disease:
    • Teeth with pulpal infection.
    • Teeth with periapical infection.
  • Periodontal disease status.
  • Number of teeth requiring extraction, as well as anticipated degree of surgical complexity.
  • Other urgent care required.
  • Time necessary to complete stabilization of oral disease.

The three categories of dental evaluation and treatment protocols before cancer therapy include the following:[2]

1. Complete protocols:
   • All dental pathologies are treated before antineoplastic chemotherapy and HSCT are initiated.
2. Partial protocols:
   • Teeth with apical periodontitis are managed only if they are symptomatic and if size of the periapical lesion is 5 mm or more.
   • Teeth are extracted only if they have severe periodontitis (probing depth of ≥8 mm) and/or Miller's Class III mobility, they are expected to exfoliate within a few weeks, or if partially erupted third molars are symptomatic and with purulence.
3. Minimal protocols:
   • Patients are treated only if they are symptomatic.

Partial dental evaluation/treatment protocols may be appropriate when there is insufficient time for complete dental evaluation/treatment protocols.[3][Level of evidence: IV]

Periodontal therapy before and maintenance after cancer therapy (both head and neck radiation and antineoplastic chemotherapy) are suggested for general good oral health.[3]

During Chemotherapy

Oral complications during chemotherapy are common. Dentists play an important role on the cancer treatment team by evaluating patients before chemotherapy, with the goal of optimizing their oral health status, minimizing complications, and educating patients to maintain optimal oral hygiene. Routine, systematic oral hygiene is important to reduce incidence and severity of oral sequelae of cancer therapy. The patient must be informed of the rationale for the oral hygiene program, as well as the potential side effects of cancer chemotherapy. Effective oral hygiene is important during cancer treatment, with an emphasis on oral hygiene management before treatment starts.[1,4]

Management of patients undergoing either high-dose chemotherapy or upper-mantle radiation share selected common principles. These principles are based on baseline oral care and reduction of physical trauma to oral mucosa (see Guidelines for the Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy).

Variation exists across institutions relative to specific nonmedicated approaches to baseline oral care, given limited published evidence. Most nonmedicated oral care protocols use topical, frequent (every 4–6 hours) rinsing with 0.9% saline. Additional interventions include dental brushing with toothpaste, dental flossing, ice chips, and sodium bicarbonate rinses. Patient compliance with these agents can be maximized with monitoring by the health care team.[1][Level of evidence: IV]

Guidelines for the Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy

Minimize denture use during first 3 weeks posttransplant.[4] Wear dentures only when eating. Discontinue use at all other times.

Clean twice a day with a soft brush and rinse well.

Soak in antimicrobial solutions when not being worn.

Perform routine oral mucosal care procedures 3 to 4 times a day with the oral appliances out of the mouth.

Leave appliances out of the mouth when sleeping and during periods of significant mouth soreness.

Dentures may be used to hold medications needed for oral care (e.g., antifungals).

Discontinue use of removable appliances until oral mucositis has healed.

Remove orthodontic appliances (e.g., brackets, wires, retainers) before conditioning.

Dental brushing and flossing are simple, cost-effective approaches to control of bacterial dental plaque. This strategy is designed to reduce the risk of oral soft tissue infection during myeloablation. For more information, see the Infection section.

Patients skilled at flossing without traumatizing gingival tissues may continue to floss throughout chemotherapy administration. Flossing allows for interproximal removal of dental bacterial plaque and promotes gingival health.

The oral cavity should be cleaned after meals, as follows:

• If dry mouth is present, plaque and food debris may accumulate secondary to reduced salivary function, and more frequent hygiene may be necessary.
• Dentures need to be cleaned with denture cleanser every day and brushed and rinsed after meals.
• Rinsing the oral cavity may not be sufficient for thorough cleansing of the oral tissues; mechanical plaque removal is often necessary.
• Care must be taken in using mechanical hygiene aids; dental floss, interproximal brushes, and wooden wedges can injure oral tissues rendered fragile by chemotherapy.
• Toothettes have limited ability to cleanse the dentition; however, they may be useful for cleaning maxillary/mandibular alveolar ridges of edentulous areas, palate, and tongue.

Preventing dry lips to reduce the risk of tissue injury is important. Mouth breathing and/or xerostomia secondary to anticholinergic medications used for nausea management can induce the condition. Graft-versus-host disease can also contribute to dry lips in allogeneic transplant patients. Lip care products containing petroleum-based oils and waxes can be useful. Lanolin-based creams and ointments may be more effective in moisturizing/lubricating the lips and protecting against trauma.

Oral mucositis (high-dose chemotherapy, HSCT, head and neck radiation)

Oral mucositis is one of the most common side effects of cytotoxic cancer regimens. The terms oral mucositis and stomatitis are often used interchangeably at the clinical level, but they do not reflect identical processes.

Oral Mucositis:

• Inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation.[5,6]
• Manifests as erythema or ulcerations.
• May be exacerbated by local factors.

Stomatitis:

• Any inflammatory condition of oral tissue, including mucosa, dentition/periapices, and periodontium.
• Includes infections of oral tissues as well as mucositis.

The current model of oral mucositis involves a complex five-step trajectory of molecular, cellular, and tissue-based changes involving the oral microbiome.[7,5]

Patients receiving cycled chemotherapy or conditioning regimens before HSCT develop the first signs of mucositis 3 to 4 days after infusion. Oral ulcer formation begins during the second week of treatment—with the highest severity between days 7 and 14—and then resolves spontaneously in the week after cessation of cytotoxic chemotherapy.[8] Clinicians need to be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate gastrointestinal mucosal toxicity.

Several health professional organizations have produced evidence-based guidelines for oral mucositis, including the following:

• Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO).[9,10,11][Level of evidence: IV]
• National Comprehensive Cancer Network.[12]
• The Cochrane Collaboration.[13]

Many recommendations are similar across the organizations. The Cochrane Collaboration, however, uses a meta-analysis approach that provides a unique context for purposes of guideline construction.

Management of oral mucositis

Oral care protocols include atraumatically cleansing the oral mucosa, maintaining lubrication of the lips and oral tissues, and relieving pain and inflammation. Oral mucositis is minimized with the use of mild-flavored fluoridated toothpaste. Avoidance of spicy, acidic, hard, and hot foods and beverages will also decrease oral mucositis.

Management of oral mucositis via topical approaches should address efficacy, patient acceptance, and appropriate dosing. A stepped approach is typically used, with progression from one level to the next.

• Bland rinses:
  • 0.9% saline solution.
  • Sodium bicarbonate solution.
  • 0.9% saline/sodium bicarbonate solution.
• Topical anesthetics:
  • Lidocaine: viscous, ointments, sprays.
  • Benzocaine: sprays, gels.
  • 0.5% or 1.0% dyclonine hydrochloride (HCl).
  • Diphenhydramine solution.
• Mucosal coating agents:
  • Amphojel.
  • Kaopectate.
  • Hydroxypropyl methylcellulose film-forming agents (e.g., Zilactin).
  • Gelclair (approved by the U.S. Food and Drug Administration as a device).
  • Caphosol.
  • Episil.
  • MuGard.
• Analgesics:
  • Opioid drugs: oral, intravenous (e.g., bolus, continuous infusion, patient-controlled analgesia), patches, transmucosal. Morphine may be used to treat pain caused by oral mucositis in patients undergoing HSCT. Morphine mouthwash (0.2%) may be used in patients receiving chemoradiation for head and neck cancer. Transdermal fentanyl may be given to patients receiving conventional or high-dose chemotherapy, with or without total body irradiation.[14][Level of evidence: IV]
• Growth factor (keratinocyte growth factor-1):
  • Palifermin for patients receiving high-dose chemotherapy and total body irradiation, followed by autologous stem cell transplant, for a hematological malignancy.[15]
• Cryotherapy in patients receiving bolus fluorouracil chemotherapy.[16]
• Low-level laser therapy to prevent oral mucositis in patients receiving HSCT conditioned with high-dose chemotherapy, with or without total body irradiation.[17][Level of evidence: IV]
• Zinc supplements administered orally in oral cancer patients receiving radiation therapy or chemoradiation.[18][Level of evidence: IV]

A soft toothbrush that is replaced regularly should be used to maintain oral hygiene.[19][Level of evidence: IV] Foam-swab brushes do not effectively clean teeth and should not be considered a routine substitute for a soft, nylon-bristled toothbrush. Additionally, the rough sponge surface may irritate and damage the mucosal surfaces opposite the tooth surfaces being brushed.

Irrigation should be performed before topical medication is applied because removal of debris and saliva allows for better coating of oral tissues and prevents material from accumulating. Frequent rinsing cleans and lubricates tissues, prevents crusting, and palliates painful gingiva and mucosa.

Systemic analgesics are administered when topical anesthetic strategies are not sufficient for clinical relief. Nonsteroidal anti-inflammatory drugs that affect platelet adhesion and damage gastric mucosa are contraindicated, especially if thrombocytopenia is present.

MASCC/ISOO recommendations against specific practices include the following:

• No PTA (polymyxin, tobramycin, amphotericin B) and BCoG (bacitracin, clotrimazole, gentamicin) for oral mucositis in patients receiving radiation therapy for head and neck cancer.[14][Level of evidence: IV]
• No iseganan antimicrobial mouthwash.[14][Level of evidence: IV]
• No sucralfate mouthwash.[14][Level of evidence: IV]
• No intravenous glutamine.[18][Level of evidence: IV]

Table 2. Oral Mucositis Scales

Grade	World Health Organization	National Cancer Institutea	RTOG
N/A = not applicable; RTOG = Radiation Therapy Oncology Group.
a Common Terminology Criteria for Adverse Events, version 5.[20].
0	No findings	No findings	No findings
1	Erythema and soreness	Asymptomatic or mild symptoms; intervention not indicated	Painless ulcers, erythema, or mild soreness
2	Oral erythema, ulcers; solid diet tolerated	Moderate pain does not interfere with oral intake, but modified diet indicated	Painful erythema, edema, or ulcers but can eat
3	Ulcers requiring liquid diet	Severe pain interfering with oral intake	Painful erythema, edema, or ulcers and cannot eat
4	Ulcers and not able to tolerate a solid or liquid diet	Life-threatening consequence; urgent intervention indicated	Requires parenteral or enteral support
5	N/A	Death	N/A

Xerostomia and salivary hypofunction caused by antiemetics

Xerostomia is defined as the subjective feeling of oral dryness and can be accompanied by salivary gland hypofunction. Xerostomia is likely to occur when the salivary flow rate is less than the rate of fluid absorption across the oral mucosa plus the rate of fluid evaporation from the oral cavity.[21][Level of evidence: IV] (See Table 3.)

Table 3. Definitions of Xerostomia, Hyposalivation, and Salivary Gland Hypofunction and Dysfunction

Term	Definition
Xerostomia	Subjective feeling of oral dryness
Dry mouth	Xerostomia and/or salivary gland hypofunction
Hyposalivation	Decreased salivary output (whole saliva flow rate of ≤0.1 mL/min of unstimulated saliva and <0.7 mL/min of stimulated saliva)
Salivary gland hypofunction	Decreased salivary output
Salivary gland dysfunction	Changes in quantity and/or quality of saliva

Administration of antiemetic agents for the management of chemotherapy-induced nausea and vomiting is related to several toxicities, including gastrointestinal, renal, hepatic, and cardiovascular adverse events.[22] Some of these agents are reported to induce xerostomia or salivary gland hypofunction. (See Table 4.)

Table 4. Antiemetic Agents Associated With Xerostomia or Salivary Gland Hypofunction

Pharmacological Class	Mechanism	Agents	References
5-HT3 = 5-hydroxytryptamine receptor 3; GABA = gamma-aminobutyric acid; NK-1 = neurokinin-1.
5-HT3 receptor antagonists	Serotonin reuptake inhibitor[22]	Granisetron	[23]
		Ondansetron	[24]
Dopamine antagonists	Blocks dopamine receptors	Prochlorperazine	[25]
		Metoclopramide	[25]
Atypical antipsychotics	Antagonist to dopamine, 5-HT, histamine, muscarinics, and alpha-1 adrenergic receptors[26]	Olanzapine	[27,28,29,30,31,32,33,34,35,36,37,38]
Cannabinoids	Stimulates receptors within the endocannabinoid system	Nabilone	[39,40,41]
Benzodiazepines	Serotonin reuptake inhibitor, GABA agonist[21,26]	Alprazolam	[42]
		Lorazepam	[43]
NK-1 receptor antagonists	Substance P binding inhibitor[22]	Rolapitant	[44]

For information about antiemetic therapy, and nausea and vomiting related to chemotherapy and radiation therapy, see Nausea and Vomiting Related to Cancer Treatment.

Oral and Dental Management After Chemotherapy

After cancer therapy, routine systematic oral hygiene is also important for reducing incidence and severity of oral sequelae, restoring functional and aesthetic impairments, and removing the remaining foci of infection.

References:

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42. Huber SJ, Paulson GW: Efficacy of alprazolam for essential tremor. Neurology 38 (2): 241-3, 1988.
43. Yamagishi H, Kawaguchi M: Characterization of central- and peripheral-type benzodiazepine receptors in rat salivary glands. Biochem Pharmacol 55 (2): 209-14, 1998.
44. Wang X, Zhang ZY, Wang J, et al.: Pharmacokinetics, Safety, and Tolerability of Rolapitant Administered Intravenously Following Single Ascending and Multiple Ascending Doses in Healthy Subjects. Clin Pharmacol Drug Dev 8 (2): 160-171, 2019.

Oral Management of Patients Receiving Hematopoietic Stem Cell Transplant

Hematopoietic stem cell transplant (HSCT) is a complex immune-based cellular therapy used to manage a wide range of malignant and nonmalignant conditions, including the following:[1]

• Blood cancers.
• Childhood immunodeficiency and metabolic disorders.
• Hemoglobinopathies.
• Autoimmune diseases.

Autologous transplant uses an individual's own isolated hematopoietic cells as a "graft" to reconstitute bone marrow function after an intensive chemotherapy regimen that would otherwise cause irreversible marrow toxicity. While recipients of autologous HSCT are at risk of anticipated toxicities of high-dose chemotherapy (e.g., neutropenia, thrombocytopenia, mucositis, and nausea and vomiting), they are not at risk of developing the immune-related complications frequently associated with allogeneic HSCT. Allogeneic HSCT similarly functions by engraftment and restoration of bone marrow function, but in the case of hematologic malignancies the graft also provides a graft-versus-tumor sustained immunological response. This response is important for maintaining long-term remission but is also associated with development of graft-versus-host disease (GVHD).

Recipients of HSCT have unique oral health needs and considerations that span from pre-HSCT workup through survivorship.[2,3,4,5,6,7] Management requires coordinated multidisciplinary care. See Table 1 for management before, during, and after HSCT.

Pretransplant Dental Evaluation

Patients undergoing HSCT experience long-term myelosuppression and immunosuppression. The oral cavity may be a potential source of local as well as systemic inflammation and infection. To reduce risk, patients should undergo a comprehensive dental evaluation by an experienced dentist before undergoing HSCT.[2,3,4,5]

The dental evaluation consists of the following:

• A thorough dental screening (caries, defective restorations, mobile teeth, teeth with deep pocketing, third molars, periapical pathology).
• A soft tissue examination.
• A full mouth series of intraoral radiographs (an orthopantomogram of the maxilla and mandible may be sufficient, and additional intraoral radiographs may be ordered, if necessary).

For children, oral care instructions and dental management are similar to those for adults.[3] When primary teeth with pulpal infection are involved, many clinicians choose to provide a more definitive treatment in the form of extraction. For more information, see the Special Considerations in Pediatric Populations section.

A dental evaluation is scheduled as early as possible to allow sufficient time to complete any necessary treatment and for tissues to heal after dental extractions and professional periodontal care. Patients who are thrombocytopenic and require invasive procedures, such as dental extractions, may require coordinated platelet transfusion support.

Table 5. Pretransplant Dental Evaluation

Finding	Management
Dental caries	Treat caries, provide endodontic therapy, or extract nonvital/abscessed teeth
Faulty or missing restorations	Replace restoration, eliminate sharp edges
Periapical pathology	Pulpitis: Provide endodontic treatment
	Periapical periodontitis >5 mm: Provide endodontic therapy or extraction
	No treatment necessary for previously endodontically treated teeth with persistent periapical pathology without evidence of infection
Periodontal disease	Perform scaling and root planing
	Extract symptomatic teeth, teeth with advanced mobility, teeth with probings >8 mm
Pericoronitis	Extract associated third molar
Prosthetic treatment	Ensure adequate fit and function

Oral Care During Transplant

Maintenance of good oral hygiene is essential to reduce the risk of infection.[2,5] Gingival inflammation caused by oral bacteria increases the risk of gingival bleeding and bacteremia. Oral hygiene aims to remove plaque from all surfaces of the teeth. A dental/oral self-examination should be performed daily. Patients need to brush their teeth two to three times a day to reduce dental plaque, using a soft manual or electric toothbrush and a fluoride toothpaste. If possible, the patient's teeth should be gently flossed daily. Removable dental prostheses are cleaned in a similar manner as teeth. Dentures are then placed in a cleaning solution overnight.

Bland oral rinses (0.9% saline and/or 0.5% sodium bicarbonate solution) can help remove debris and maintain moist and healthy mucosa, but they are not a substitute for mechanical cleaning. Chlorhexidine rinses are often prescribed for the duration of neutropenia. The nonalcoholic chlorhexidine digluconate (0.12%–0.2%) solution is easier to tolerate for patients with sensitive oral mucosa.

Mucositis

Oral mucositis is one of the most debilitating toxicities of stem cell transplant and requires a multidisciplinary approach.[6,7,8] For more information, see the Oral mucositis (high-dose chemotherapy, HSCT, head and neck radiation) section.

Oral infections

Infections are a frequent complication of HSCT during neutropenic periods. Infections may be fungal, viral, or bacterial. Coexistent oral conditions such as oral mucositis and GVHD often complicate prompt diagnosis of infections. For more information, see the Infection section.

Other common noninfectious oral findings

Hairy tongue is characterized by marked accumulation of keratin on the dorsum of the tongue, resulting in a hair-like appearance. This occurs largely because of limited oral intake, soft/liquid diet, and xerostomia. Similar hyperkeratosis (although not hair-like) may be observed on the hard palate and gingiva. Thrombocytopenia predisposes the oral mucosa to development of asymptomatic petechiae and ecchymoses and sometimes hematomas. The lesions may appear at the buccal mucosa, lateral tongue, and soft palate, secondary to chewing and swallowing, and resolve with the restoration of platelet count.

Oral Health After Transplant

Mouth care and dental care

Following hospital discharge after HSCT, patients are instructed to continue daily routine mouth care and see a dentist for a routine follow-up examination and dental prophylaxis approximately 6 months after a HSCT and every 6 months thereafter.[2,5][Level of evidence: IV]

GVHD

GVHD can be broadly classified as acute or chronic, with defining features being largely clinical rather than by time frame of onset.[9] (See Table 6 and Table 7.)

Table 6. Graft-Versus-Host Disease Classification

Category (Acute and Chronic)	Timing of Onset After HSCT or DLI	Presence of Acute GVHD Features	Presence of Chronic GVHD Features
DLI = donor lymphocyte infusion; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplant.
Classic acute GVHD	≤100 days	Yes	No
Late-onset acute GVHD	>100 days	Yes	No
Classic chronic GVHD	No time limit	No	Yes
Overlap syndrome	No time limit	Yes	Yes

Table 7. Clinical Features of Graft-Versus-Host Disease (GVHD)

System/Organ	Acute GVHD	Chronic GVHD
Eyes		Xerophthalmia
Mouth	Mucositis (nonspecific erythema multiforme–like), lip crusting	Lichen planus-like changes, xerostomia
Skin	Maculopapular rash, erythroderma with or without bulla	Poikiloderma, lichen planus-like changes, scleroderma, nail dystrophy
Gastrointestinal	Nausea, vomiting, diarrhea, anorexia
Liver	Elevated bilirubin levels
Lung		Bronchiolitis obliterans
Genital		Lichen planus-like changes

Acute GVHD

Acute GVHD typically occurs within the first 100 days and classically presents with skin, liver, and gastrointestinal tract involvement. Infrequently, the mouth can be affected, presenting with erythema multiforme-like features, including lip crusting and diffuse intraoral erythema and ulcerations.[10]

Chronic GVHD

Chronic GVHD, which affects 50% to 80% of allogeneic HSCT recipients, is an autoimmune-like condition characterized by chronic inflammation, fibrosis, disability, and diminished quality of life.[9,11] The oral cavity is commonly affected and is often the initial site of involvement. GVHD can persist in the oral cavity after it has resolved in other affected areas.

Clinical features of oral chronic GVHD

Oral mucosal involvement resembles oral lichen planus, with characteristic lacy white striations, erythema, and ulcerations.[10,11] Lesions can present on all oral mucosal surfaces but most frequently affect the buccal mucosa and tongue. Lip involvement can also be prominent, ranging from hyperkeratosis and dryness to extensive ulceration. Superficial mucoceles—characterized by small, transient, clear-fluid–filled vesicles—are particularly common on the palate, which has a high concentration of minor salivary gland tissue. While oral mucosal chronic GVHD can be painful at rest, the most common symptom is sensitivity, defined as oral discomfort with stimulation, typically with acidic, spicy, or strongly flavored items (e.g., mint, chocolate), as well as hard and crusty foods.

Chronic GVHD affecting the salivary glands resembles Sjögren syndrome, and affected patients frequently have concurrent involvement of the lacrimal glands and associated ocular chronic GVHD. In addition to experiencing symptoms of xerostomia, patients are at increased risk of developing dental caries and recurrent oral candidiasis. Oral mucosal sensitivity, even in the absence of mucosal lichenoid changes, is common.

Sclerodermatous chronic GVHD affecting the oral cavity is uncommon but can be debilitating. Patients with cutaneous, sclerodermatous chronic GVHD may have extension to the perioral tissues, leading to limited mouth opening, as seen in patients with progressive systemic sclerosis. Intraoral fibrosis can also occur, typically in patients with long-standing oral mucosal chronic GVHD. This condition presents with tight bands in the buccal mucosa. In addition to experiencing pain and disability, patients can have difficulty maintaining oral hygiene, and provision of dental care can be challenging.

Diagnosis and management of oral chronic GVHD

The presence of lacy white changes in the oral cavity is diagnostic for chronic GVHD, according to the National Institutes of Health Consensus.[11] Biopsy is rarely necessary for diagnosis. Ancillary management of oral mucosal chronic GVHD includes topical steroids and topical tacrolimus. Patients often avoid bothersome foods and drinks.[12]

Table 8. Management of Oral Chronic Graft-Versus-Host Disease^a

Oral Complications	Management Considerations	Long-Term Follow-Up Considerations
a Adapted from Rizzo et al.[13]and Carpenter et al.2014,[12]
Mucosal lichenoid changes	Topical corticosteroids	Increased risk of oral squamous cell carcinoma; cancer screening
	Intralesional corticosteroid therapy
	Topical tacrolimus
	Topical analgesics
	Children's toothpaste
	Avoidance of spicy, acidic, and hard/crunchy foods and drinks
Salivary gland hypofunction	Topical fluoride	Dental follow-up at least annually (risk of dental caries); monitoring of tooth development in children
	Sialogogue therapy
	Over-the-counter dry mouth products
	Sugar-free gum/candy
	Education regarding preventive practices
	Management of recurrent candidiasis
Sclerodermatous chronic graft-versus-host disease	Physical therapy

Other associated lesions

A wide range of oral mucosal lesions frequently arises in the context of chronic GVHD. These lesions include both benign (infectious and noninfectious) and malignant conditions.

Benign lesions

Herpes simplex virus and oral candidiasis can occur in the context of oral chronic GVHD owing to several factors, including generalized immunosuppression, salivary gland hypofunction, and the use of topical steroids. For more information, see the Infection section.

Malignant lesions

Recipients of allogeneic HSCT are at increased risk of various cancers. Posttransplant lymphoproliferative disease can present with oral features similar to those seen in other presentations of lymphoma (mass, ulceration), typically in the early posttransplant period. Patients with chronic GVHD are at increased risk of developing oral squamous cell carcinoma, with this risk increasing with time since HSCT. Cancerous and precancerous oral lesions can be difficult to distinguish from those of chronic GVHD.

Long-term follow-up

Recipients of HSCT (in particular, allogeneic HSCT) are encouraged to maintain good oral health and receive long-term oral health care.[3,13] Patients are instructed to brush and floss daily, and to visit a dentist at least every 6 months. Patients with GVHD and salivary hypofunction are at risk of developing dental caries and experiencing tooth loss. Children, especially those who were younger than 6 years at HSCT, are at risk of developmental abnormalities affecting the skeleton and teeth. There is a significantly increased risk of oral squamous cell carcinoma in allogeneic HSCT recipients, especially in those with a history of oral chronic GVHD.

Table 9. Diseases Commonly Treated With Hematopoietic Stem Cell Transplant^a

Indications	Autologous Transplant	Allogeneic Transplant
a Adapted from Copelan et al.[14].
Malignant indications	Multiple myeloma	Acute myeloid leukemia
	Non-Hodgkin lymphoma	Acute lymphoblastic leukemia
	Hodgkin disease	Chronic myeloid leukemia
	Neuroblastoma	Myelodysplastic syndromes
	Ovarian cancer	Myeloproliferative disorders
	Germ cell tumors	Non-Hodgkin lymphoma
		Hodgkin disease
		Chronic lymphocytic leukemia
		Multiple myeloma
Nonmalignant indications	Autoimmune diseases	Aplastic anemia
	Amyloidosis	Paroxysmal nocturnal hemoglobinuria
		Fanconi anemia
		Diamond-Blackfan anemia
		Thalassemia major
		Sickle cell anemia
		Severe combined immunodeficiency
		Wiskott-Aldrich syndrome
		Inborn errors of metabolism

References:

1. Majhail NS, Farnia SH, Carpenter PA, et al.: Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 21 (11): 1863-1869, 2015.
2. Elad S, Raber-Durlacher JE, Brennan MT, et al.: Basic oral care for hematology-oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT). Support Care Cancer 23 (1): 223-36, 2015.
3. Guideline on Dental Management of Pediatric Patients Receiving Chemotherapy, Hematopoietic Cell Transplantation, and/or Radiation Therapy. Pediatr Dent 38 (6): 334-342, 2016.
4. Bogusławska-Kapała A, Hałaburda K, Rusyan E, et al.: Oral health of adult patients undergoing hematopoietic cell transplantation. Pre-transplant assessment and care. Ann Hematol 96 (7): 1135-1145, 2017.
5. Bollero P, Passarelli PC, D'Addona A, et al.: Oral management of adult patients undergoing hematopoietic stem cell transplantation. Eur Rev Med Pharmacol Sci 22 (4): 876-887, 2018.
6. Lalla RV, Bowen J, Barasch A, et al.: MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 120 (10): 1453-61, 2014.
7. Sung L, Robinson P, Treister N, et al.: Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. BMJ Support Palliat Care 7 (1): 7-16, 2017.
8. Cinausero M, Aprile G, Ermacora P, et al.: New Frontiers in the Pathobiology and Treatment of Cancer Regimen-Related Mucosal Injury. Front Pharmacol 8: 354, 2017.
9. Lee SJ: Classification systems for chronic graft-versus-host disease. Blood 129 (1): 30-37, 2017.
10. Ion D, Stevenson K, Woo SB, et al.: Characterization of oral involvement in acute graft-versus-host disease. Biol Blood Marrow Transplant 20 (11): 1717-21, 2014.
11. Jagasia MH, Greinix HT, Arora M, et al.: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 21 (3): 389-401.e1, 2015.
12. Carpenter PA, Kitko CL, Elad S, et al.: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 21 (7): 1167-87, 2015.
13. Rizzo JD, Wingard JR, Tichelli A, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 37 (3): 249-61, 2006.
14. Copelan EA: Hematopoietic stem-cell transplantation. N Engl J Med 354 (17): 1813-26, 2006.

Oral Management of Patients Receiving Targeted Therapy / Cancer Immunotherapy

Targeted Therapy

Targeted therapy acts either directly on specific tissues, cells, and/or genes or indirectly on growth-related tissues and the nutrition of cancer cells. Antiangiogenesis therapies can suppress the formation of new blood vessels that nourish cancer tissue, preventing its growth.[1,2]

Table 10. Oral Management of Patients Receiving Targeted Cancer Therapy or Immunotherapy

Before Cancer Therapy	During Cancer Therapy	After Cancer Therapy
Document baseline oral mucosal status	Assess number and severity of oral mucosal lesions clinically documented to be caused by targeted therapy/immunotherapy	Monitor for possible late adverse oral effects
Provide patient education	Provide topical, intralesional, or systemic steroid treatment if oral pain is severe	Targeted therapy: Monitor for and treat gingival bleeding, necrotizing ulcerative gingivitis, stomatitis, aphthous-like ulcers, hyperkeratosis
		Immunotherapy: Monitor for and treat lichenoid reactions (ulcerative or reticular), benign membrane pemphigoid, xerostomia, taste changes
		Oral lesions are common for both classes of medications; consider in differential diagnosis of candidiasis and herpes simplex infections, medication-related osteonecrosis of the jaw

As with other cancer therapy modalities, targeted therapy has toxicities inherent to the drug group. Among the most significant side effects are the cutaneous adverse effects.[3][Level of evidence: IV] The oral side effects are seen in more than 20% of patients. In severe cases, there is an indication of dose reduction or permanent treatment discontinuation.[3,4,5]

Table 11. Oral Toxicities of Cancer Drugs

Cancer Drug	Oral Side Effects
EGFR = epidermal growth factor receptor; MRONJ = medication-related osteonecrosis of the jaw; mTOR = mechanistic target of rapamycin; PDGF = platelet-derived growth factor; VEGF = vascular endothelial growth factor.
mTOR[6,4,5,7,8,9]	Stomatitis, gingival bleeding, gingivitis, periodontal abscess, MRONJ, benign migratory glossitis, dysgeusia, xerostomia
EGFR[4,8]	Mucositis, dysgeusia, xerostomia
VEGF[4,5,10]	Gingival bleeding, MRONJ, mucositis, benign migratory glossitis
Sunitinib-VEGF receptors[4,5]	Gingival bleeding, painful soft tissue necrosis, MRONJ, altered taste, dry mouth, mucosal sensitivity, oral pain, oral mucositis/stomatitis, benign migratory glossitis, xerostomia
PDGF receptors[6,7]	Associated with MRONJ, liquenoid lesions, and necrosis
BRAF inhibitors[4,5]	MRONJ, hyperkeratotic lesions
Imatinib[4,8]	MRONJ, erythema and atrophy of tissue, pigmentary changes and lichenoid reaction, mucositis, dysgeusia

Cancer Immunotherapy

Immunotherapies have a different profile than targeted therapies and a new spectrum of toxicities compared with cytotoxic agents. The mechanism of action of immune checkpoint inhibitors involves triggering cytotoxic T-cell activation and inducing a specific toxicity profile that is primarily of immunologic origin. The most commonly reported immune-related systemic adverse events include the following:[11,12][Level of evidence: IV]

• Dermatitis.
• Enterocolitis.
• Liver toxicities.
• Endocrinopathies.
• Pneumonitis.
• Renal toxicity and other less common toxicities.

Reports of oral complications related to immunotherapies are sparse in the literature and most often include xerostomia, dysgeusia, and lichenoid reactions.[4,13] Other side effects are bullous skin eruptions. Two cases of Stevens-Johnson syndrome with severe hemorrhagic cheilitis and erosions have been reported.[14,15,16]

Table 12. Systemic and Oral Toxicities of Cancer Immunotherapy

Side Effects	Systemic Toxicities	Oral Toxicities
Acute side effects	Dermatitis	Lichenoid reactions; other immune-related lesions; xerostomia; taste changes; infections such as candidiasis and herpes simplex; osteonecrosis of the jaw
	Lichenoid lesions
	Bullous eruptions
	Stevens-Johnson syndrome
	Enterocolitis clinical expressed as diarrhea, liver toxicity
	Endocrinopathies such as hypophysitis, thyroiditis, uveitis, pneumonitis, renal toxicity, infections, neurological events
Delayed events	Pneumonitis

The largest reported series of oral immune-related lichenoid reactions included ten cases.[17] Four patients also showed skin, nail, or genital lesions. Tenderness and/or irritation and xerostomia were present in three patients. The lesions were self-limited and low grade, did not lead to discontinuation or interruption in oncologic treatment, and improved after several weeks of topical corticosteroid treatment. The authors reported that oral lichenoid reactions were common in their clinical practice.

Exacerbations of preexisting autoimmune disease have been reported and necessitated systemic treatment. A detailed history of preexisting autoimmune disease and vigilant clinical monitoring are important for these patients.[18,19,20,21]

Osteonecrosis related to immunotherapy alone has rarely been reported.[3,22] However, with the increasing use of combinations of medications, clinicians should remain alert for these complications.

Cancer immunotherapy can cause other side effects, which may be acute or delayed.

Consequences of cancer immunotherapy oral side effects and toxicities include the following:

• Therapy dose modifications or discontinuation.
• Inadequate food intake and diet changes.
• Poor oral health.
  • Risk of oral infections.
  • Increased dental caries.
  • Need for dental extractions.
• Weight loss.

Clinicians should be aware of immune-related oral adverse events. Routine evaluation of the oral cavity should be incorporated into the care of all patients, particularly those who are already at risk of oral complications—for example, patients with head and neck cancer who receive radiation therapy and patients who receive bone-targeting agents, targeted therapies (mainly inhibitors of angiogenesis), and other drugs.

Before targeted therapy/cancer immunotherapy

A patient's medical history report will disclose any preexisting autoimmune oral disease. As in any cancer therapy, oral and dental examination and stabilization are mandatory. Patient education on the importance of good oral health and oral hygiene is needed.[23,24,25]

During targeted therapy/cancer immunotherapy

Oral management during targeted therapy follows the same guidelines as those used for chronic graft-versus-host disease in patients with hematological conditions after bone marrow transplant.[23] Patients are encouraged to maintain good oral hygiene and to report any symptoms. If an oral lesion is suspected or diagnosed, the dentist will refer the patient to an oral oncology clinic and communicate this information to the treating oncologist. Early intervention and continued monitoring are required to limit exacerbation of the oral changes. Mucosal changes may be managed with topical anti-inflammatory agents. Severe cases may require systemic steroids. Dysplasia in lichenoid lesions is possible. If mucosal pain is present, topical analgesics may be considered. Dry mouth may include treatment with mouth-wetting agents and management of dental caries risk in the presence of hyposalivation, as well as prevention and management of oral candidiasis, herpes simplex, or other oral infections.[26]

After targeted therapy/cancer immunotherapy

Follow-up after targeted therapy or immunotherapy is important, as late adverse events may develop. The increased use of combination treatment may disclose new adverse events that have not yet been recognized.

Having an oral specialist on the oncology team greatly helps in the description, identification, early diagnosis, and timely and successful management of oral side effects related to immunotherapies alone or combined with other biological therapies.

References:

1. National Cancer Institute: Targeted Therapy to Treat Cancer. Bethesda, Md: National Institutes of Health, 2022. Available online. Last accessed Feb. 14, 2024.
2. Carrington C: Oral targeted therapy for cancer. Aust Prescr 38 (5): 171-6, 2015.
3. Nicolatou-Galitis O, Kouri M, Papadopoulou E, et al.: Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review. Support Care Cancer 27 (2): 383-394, 2019.
4. Vigarios E, Epstein JB, Sibaud V: Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer 25 (5): 1713-1739, 2017.
5. Lacouture M, Sibaud V: Toxic Side Effects of Targeted Therapies and Immunotherapies Affecting the Skin, Oral Mucosa, Hair, and Nails. Am J Clin Dermatol 19 (Suppl 1): 31-39, 2018.
6. Gomez-Fernandez C, Garden BC, Wu S, et al.: The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: a systematic review of the literature and meta-analysis. Eur J Cancer 48 (3): 340-6, 2012.
7. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, et al.: Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 17 (1): 135-44, 2012.
8. Watters AL, Epstein JB, Agulnik M: Oral complications of targeted cancer therapies: a narrative literature review. Oral Oncol 47 (6): 441-8, 2011.
9. Martins F, de Oliveira MA, Wang Q, et al.: A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol 49 (4): 293-8, 2013.
10. Nicolatou-Galitis O, Migkou M, Psyrri A, et al.: Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications. Oral Surg Oral Med Oral Pathol Oral Radiol 113 (2): 234-8, 2012.
11. Michot JM, Bigenwald C, Champiat S, et al.: Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54: 139-148, 2016.
12. Wang PF, Chen Y, Song SY, et al.: Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis. Front Pharmacol 8: 730, 2017.
13. Nikolaou V, Voudouri D, Tsironis G, et al.: Cutaneous toxicities of antineoplastic agents: data from a large cohort of Greek patients. Support Care Cancer 27 (12): 4535-4542, 2019.
14. Jour G, Glitza IC, Ellis RM, et al.: Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol 43 (8): 688-96, 2016.
15. Saw S, Lee HY, Ng QS: Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients. Eur J Cancer 81: 237-239, 2017.
16. Salati M, Pifferi M, Baldessari C, et al.: Stevens-Johnson syndrome during nivolumab treatment of NSCLC. Ann Oncol 29 (1): 283-284, 2018.
17. Sibaud V, Eid C, Belum VR, et al.: Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings. J Eur Acad Dermatol Venereol 31 (10): e464-e469, 2017.
18. Johnson DB, Sullivan RJ, Ott PA, et al.: Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Oncol 2 (2): 234-40, 2016.
19. Danlos FX, Voisin AL, Dyevre V, et al.: Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. Eur J Cancer 91: 21-29, 2018.
20. Ijaz A, Khan AY, Malik SU, et al.: Significant Risk of Graft-versus-Host Disease with Exposure to Checkpoint Inhibitors before and after Allogeneic Transplantation. Biol Blood Marrow Transplant 25 (1): 94-99, 2019.
21. Economopoulou P, Nicolatou-Galitis O, Kotsantis I, et al.: Nivolumab-related lichen planus of the lip in a patient with head and neck cancer. Oral Oncol 104: 104623, 2020.
22. Nifosì AF, Zuccarello M, Nifosì L, et al.: Osteonecrosis of the jaw in the era of targeted therapy and immunotherapy in oncology. J Korean Assoc Oral Maxillofac Surg 45 (1): 3-8, 2019.
23. Epstein JB, Smutzer G, Doty RL: Understanding the impact of taste changes in oncology care. Support Care Cancer 24 (4): 1917-31, 2016.
24. Elad S, Jensen SB, Raber-Durlacher JE, et al.: Clinical approach in the management of oral chronic graft-versus-host disease (cGVHD) in a series of specialized medical centers. Support Care Cancer 23 (6): 1615-22, 2015.
25. Elad S, Raber-Durlacher JE, Brennan MT, et al.: Basic oral care for hematology-oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT). Support Care Cancer 23 (1): 223-36, 2015.
26. Rapoport BL, van Eeden R, Sibaud V, et al.: Supportive care for patients undergoing immunotherapy. Support Care Cancer 25 (10): 3017-3030, 2017.

Orofacial Pain in Patients With Cancer

Orofacial pain may be present throughout the cancer continuum. In patients with head and neck cancer (HNC), orofacial pain has been reported to be as high as 85% at the time of cancer diagnosis.[1];[2][Level of evidence: II][3]

Orofacial pain is frequently associated with locoregional cancer, but it can also be a sign of systemic and distant cancers. It may arise from the onset of the disease and develops as the disease progresses. Orofacial pain is also highly associated with acute-treatment side effects and may continue after treatment ends due to persistence, recurrence, or metastasis of the primary cancer or acute and chronic toxicities of cancer therapy.[4] It is important to recognize not only the diverse symptoms of orofacial pain in patients with cancer, but also pain's significant impact on their quality of life.

The management of head and neck pain and oral and oropharyngeal pain may be particularly challenging because the area is a highly innervated sensory region, and eating, speech, swallowing, and other motor functions of the head and neck and oropharynx are constant pain triggers. Classification of head and neck pain can assist in management.[5]

For more information on pain in patients with cancer, see Cancer Pain.

Orofacial Pain Caused by Cancer Persistence, Recurrence, or Metastasis

Etiology and epidemiology

Pain caused by cancer is often low intensity, but it typically becomes more frequent and increasingly severe with advancing disease. Cancer pain may be caused by local tumor effects via direct invasion of adjacent structures, leading to pressure, ulceration, tissue necrosis, and perineural invasion.[6,7]

Pain may also be aggravated by distant tumors or systemic cancer activity (e.g., blood and lymphatic cancers) due to nociceptive, inflammatory, and neuropathic mechanisms. For instance, oral manifestations of blood cancers such as leukemia, lymphoma, and multiple myeloma may cause pain and loss of function by infiltrating pain-sensitive structures [5] or inducing secondary oral infections due to a compromised immune system.[8] Furthermore, intracranial malignancies may give rise to orofacial pain and headaches due to pressure or infiltration of specific brain centers and structures.

Signs and symptoms

In the orofacial region, pain may present similarly to classic trigeminal neuralgia/neuropathic pain or musculoskeletal temporomandibular disorders. Symptoms range from acute, localized, sharp shooting episodes to chronic, diffuse, pressing, and aching pain.[5]

Patients with nasopharyngeal and oropharyngeal cancer may report pain in the temporomandibular joint region with limited mouth opening; ear blockage, ringing, or pain; headaches; facial numbness; and masticatory muscle stiffness. These signs and symptoms may result from direct tumor invasion or represent a pattern of referred pain that can masquerade as a temporomandibular joint disorder.[9,10]

Paraneoplastic neuropathies may present in cancer patients, particularly those with lung cancer or lymphoma.[11,12][Level of evidence: IV] This effect may manifest as difficulty swallowing, slurred speech, disturbed vision, seizures, facial muscle weakness, stiffness, or unusual involuntary contractions.[12][Level of evidence: IV]

Diagnosis and management strategies

Meticulous clinical examination is a critical step in reporting orofacial pain or dysfunction. Pain can be reported in any structure of the craniofacial region, such as a toothache or pain in the gingiva, tongue, face, neck, ear, and pharynx.[6] Management relies mainly on treating the malignancy. Since pain caused by cancer therapy is common, further pharmacotherapeutics and supportive treatment regimens may be needed. For more information on pharmacotherapeutic interventions and supportive regimens, see the Diagnostic investigations and management strategies section.

Orofacial Pain Caused by Cancer Management

Etiology and epidemiology

While surgical resection provides near complete relief of HNC-related pain, some patients require adjuvant therapies such as chemotherapy (i.e., cytotoxic agents and targeted biological agents) and/or radiation therapy to further combat the disease.[13][Level of evidence: IV] Other cancer patients may be restricted to nonsurgical interventions because of the type or extent of their cancers. Stem cell transplant, another approach for managing hematologic malignancies, can involve chemotherapy and/or total body radiation as part of the management regimen. These surgical and nonsurgical interventions, especially concomitant chemoradiotherapy, are tied to short- and long-lasting painful complications that may affect patient well-being and quality of life.[5]

More than 70% of patients with HNC report variable forms of pain during and after their cancer therapy.[5]

Signs and symptoms

Pain associated with surgical interventions

For patients with HNC undergoing surgical interventions, acute nociceptive regional orofacial pain, scar formation, and sensory impairment are inevitable. These complications increase dramatically with concomitant procedures, such as neck dissection, and may evolve to long-term, painful, postsurgical fibrosis and neuropathy.[5] Fifty percent to 90% of patients who undergo mandibulectomy or maxillectomy have regional hyperalgesia and allodynia. Pain scores following HNC surgery are the highest for the oral cavity, followed by the larynx, oropharynx, and nasopharynx. The most common locations for orofacial pain complaints are the oral cavity, followed by the temporomandibular joint, face, neck, and shoulders.[5] Musculoskeletal syndromes, including temporomandibular disorders associated with muscular fibrosis and limited jaw opening, lead to significant pain and loss of orofacial function. The persistence of these complications may severely impact cancer survivors' quality of life and well-being.[14][Level of evidence: II];[15]Level of evidence: IV

Pain associated with chemotherapy and radiation therapy

Orofacial pain as a result of cancer chemotherapy and radiation therapy is a well-recognized complication that may longitudinally affect cancer survivors' quality of life.[1,4,16,17] Generally, 60% to 80% of cancer patients experience pain during these interventions, with a significant number continuing to struggle from long-term, persistent pain complaints after the completion of therapy.[18]

Severe peripheral neurotoxicity leads to neuropathic orofacial pain, changes in taste, and loss of sensory perception and motor coordination. Localized oral burning pain, comparable to burning mouth syndrome, can also occur. Cytotoxic effects of chemotherapy and radiation therapy may cause oral mucositis. For more information, see the Oral mucositis (high-dose chemotherapy, HSCT, head and neck radiation) section. Oral ulcerations due to neutropenia or oral bacterial, fungal, and viral infections are other examples of common, acute, painful complications encountered during and after anticancer therapy.[13,19] In addition, compromised immune function may lead to reactivation of dormant herpes viruses, causing painful oral and para-oral lesions. Postherpetic neuralgia, if emerged, can cause chronic dysesthesias in the affected area that may persist for years.[20] Moreover, hyposalivation, especially in those receiving head and neck radiation, may enhance susceptibility to oral candidiasis and rampant caries.[21][Level of evidence: II]

Several targeted biological agents, such as tyrosine-kinase inhibitors and immune checkpoint inhibitors, have proven efficacy in managing patients with cancer. In the orofacial pain region, these therapies may cause taste alterations, aphthous-like ulceration, and mucosal lichenoid reactions.[22][Level of evidence: III];[23] Combinations of multiple agents may result in increasingly complex mucosal changes and related symptoms.[5,22] For more information, see the Oral management during targeted therapy/cancer immunotherapy section.

When they occur during cancer therapy, these complications can negatively affect patients' nutritional status and lead to undesired interruption or reduction of the dose or frequency of the cancer treatment regimen.[17,24] Furthermore, the long-term impact of anticancer therapy may significantly compromise the physical, psychological, and financial well-being of cancer survivors.[25,26,27][Level of evidence: II]

Pain associated with stem cell transplant therapy

Graft-versus-host disease is a common complication of allogeneic hematopoietic stem cell transplant, occurring in 25% to 70% of patients and presenting in both acute and chronic forms. Head and neck involvement is manifested as mucosal striation/ulceration, superficial mucocele, and temporomandibular joint arthritic dysfunction that are often painful.[20,28] Additionally, increased thermal sensitivity has been observed in patients being treated with cyclosporine after their hematopoietic stem cell transplants.[29][Level of evidence: III]

Oral mucositis

For information on oral mucositis, see the Oral mucositis (high-dose chemotherapy, HSCT, head and neck radiation) section.

Diagnostic investigations and management strategies

As cancer pain is mixed in nature and presentation, specific screening and assessment questionnaires are useful in differentiating nociceptive and neuropathic pain and help to better manage orofacial pain. In the oncology setting, it is important that a thorough health history and oral physical examination be performed when oral pain is present. The role of routine high-maintenance levels of oral hygiene cannot be understated. Radiographic imaging and vitality testing of the dental pulp are typically necessary.[13]

Persistent neuropathies are a common complication after HNC surgical interventions and radiation therapies.[13,30] Selected classes of chemotherapy, such as vinca alkaloids, vincristine, vinblastine, platinum-based drugs, taxanes, and targeted biological agents, can also cause direct neurotoxicity.[13,31] Additionally, drugs such as thalidomide and lenalidomide are associated with peripheral neuropathies that can affect the orofacial region. Deeply-seated mandibular pain may be of dental etiology as a consequence of pulpal neurotoxicity or necrosis.

Management of neuropathic orofacial pain is complex and challenging, often involving centrally and peripherally acting pharmacotherapeutic agents. Topical and systemic gabapentinoids, membrane stabilizers, small doses of tricyclic antidepressants, selective serotonin-norepinephrine reuptake inhibitors, vanilloid receptor inhibitors, and cannabinoids are often prescribed.[32][Level of evidence: I];[33][Level of evidence: IV];[34,35] Supportive approaches such as counseling, acupuncture, photobiomodulation, and neurosensory stents may also be considered. Preventive measures such as physical shielding and cryotherapy should be considered before and during anticancer therapy to reduce cytotoxic and neurotoxic outcomes.[36]

Dental hypersensitivity may occasionally arise in the weeks or months after the discontinuation of chemotherapy and/or radiation therapy.[13] Topical application of fluorides and desensitizing agents may ameliorate dental discomfort.[13] In most instances, thermal sensitivity observed in patients who received hematopoietic stem cell transplant is self-resolving after discontinuation of cyclosporine.[29][Level of evidence: III]

Patients may also experience musculoskeletal pain and dysfunction involving muscles of mastication, the neck, and/or the temporomandibular joints.[37] These conditions may be further aggravated by stress, sleep disturbance, and parafunctional habits (i.e., bruxism and clenching) after treatment of HNC.[38][Level of evidence: IV] Physical management of orofacial pain, including cold compresses or moist heat combined with physical therapy, custom occlusal splints, and masticatory/neck muscle exercises, help significantly. Judicious use of muscle relaxants or anxiolytic agents can be considered. Acupuncture, transcutaneous nerve stimulation, low-level laser use, and massage therapy are adjuvant modalities to alleviate pain in patients with cancer.[39,40][Level of evidence: I];[41][Level of evidence: I] For more information, see Acupuncture.

Additionally, psychological approaches such as counseling, distraction, relaxation techniques, biofeedback, group therapy, self-hypnosis, imagery, and cognitive behavioral training programs have shown promising results in randomized clinical trials.[39,42][Level of evidence: I];[43][Level of evidence: I]

References:

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2. Carpén T, Sjöblom A, Lundberg M, et al.: Presenting symptoms and clinical findings in HPV-positive and HPV-negative oropharyngeal cancer patients. Acta Otolaryngol 138 (5): 513-518, 2018.
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4. Saunders DP, Rouleau T, Cheng K, et al.: Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer 28 (5): 2473-2484, 2020.
5. Epstein JB, Miaskowski C: Oral Pain in the Cancer Patient. J Natl Cancer Inst Monogr 2019 (53): , 2019.
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8. Silva TD, Ferreira CB, Leite GB, et al.: Oral manifestations of lymphoma: a systematic review. Ecancermedicalscience 10: 665, 2016.
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12. Zoccarato M, Grisold W, Grisold A, et al.: Paraneoplastic Neuropathies: What's New Since the 2004 Recommended Diagnostic Criteria. Front Neurol 12: 706169, 2021.
13. Sroussi HY, Epstein JB, Bensadoun RJ, et al.: Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer Med 6 (12): 2918-2931, 2017.
14. Pauli N, Mejersjö C, Fagerberg-Mohlin B, et al.: Temporomandibular disorder in head and neck cancer patients undergoing radiotherapy: Clinical findings and patient-reported symptoms. Head Neck 41 (10): 3570-3576, 2019.
15. Nicot R, Raoul G, Ferri J, et al.: Temporomandibular disorders in head and neck cancers: Overview of specific mechanisms and management. J Stomatol Oral Maxillofac Surg 121 (5): 563-568, 2020.
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18. Mirabile A, Airoldi M, Ripamonti C, et al.: Pain management in head and neck cancer patients undergoing chemo-radiotherapy: Clinical practical recommendations. Crit Rev Oncol Hematol 99: 100-6, 2016.
19. Binczak M, Navez M, Perrichon C, et al.: Management of somatic pain induced by head-and-neck cancer treatment: definition and assessment. Guidelines of the French Oto-Rhino-Laryngology- Head and Neck Surgery Society (SFORL). Eur Ann Otorhinolaryngol Head Neck Dis 131 (4): 243-7, 2014.
20. Vickers ER, Karsten E, Flood J, et al.: A preliminary report on stem cell therapy for neuropathic pain in humans. J Pain Res 7: 255-63, 2014.
21. Lin A, Helgeson ES, Treister NS, et al.: The impact of head and neck radiotherapy on salivary flow and quality of life: Results of the ORARAD study. Oral Oncol 127: 105783, 2022.
22. Shazib MA, Woo SB, Sroussi H, et al.: Oral immune-related adverse events associated with PD-1 inhibitor therapy: A case series. Oral Dis 26 (2): 325-333, 2020.
23. Carrozzo M, Eriksen JG, Bensadoun RJ, et al.: Oral Mucosal Injury Caused by Targeted Cancer Therapies. J Natl Cancer Inst Monogr 2019 (53): , 2019.
24. Hunter M, Kellett J, Toohey K, et al.: Toxicities Caused by Head and Neck Cancer Treatments and Their Influence on the Development of Malnutrition: Review of the Literature. Eur J Investig Health Psychol Educ 10 (4): 935-949, 2020.
25. Han X, Zhao J, Zheng Z, et al.: Medical Financial Hardship Intensity and Financial Sacrifice Associated with Cancer in the United States. Cancer Epidemiol Biomarkers Prev 29 (2): 308-317, 2020.
26. Yabroff KR, Bradley C, Shih YT: Understanding Financial Hardship Among Cancer Survivors in the United States: Strategies for Prevention and Mitigation. J Clin Oncol 38 (4): 292-301, 2020.
27. Utley M, Adeyanju T, Bernardo B, et al.: The association between mental health, social support and physical health outcomes among older female cancer survivors. J Geriatr Oncol 13 (6): 834-838, 2022.
28. Fall-Dickson JM, Pavletic SZ, Mays JW, et al.: Oral Complications of Chronic Graft-Versus-Host Disease. J Natl Cancer Inst Monogr 2019 (53): , 2019.
29. Epstein JB, Raber-Durlacher JE, Epstein GL, et al.: Chronic oral graft-versus-host disease: induction and maintenance therapy with photobiomodulation therapy. Support Care Cancer 29 (3): 1387-1394, 2021.
30. Van den Bosch L, van der Schaaf A, van der Laan HP, et al.: Comprehensive toxicity risk profiling in radiation therapy for head and neck cancer: A new concept for individually optimised treatment. Radiother Oncol 157: 147-154, 2021.
31. Brook I: Early side effects of radiation treatment for head and neck cancer. Cancer Radiother 25 (5): 507-513, 2021.
32. Smith DK, Cmelak A, Niermann K, et al.: Preventive use of gabapentin to decrease pain and systemic symptoms in patients with head and neck cancer undergoing chemoradiation. Head Neck 42 (12): 3497-3505, 2020.
33. Häuser W, Finn DP, Kalso E, et al.: European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management. Eur J Pain 22 (9): 1547-1564, 2018.
34. Häuser W, Finnerup NB, Moore RA: Systematic reviews with meta-analysis on cannabis-based medicines for chronic pain: a methodological and political minefield. Pain 159 (10): 1906-1907, 2018.
35. Mücke M, Phillips T, Radbruch L, et al.: Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 3 (3): CD012182, 2018.
36. de Pauli Paglioni M, Alves CGB, Fontes EK, et al.: Is photobiomodulation therapy effective in reducing pain caused by toxicities related to head and neck cancer treatment? A systematic review. Support Care Cancer 27 (11): 4043-4054, 2019.
37. Brook I: Late side effects of radiation treatment for head and neck cancer. Radiat Oncol J 38 (2): 84-92, 2020.
38. Buglione M, Cavagnini R, Di Rosario F, et al.: Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: Xerostomia and trismus (Part 2). Literature review and consensus statement. Crit Rev Oncol Hematol 102: 47-54, 2016.
39. Bennett MI, Eisenberg E, Ahmedzai SH, et al.: Standards for the management of cancer-related pain across Europe-A position paper from the EFIC Task Force on Cancer Pain. Eur J Pain 23 (4): 660-668, 2019.
40. Wan Q, Chen H, Wang X, et al.: Effectiveness of different acupuncture therapies for chronic cancer pain: A protocol for systematic review and Bayesian network meta-analysis. Medicine (Baltimore) 101 (4): e27965, 2022.
41. Dymackova R, Selingerova I, Kazda T, et al.: Effect of Acupuncture in Pain Management of Head and Neck Cancer Radiotherapy: Prospective Randomized Unicentric Study. J Clin Med 10 (5): , 2021.
42. Abbas Q, Arooj N, Baig KB, et al.: A clinical trial of cognitive behavior therapy for psychiatric comorbidity and quality of life with Cancer Patients during Chemotherapy (CPdC). BMC Psychiatry 22 (1): 222, 2022.
43. Okuyama T, Akechi T, Mackenzie L, et al.: Psychotherapy for depression among advanced, incurable cancer patients: A systematic review and meta-analysis. Cancer Treat Rev 56: 16-27, 2017.

Infection

The intactness of skin and mucosa are physical barriers to infection. The epithelium of the oral mucosa impedes the attachment of pathogenic organisms by shedding dead cells and pathogens. This process limits the penetration of many compounds into the epithelium by maintaining a chemical barrier of antimicrobial molecules. These molecules are part of salivary protection and saliva, which are also responsible for protectively cleaning the teeth and mucosa and maintaining neutral pH, and lubrication.[1]

Oral infections in cancer patients could be caused by a preexisting acute oral infection before the therapy is administered; therefore, control and elimination of these infections play a crucial role.[2] Other infections typically arise in the setting of the immunocompromised host response during therapy.

Oral mucositis is a common complication of cancer therapy. In addition to causing severe pain and nutritional impairment, there is an increased risk of local and systemic infections.[3] Oral mucositis can be complicated by infection in immunocompromised patients. Importantly, disruption of the oral mucosa provides a major route of entry for pathological microorganisms. This situation can lead to various infections, including fatal septicemia.[4] For more information, see the Oral mucositis (high-dose chemotherapy, HSCT, head and neck radiation) section.

Both indigenous oral flora and hospital-acquired pathogens have been associated with bacteremias and systemic infection. As the absolute neutrophil count falls below 1,000/µL, the incidence and severity of infection rise. Patients with prolonged neutropenia are at higher risk of developing serious infectious complications. The rate and severity of these infections mostly depend on prolonged periods of neutropenia (more than 7 days).[5][Level of evidence: IV] Compromised salivary function and poor oral hygiene alter oral microbial flora and increase oral microbial load, making patients susceptible to opportunistic bacterial, viral, and fungal infections. Patients have a higher risk of developing odontogenic infections if they do not receive prompt care for any dental or periodontal disorder.[6]

Other oral sites, including the dentition, periapices, and periodontium, can also become acutely infected during myelosuppression secondary to high-dose chemotherapy.[2]

A literature search was conducted in the MEDLINE/PubMed and EMBASE databases for articles published between 2009 and 2016. Dental-related infections and abscesses during cancer therapy (primarily antineoplastic chemotherapy) were reported in six studies. The mean weighted prevalence was 5.4% (standard of error, 1.16; 95% confidence interval, 3.14–7.7).[7]

Dental management undertaken before cytoreductive therapy can substantially reduce the risk of infectious complications.[2] Researchers have shifted toward the idea that if there is a close relationship between the dental and oncology team, clearance of only acute infection before cancer therapy has similar results as completed dental management regarding oral infection during myelosuppression.[8][Level of evidence: II];[2,9][Level of evidence: III]

Bacterial Infections

Changes in infection profiles in patients with cancer-related myelosuppression have occurred over the past three decades. Multiple factors have caused this evolving epidemiology, including the use of prophylactic and therapeutic antimicrobial regimens and decreased depth and duration of myelosuppression.[10] Gram-positive organisms, including Viridans streptococci and Enterococci species, are associated with systemic infection of oral origin. In addition, gram-negative pathogens, including Pseudomonas aeruginosa, Neisseria species, and Escherichia coli, remain a concern.

Myeloablated cancer patients with chronic periodontal disease may develop acute periodontal infections, with associated systemic sequelae.[11,12,13]

Pulpal/periapical infections of dental origin can cause complications for the chemotherapy patient and need to be resolved before chemotherapy begins.[14,15]

Fungal Infections

Candidiasis

Candidiasis is typically caused by opportunistic overgrowth of Candida albicans, a normal inhabitant of the oral cavity in many individuals. Several variables contribute to its clinical expression, including drug- or disease-induced immunosuppression, mucosal injury, and salivary compromise. In addition, the use of antibiotics may alter the oral flora, creating a favorable environment for fungal overgrowth.[16,17][Level of evidence: IV]

The weighted mean prevalence of clinical oral fungal infection during chemotherapy or head and neck radiation therapy was found to be 31% in a retrospective multicenter study.[18][Level of evidence: III] The appearance of erythematous candidiasis is relatively nonspecific, and laboratory testing may be needed to confirm the diagnosis. It may be accompanied by a burning sensation of the affected tissues.[16]

Although topical agents may be helpful for superficial oral candidiasis, systemic agents are used for persistent fungal infections and in patients with significant immunosuppression. Systemic fluconazole is highly effective for prophylaxis and treatment of oral fungal infections in the oncology population.[19][Level of evidence: II];[20][Level of evidence: III]

Noncandidal fungal infections

Although most oral fungal infections involve Candida, there are occasional case reports of other oral fungal infections in immunosuppressed populations, including cancer patients. For example, a few cases of oral mucormycosis have been reported in patients with hematologic malignancies who receive a bone marrow transplant.[21] Such noncandidal oral fungal infections carry a high risk of fungemia and mortality in immunocompromised patients; systemic antifungal therapy must be promptly initiated.

Viral Infections

Herpes virus

Herpes group viral infections, including those caused by oral lesions, can cause a variety of diseases that range from mild to serious in patients undergoing treatment for cancer. The severity and impact of these lesions and systemic sequelae are directly related to the patient's extent of immunocompromise. Comorbid oral conditions such as mucositis or graft-versus-host disease can dramatically increase the severity of oral lesions and significantly increase the difficulty of diagnosis.

A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology.[22] Eighteen of 41 studies focused on outcome measures in preventing oral viral infection. This review reported findings to confirm the use of acyclovir and valacyclovir in preventing and treating oral herpetic infections.

Early diagnosis and prompt therapy remain hallmarks of management. As with other infections, the risk of systemic dissemination and morbidity/mortality increases with the degree and duration of immunocompromise. The infections can be fatal, depending on the degree of immunosuppression.

Herpes simplex virus (HSV)

Oral herpetic lesions can range from routine herpes labialis to severe stomatitis causing large, painful ulcerations throughout the mouth. Lesion severity increases with higher degrees of immunosuppression.

The introduction of valacyclovir appears to have reduced the incidence of breakthrough oral HSV infections. Topical therapy alone is generally not efficacious in patients who are immunocompromised.

In patients who are not receiving antiviral prophylaxis, oral lesions typically emerge concurrent with chemotherapy or chemoradiation therapy during the period of most significant immunosuppression (white blood cell nadir). Typically, in patients receiving a hematopoietic stem cell transplant, this represents the period a few days pretransplant through day 35 posttransplant. The risk of HSV reactivation remains higher than normal until immune reconstitution occurs. Similar patterns of risk are noted in patients receiving high-dose (immunosuppressive) chemotherapy.

Recurrent oral HSV infections occurring simultaneously with cancer therapy–induced oral mucositis can result in the development of extensive, confluent mucosal ulcerations clinically similar to primary herpetic stomatitis. Thus, HSV stomatitis can be confused with cancer therapy–induced ulcerative mucositis. Viral cultures from lesions in HSV-seropositive patients are essential for accurate diagnoses. Assays that produce more rapid results, including direct immunofluorescence, shell vial testing, and specific immunoassays for HSV antigen and/or biopsy, may also be useful.

Varicella-zoster virus (VZV)

VZV infection classically distributes via dermatomes, although the clinical manifestations can be altered in immunocompromised patients, and multiple dermatomes or more widespread distribution of lesions can be seen. In patients who are receiving high-dose chemotherapy, orofacial VZV lesions are typically observed several weeks after cessation of chemotherapy—unlike HSV, which often occurs within 2 to 3 weeks after chemotherapy is discontinued.

Cytomegalovirus

Oral lesions associated with cytomegalovirus have been documented in immunocompromised patients, including those who have undergone a bone marrow transplant.[23][Level of evidence: IV]

Appearance is not pathognomonic and is characterized by multiple mild to moderate ulcerations with irregular margins. The lesions initially present during early periods of marrow regeneration (e.g., 3 weeks after chemotherapy is discontinued) and are characterized by nonspecific pseudomembranous fibrin exudate–covered ulcerations with a granulomatous-appearing base. Surface swab cultures may yield false-negative results, perhaps because of viral propensity for infecting endothelial cells and fibroblasts, resulting in low levels of free virus.

Epstein-Barr virus (EBV)

EBV is linked to tumor development. In addition, oral hairy leukoplakia has been attributed to EBV infection in immunocompromised patients, as seen in HIV-infected patients and solid organ transplant patients. However, the lesion does not appear to be clinically significant in chemotherapy recipients.

Non–herpes group virus infections

Infections caused by non–herpes group viruses are more common in immunocompromised patients, with the risk of infection apparently increasing with the depth and duration of immunosuppression. Oral lesions caused by adenovirus and oral human papillomavirus (HPV) have been described.[23][Level of evidence: IV] Often, patients with increased cutaneous HPV lesions will develop oral lesions. These lesions can present as hyperkeratotic verrucoid lesions or as flat acuminata-like lesions.

Restoration of immune function often results in a digression and, possibly, the disappearance of the oral mucosal lesions. Laser surgery or cryotherapy are typically used to remove oral HPV lesions when medically or cosmetically required. Intralesional injections of interferon-alpha may prove effective for recurrent lesions. Infection with coxsackie viruses can occur but is generally uncommon. Although adenovirus infections are often implicated as a potential cause of oral lesions, their true incidence is not known.[23][Level of evidence: IV]

References:

1. Pedersen AML, Sørensen CE, Proctor GB, et al.: Salivary secretion in health and disease. J Oral Rehabil 45 (9): 730-746, 2018.
2. Spijkervet FKL, Schuurhuis JM, Stokman MA, et al.: Should oral foci of infection be removed before the onset of radiotherapy or chemotherapy? Oral Dis 27 (1): 7-13, 2021.
3. de Oliveira MCQ, Lebre Martins BNF, Santos-Silva AR, et al.: Dental treatment needs in hospitalized cancer patients: a retrospective cohort study. Support Care Cancer 28 (7): 3451-3457, 2020.
4. Hong BY, Sobue T, Choquette L, et al.: Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis. Microbiome 7 (1): 66, 2019.
5. Ullmann AJ, Schmidt-Hieber M, Bertz H, et al.: Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016. Ann Hematol 95 (9): 1435-55, 2016.
6. Villa A, Akintoye SO: Dental Management of Patients Who Have Undergone Oral Cancer Therapy. Dent Clin North Am 62 (1): 131-142, 2018.
7. Hong CHL, Hu S, Haverman T, et al.: A systematic review of dental disease management in cancer patients. Support Care Cancer 26 (1): 155-174, 2018.
8. Kishimoto M, Akashi M, Tsuji K, et al.: Intensity and duration of neutropenia relates to the development of oral mucositis but not odontogenic infection during chemotherapy for hematological malignancy. PLoS One 12 (7): e0182021, 2017.
9. Mauramo M, Grolimund P, Egli A, et al.: Dissociations of oral foci of infections with infectious complications and survival after haematopoietic stem cell transplantation. PLoS One 14 (12): e0225099, 2019.
10. Castagnola E, Mikulska M, Viscoli C: Prophylaxis and Empirical Therapy of Infection in Cancer Patients. In: Bennett JE, Dolin R, Blaser MJ, eds.: Principles and Practice of Infectious Diseases. 8th ed.: Elsevier, Inc., 2015, Elsevier, Inc., 2015, pp 3395-413. Available online. Last accessed October 10, 2023.
11. Ohbayashi Y, Imataki O, Uemura M, et al.: Oral microorganisms and bloodstream infection in allogeneic hematopoietic stem cell transplantation. Clin Oral Investig 25 (7): 4359-4367, 2021.
12. Zecha JAEM, Raber-Durlacher JE, Laheij AMGA, et al.: The impact of the oral cavity in febrile neutropenia and infectious complications in patients treated with myelosuppressive chemotherapy. Support Care Cancer 27 (10): 3667-3679, 2019.
13. Decker AM, Taichman LS, D'Silva NJ, et al.: Periodontal Treatment in Cancer Patients: An Interdisciplinary Approach. Curr Oral Health Rep 5 (1): 7-12, 2018.
14. Bogusławska-Kapała A, Hałaburda K, Rusyan E, et al.: Oral health of adult patients undergoing hematopoietic cell transplantation. Pre-transplant assessment and care. Ann Hematol 96 (7): 1135-1145, 2017.
15. Bollero P, Passarelli PC, D'Addona A, et al.: Oral management of adult patients undergoing hematopoietic stem cell transplantation. Eur Rev Med Pharmacol Sci 22 (4): 876-887, 2018.
16. Hellstein JW, Marek CL: Candidiasis: Red and White Manifestations in the Oral Cavity. Head Neck Pathol 13 (1): 25-32, 2019.
17. Lewis MAO, Williams DW: Diagnosis and management of oral candidosis. Br Dent J 223 (9): 675-681, 2017.
18. Nishii M, Soutome S, Kawakita A, et al.: Factors associated with severe oral mucositis and candidiasis in patients undergoing radiotherapy for oral and oropharyngeal carcinomas: a retrospective multicenter study of 326 patients. Support Care Cancer 28 (3): 1069-1075, 2020.
19. Singh GK, Capoor MR, Nair D, et al.: Spectrum of fungal infection in head and neck cancer patients on chemoradiotherapy. J Egypt Natl Canc Inst 29 (1): 33-37, 2017.
20. Kawashita Y, Funahara M, Yoshimatsu M, et al.: A retrospective study of factors associated with the development of oral candidiasis in patients receiving radiotherapy for head and neck cancer: Is topical steroid therapy a risk factor for oral candidiasis? Medicine (Baltimore) 97 (44): e13073, 2018.
21. Cheong HS, Kim SY, Ki HK, et al.: Oral mucormycosis in patients with haematologic malignancies in a bone marrow transplant unit. Mycoses 60 (12): 836-841, 2017.
22. Elad S, Zadik Y, Hewson I, et al.: A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea. Support Care Cancer 18 (8): 993-1006, 2010.
23. Schubert MM, Correa MEP, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Forman SJ, Negrin RS, Antin JH, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 5th ed. John Wiley & Sons, Ltd, 2016, pp 1242-56.

Hemorrhage

Hemorrhage is a concern for patients who are receiving high-dose chemotherapy or undergoing hematopoietic stem cell transplant. It may occur during treatment-induced thrombocytopenia and/or coagulopathy.[1] Spontaneous gingival oozing may occur when platelet counts drop below 20,000/µL, especially when there is preexisting gingivitis or periodontitis. Even normal function or routine oral hygiene (brushing and flossing) can induce gingival oozing with preexisting gingivitis and periodontitis, compounded by hematologic change and biochemical changes in coagulation. Management requires attention by a multidisciplinary team to local measures, platelet count and function, and coagulation.

Although rarely serious, oral bleeds can be of concern to the patient and family. Oral bleeding may be mild (e.g., petechiae located on the lips, soft palate, or floor of the mouth) or severe (e.g., persistent gingival hemorrhage or bleeding from herpes simplex virus ulcers in the face of severe thrombocytopenia).

Healthy gingival tissues do not bleed unless traumatized. Discontinuation of routine oral hygiene can increase the risk of gingival infection, which may promote bleeding and increase the risk of local and systemic infection due to accumulation of bacterial plaque. This may lead to periodontal infections and tissue breakdown.

The degree of health professional oversight of thrombocytopenic patients is an important consideration relative to risk of mechanical hygiene procedures. With comprehensive monitoring, patients can often safely use dental brushing and interdental cleaning throughout the thrombocytopenic episode.

Local measures to manage oral bleeds include the following:

• Pressure application. Pressure can be applied by gauze or custom-made oral appliances; these can also be used to deliver and maintain topical agents at the site of bleeding.
• Locally applied clot-forming agents. Topical thrombin and/or hemostatic collagen agents and tranexamic acid can be used to stabilize clots.
• Vasoconstrictors. Epinephrine can be used topically to reduce blood flow rates through bleeding vessels, although vessel rebound is a potential concern.
• Tissue protectants. Application of mucosal adherent products (including cyanoacrylate products) help seal bleeding sites and protect organized clots; platelet-rich plasma may be used.

Patients who tend to form friable and easily dislodged clots will benefit from topical application of aminocaproic acid. In some instances, intravenous administration can be considered to improve coagulation and the formation of stable clots.

Application of 3% hydrogen peroxide and 0.9% saline (1:2 to 1:3 by volume) can aid in wound cleansing and removal of superficial blood debris. Care must be taken not to disturb clots, which might promote bleeding.[1] Laser application for local coagulation may be considered.

References:

1. Schubert MM, Correa MEP, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Forman SJ, Negrin RS, Antin JH, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 5th ed. John Wiley & Sons, Ltd, 2016, pp 1242-56.

Relapse and Second Malignancy

Gingival infiltrates, oral infection, and/or bleeding disproportionate to local etiology can indicate a possible relapse, especially in patients treated for leukemias or lymphomas.

Relapse of non–head and neck solid tumors occurring as oral metastases is rarely observed. Second head and neck tumors are expected to occur in up to 15% of head and neck cancer patients in a stable incidence over the years, and human papillomavirus status may influence this outcome.[1] Locoregional recurrences usually occur in the first 2 years after treatment. The same follow-up protocol is indicated in cases of a second malignant event.[2]

References:

1. Adjei Boakye E, Buchanan P, Hinyard L, et al.: Risk and outcomes for second primary human papillomavirus-related and -unrelated head and neck malignancy. Laryngoscope 129 (8): 1828-1835, 2019.
2. Brands MT, Smeekens EAJ, Takes RP, et al.: Time patterns of recurrence and second primary tumors in a large cohort of patients treated for oral cavity cancer. Cancer Med 8 (12): 5810-5819, 2019.

Taste Disorder

Dysgeusia, taste disorder, can be a prominent symptom in patients who are receiving chemotherapy or head/neck radiation.[1] Etiology is likely associated with several factors, including direct neurotoxicity to taste buds, xerostomia, infection, and psychologic conditioning. Also, cancer treatments may impair taste bud cell regeneration, leading to a diminished function.[2] In addition, taste dysfunction can be associated with damage caused by graft-versus-host disease to the taste perception units. For more information, see the GVHD section.

Patients receiving chemotherapy may experience unpleasant taste secondary to diffusion of drug into the oral cavity. In addition, patients often describe dysgeusia in the early weeks after cessation of cytotoxic therapy that has a negative impact on quality of life. Taste disturbances during chemotherapy are influenced by nausea and reduced appetite, so they can impact nutrition. This symptom is generally reversible, and taste sensation returns to normal in the ensuing months. For more information, see Nutrition in Cancer Care.

By comparison, a total fractionated radiation dose higher than 3,000 Gy reduces acuity of sweet, sour, bitter, and salt tastes. Damage to the microvilli and outer surface of taste cells has been proposed as the principal mechanism for loss of the sense of taste. Even patients with non-oral head and neck cancer frequently show disturbed taste when they are treated with mouth-sparing radiation therapy.[3]

References:

1. Hovan AJ, Williams PM, Stevenson-Moore P, et al.: A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer 18 (8): 1081-7, 2010.
2. Epstein JB, Smutzer G, Doty RL: Understanding the impact of taste changes in oncology care. Support Care Cancer 24 (4): 1917-31, 2016.
3. Barbosa da Silva JL, Doty RL, Miyazaki JVMK, et al.: Gustatory disturbances occur in patients with head and neck cancer who undergo radiotherapy not directed to the oral cavity. Oral Oncol 95: 115-119, 2019.

Medication-Related Osteonecrosis of the Jaw

Overview

Bisphosphonates are potent inhibitors of osteoclasts. They are used in cancer patients with skeletal metastases, including breast, prostate, or lung cancer, and in patients with multiple myeloma. Bisphosphonates are also used to treat hypercalcemia of malignancy and to prevent osteoporosis in patients with cancer.[1,2] For more information on bisphosphonates, see the Bisphosphonates and denosumab section in Cancer Pain.

Clinical trials reveal that antiangiogenic drugs can be associated with the development of medication-related osteonecrosis of the jaw (MRONJ) when used as a single drug or in combination with bone-modifying agents (BMAs). When antiangiogenics are used with bisphosphonates, the risk of MRONJ increases significantly.[3,4,5,6]

Osteonecrosis of the jaw is no longer a problem exclusively associated with the use of bisphosphonates; it is also associated with the use of other drugs such as the monoclonal antibody denosumab and antiangiogenics such as bevacizumab and sorafenib. For this reason, the term MRONJ, rather than the term bisphosphonate-related osteonecrosis of the jaw, should be used to refer to bone necrosis associated with pharmacological therapies.[7,8]

Table 13. Cancer Drugs and Biologics Associated With Medication-Related Osteonecrosis of the Jaw

Generic Drug (Trade Name)	Indication	Class of Drug	Mode of Action	Reported to Cause MRONJ?
GIST = gastrointestinal stromal tumor; MRONJ = medication-related osteonecrosis of the jaw; RANKL = receptor activator of nuclear factor kappa beta ligand; VEGF = vascular endothelial growth factor.
Zoledronic acid	Bone metastasis; bone loss from cancer therapy)	Bisphosphonate	Inhibition of osteoclasts	Yes
Pamidronate	Bone loss from cancer therapy	Bisphosphonate	Inhibition of osteoclasts	Yes
Alendronate	Bone loss from cancer therapy	Bisphosphonate	Inhibition of osteoclasts	Yes
Denosumab	Bone metastasis; osteoporosis; bone loss from cancer therapy	Humanized monoclonal antibody	Suppression of bone remodeling by inhibition of RANKL	Yes
Bevacizumab	Metastatic colorectal cancer; nonsquamous non-small cell lung cancer; metastatic breast cancer; glioblastoma; metastatic renal cell carcinoma	Antiangiogenic	Inhibition of angiogenesis by blocking the action of VEGF	Yes
Sunitinib	Advanced renal cell carcinoma; GIST	Antiangiogenic	Inhibition of angiogenesis by blocking VEGF tyrosine kinase	Yes
Sorafenib	Renal cell carcinoma; hepatocellular carcinoma	Antiangiogenic	Inhibition of angiogenesis by blocking VEGF tyrosine kinase	Yes, when combined with bone-modifying agent

Incidence

The occurrence of MRONJ ranges between 1% and 8% in patients treated with a BMA for bone metastases or multiple myeloma, and between 0 and 1.8% in cancer patients treated with adjuvant BMA for osteoporosis prevention.[8] The prevalence of MRONJ varies according to study design, diagnostic criteria, type of BMA, and dosage. MRONJ lesions are also more prevalent in areas with thin mucosa overlying bone prominences, such as tori, exostoses, and the mylohyoid ridge.[9]

Diagnosis

A diagnosis of MRONJ is based on the following factors:[6,9]

• Exposed bone or bone that can be probed through an intraoral or extra oral fistula(e) in the maxillofacial region and that does not heal within 8 weeks.
• Patient has received a BMA or angiogenic inhibitor agent.
• Patient has no history of head and neck radiation.

It is also possible that symptoms of dental disease, periodontal disease, or both may be present, without visible exposed bone.[6]

Table 14. Bone-Modifying Agents and Risk of Medication-Related Osteonecrosis of the Jaw^a

Drug	Indication	Route	Dose (mg)	Schedule	Frequency of MRONJ, %b
IV = intravenous; MRONJ = medication-related osteonecrosis of the jaw; SC = subcutaneous.
a Adapted from Yarom et al.[8]
b Risk of MRONJ varies by duration of treatment.
c The estimate of 6.9% is from the open-label extension phase of two phase III studies.[7]It is not adjusted for patient-years of exposure or patient follow-up and does not include cases that occurred during the blinded treatment phase. The patient-year adjusted incidence of confirmed MRONJ was 1.1% during the first year of denosumab treatment, 3.7% in the second year, and 4.6% per year thereafter.
Pamidronate	Bone metastasis of solid tumors; multiple myeloma	IV	90	Every 3-4 wk	3.2–5.0[10,11]
Zoledronic acid	Bone metastasis of solid tumors	IV	4	Every 3–4 wk or 12 wk	1.0–8.0[12,13]
	Adjuvant treatment	IV	4	Every 3–6 mo	0–1.8[14,15,16]
Denosumab	Bone metastasis of solid tumors	SC	120	Every 4 wk	0.7–6.9c[7,17,18]
	Adjuvant treatment	SC	60	Every 6 mo	0[19]

Staging of MRONJ

A well-established staging system should be used to quantify the severity and extent of MRONJ and to guide management decisions. The same system should be used throughout the patient's MRONJ course of case. Diagnostic imaging may be used as an adjunct to these staging systems. Optimally, staging should be performed by a clinician who is experienced with the management of MRONJ.[8]

The following two staging systems represent the most frequently used scales, as reported in the literature:

• American Association of Oral and Maxillofacial Surgeons (AAOMS) system.[6]
• Osteonecrosis of the jaw severity scale (Common Terminology Criteria for Adverse Events).[20]

In 2009, AAOMS added a stage 0, which refers to any symptoms of bone pain, fistulous track formation, abscess formation, and altered sensory function. It also includes abnormal radiographic findings that, in the absence of a fistula to bone or frank bone exposure, extend beyond the confines of the alveolar bone as a definitive precursor to MRONJ in patients receiving BMA therapy. The risk of a patient's stage 0 disease progressing to a higher disease stage remains unclear, although case studies suggest that such progression may occur in up to 50% of patients.[21]

The International Task Force of Osteonecrosis of the Jaw expressed concern that the use of stage 0 terminology may lead to overdiagnosis of MRONJ because initial presenting symptoms may ultimately lead to an alternative diagnosis.[22,23] The Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology/American Society of Clinical Oncology Expert Panel shares these concerns and suggests considering stage 0 as an indicator of increased risk of MRONJ. Identifying the increased risk status could prompt a referral to a dental specialist for close follow-up with assessment for early-stage MRONJ, should it develop, to optimize oral health.

Table 15. Staging and Treatment Strategies for Medication-Related Osteonecrosis of the Jaw^a

MRONJ Staging	Clinical and Radiographic Presentations	Treatment Strategies
IV = intravenous; MRONJ = medication-related osteonecrosis of the jaw.
a Adapted from Yarom et al.[8]and Ruggiero et al.[6]
At-risk category	No apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates	No treatment indicated; patient education and reduction of modifiable risk factors
Increased risk	No clinical evidence of necrotic bone, but nonspecific clinical findings and symptoms	Systemic management, including use of pain medication and close scrutiny and follow-up; refer to dental specialist and follow up every 8 wk with communication of lesion status to oncologist; patient education and reduction of modifiable risk factors
Stage 1	Exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection	Antibacterial mouth rinse; clinical follow-up every 3 mo; patient education; review of indications for continued bisphosphonate therapy
Stage 2	Exposed and necrotic bone associated with infection, as evidenced by pain and erythema in the region of the exposed bone, with or without purulent drainage	Symptomatic treatment with oral antibiotics; oral antibacterial mouth rinse; pain control; superficial debridement to relieve irritation of soft tissue
Stage 3	Exposed and necrotic bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e., inferior border and ramus in the mandible, maxillary sinus, and zygoma in the maxilla), resulting in pathological fracture, extraoral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor	Antibacterial mouth rinse; antibiotic therapy and pain control; surgical debridement/resection for longer-term palliation of infection and pain

Management of MRONJ measures

Aggressive surgical interventions (e.g., mucosal flap elevation, block resection of necrotic bone, soft tissue closer) may be used if MRONJ results in persistent symptoms or impacts function despite initial conservative treatment. Aggressive surgical intervention is not recommended for asymptomatic bone exposure. In advance of the aggressive surgical intervention, the multidisciplinary care team and the patient should thoroughly discuss the risks and benefits of the proposed intervention.[24]

Table 16. Proposed Terms to Characterize Osteonecrosis of the Jaw After Treatment^a

Term	Mucosal Coverage	Symptom/Pain	Sign of Infection/Inflammation	Radiographic Presentation
VAS = visual analog scale.
a Adapted from Yarom et al.[8]
Resolved	Complete healing	No pain	None	Trabecular pattern, formation lamina dura resorbed
Improving	Significant improvement (>50% of mucosal coverage)	Significant improvement (>50% reduction of pain, VAS)	Significant improvement (no signs of infection/inflammation)	Improved trabecular pattern, signs of sequestra
Stable	Mild improvement (<50% of mucosal coverage)	Mild improvement (<50% reduction of pain, VAS)	Mild improvement (mild signs of infection/inflammation)	No changes
Progressive	No improvement or worsening	No improvement or worsening	No improvement	Lytic changes, decreasing trabeculation, increased size of radiographic lesion

Reducing Risk of Development of MRONJ

For cancer patients scheduled to receive a BMA in a nonurgent setting, oral care assessment (including a comprehensive dental, periodontal, and oral radiographic exam, when feasible to do so) is undertaken before therapy is initiated. After the assessment, the dentist and oncologist will develop and implement a dental care plan and coordinate with each other to ensure that medically necessary dental procedures are undertaken before a BMA is initiated. The dentist will follow up on a routine schedule once therapy with a BMA has started.

Table 17. Complete, Partial, and Minimal Dental Evaluation Protocols, Based on Dental and/or Periodontal Pathology^a

Dental Pathology	Completeb	Partialc	Minimal, Incomplete, or No Clearanced
a Adapted from Hong et al.[25]
b Adapted from Haytac et al.[26]and Melkos et al.[27]
c Adapted from Schuuhuis et al.[28]and Tsuji et al.[29]
d Adapted from Haytac et al.,[26]Melkos et al.,[27]Schuuhuis et al.,[28], Tsuji et al.[29], and Gurgan et al.[30]
Caries	Restore all teeth	Restore mild/moderate caries if time permits	Intervene only if symptomatic
Severe caries/pulp involvement/dental abscess	Perform root canal treatment or extraction
Apical periodontitis	Retreat	Treat symptomatic lesions and lesions >5 mm
	Perform apicoectomy	Observe asymptomatic lesions and lesions <5 mm
	Extract teeth
Advanced periodontal disease	Extract teeth with:	Extract teeth with:
	– Probing depth >6 mm	– Probing depth >8 mm
	– Furcation I, II, III; Mobility III	– Mobility III
	– Severe inflammation	– Severe inflammation
Partially erupted third molars	Extract partially erupted third molars	Observe asymptomatic teeth
		Extract partially erupted third molars with purulence of pericoronitis

Members of the multidisciplinary team should address modifiable risk factors for MRONJ with the patient as early as possible. These risk factors include:

• Dental extractions.[31,32,33]
• Other oral surgeries.[32,34]
• Ill-fitting dentures.[12,33,35]
• Intravenous bisphosphonates (pamidronate, zoledronic acid, denosumab).[31,33]
• Time on medication.[31,33,36]
• Poor dental and periodontal health.[22,37]
• Tobacco use.[38]

Elective dentoalveolar surgical procedures (e.g., medically unnecessary extractions, alveoplasties, and implants) should not be performed during active therapy with a BMA at an oncologic dose. Exceptions may be considered when a dental specialist with expertise in prevention and treatment of MRONJ has reviewed the benefits and risks of the proposed invasive procedure with the patient and the oncology team.[8]

If dentoalveolar surgery is performed, the dental specialist must evaluate patients frequently until full mucosal coverage of the surgical site has occurred. Communication with the oncologist regarding the status of healing is encouraged, particularly when considering future use of BMA.[8]

For patients with cancer who are receiving a BMA at an oncologic dose, there is insufficient evidence to support or refute discontinuation of the BMA before dentoalveolar surgery. Administration of the BMA may be deferred at the discretion of the treating physician, in consultation with the patient and oral health-provider.[8,39]

Table 18. Daily Oral Care Plan for Patients (Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology)^a

Intervention	Basic Oral Care Plan
a Adapted from Yarom et al.[8]
Flossing	Floss at least once/d; waxed floss may be easier to use and minimize trauma to the gingivae.
	If flossing causes bleeding of the gums that does not stop after 2 minutes, consult oncology team.
Brushing	Use a small, ultra-soft-headed, round-end, bristle toothbrush (an ultrasonic toothbrush may be acceptable).
	Rinse toothbrush in hot water to soften brush before using.
	Use prescription-strength fluoride toothpaste; spit out the foam but do not rinse the mouth.
	Use remineralizing pastes and chewing gum containing calcium and phosphate.
	Brush within 30 min after eating and before bed; include the gingival portion of the tooth and periodontal sulcus.
	Brush tongue gently from back to front.
	Rinse brush after use in hot water and allow to air dry.
	Change toothbrush when bristles are not standing up straight.
For patients with dentures	Remove dentures before brushing.
	Brush and rinse dentures after meals and at bedtime.
	Remove from mouth for long periods (at least 8 hours per 24 hours) and soak in rinsing solution.
Rinsing	Rinse the oral cavity vigorously to help maintain moisture in the mouth, remove remaining debris, and reduce accumulation of plaque and infection.
	Rinse, swish, and spit with a bland rinse (1 tsp salt and 1 tsp baking soda in 4 c water) several times a day.
	Avoid club soda because of the presence of carbonic acids.
	Commercial mouthwashes with alcohol base or astringent properties are not recommended for patients with oral complications.
	Debride only if absolutely necessary and if loose tissue causes gagging or choking.
Moisturizing the oral cavity	Moisturize the mouth with water, artificial saliva products, or other water-soluble lubricants for use inside the mouth.
	Avoid glycerin or lemon-glycerin swabs, as they dry the mouth and do not moisturize.
	Apply lubricant after each cleaning, at bedtime, and as needed. Apply water-based lubricant more frequently.
	Rinse often with basic mouth rinse.
Lip care	To keep lips lubricated and moisturized, use only animal- or plant-based oils such as beeswax, cocoa butter, and lanolin. Avoid petroleum-based products, as these cause drying and cracking.
Visit the dentist at least every 6 mo.
Notify dentist or oncologist of any oral signs or symptoms.

References:

1. Shapiro CL, Van Poznak C, Lacchetti C, et al.: Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic Disease: ASCO Clinical Practice Guideline. J Clin Oncol 37 (31): 2916-2946, 2019.
2. Migliorati CA, Casiglia J, Epstein J, et al.: Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 136 (12): 1658-68, 2005.
3. Smidt-Hansen T, Folkmar TB, Fode K, et al.: Combination of zoledronic Acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg 71 (9): 1532-40, 2013.
4. Nicolatou-Galitis O, Kouri M, Papadopoulou E, et al.: Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review. Support Care Cancer 27 (2): 383-394, 2019.
5. Otto S, Pautke C, Van den Wyngaert T, et al.: Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat Rev 69: 177-187, 2018.
6. Ruggiero SL, Dodson TB, Fantasia J, et al.: American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg 72 (10): 1938-56, 2014.
7. Stopeck AT, Fizazi K, Body JJ, et al.: Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer 24 (1): 447-455, 2016.
8. Yarom N, Shapiro CL, Peterson DE, et al.: Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol 37 (25): 2270-2290, 2019.
9. Khan A, Morrison A, Cheung A, et al.: Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015. Osteoporos Int 27 (3): 853-859, 2016.
10. Gimsing P, Carlson K, Turesson I, et al.: Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. Lancet Oncol 11 (10): 973-82, 2010.
11. Jadu F, Lee L, Pharoah M, et al.: A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann Oncol 18 (12): 2015-9, 2007.
12. Himelstein AL, Foster JC, Khatcheressian JL, et al.: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 317 (1): 48-58, 2017.
13. Vahtsevanos K, Kyrgidis A, Verrou E, et al.: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27 (32): 5356-62, 2009.
14. Coleman RE, Collinson M, Gregory W, et al.: Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04). J Bone Oncol 13: 123-135, 2018.
15. Hershman DL, McMahon DJ, Crew KD, et al.: Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 26 (29): 4739-45, 2008.
16. Shapiro CL, Halabi S, Hars V, et al.: Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. Eur J Cancer 47 (5): 683-9, 2011.
17. Qi WX, Tang LN, He AN, et al.: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol 19 (2): 403-10, 2014.
18. Scagliotti GV, Hirsh V, Siena S, et al.: Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 7 (12): 1823-1829, 2012.
19. Gnant M, Pfeiler G, Dubsky PC, et al.: Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386 (9992): 433-43, 2015.
20. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Bethesda, Md: U.S. Department of Health and Human Services, National Institutes of Health, 2017. Available online. Last accessed Feb. 14, 2024.
21. Schiodt M, Reibel J, Oturai P, et al.: Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system. Oral Surg Oral Med Oral Pathol Oral Radiol 117 (2): 204-13, 2014.
22. Khan AA, Morrison A, Hanley DA, et al.: Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30 (1): 3-23, 2015.
23. Khan AA, Morrison A, Kendler DL, et al.: Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ. J Clin Densitom 20 (1): 8-24, 2017 Jan - Mar.
24. El-Rabbany M, Sgro A, Lam DK, et al.: Effectiveness of treatments for medication-related osteonecrosis of the jaw: A systematic review and meta-analysis. J Am Dent Assoc 148 (8): 584-594.e2, 2017.
25. Hong CHL, Hu S, Haverman T, et al.: A systematic review of dental disease management in cancer patients. Support Care Cancer 26 (1): 155-174, 2018.
26. Haytac MC, Dogan MC, Antmen B: The results of a preventive dental program for pediatric patients with hematologic malignancies. Oral Health Prev Dent 2 (1): 59-65, 2004.
27. Melkos AB, Massenkeil G, Arnold R, et al.: Dental treatment prior to stem cell transplantation and its influence on the posttransplantation outcome. Clin Oral Investig 7 (2): 113-5, 2003.
28. Schuurhuis JM, Span LF, Stokman MA, et al.: Effect of leaving chronic oral foci untreated on infectious complications during intensive chemotherapy. Br J Cancer 114 (9): 972-8, 2016.
29. Tsuji K, Shibuya Y, Akashi M, et al.: Prospective study of dental intervention for hematopoietic malignancy. J Dent Res 94 (2): 289-96, 2015.
30. Gürgan CA, Özcan M, Karakuş Ö, et al.: Periodontal status and post-transplantation complications following intensive periodontal treatment in patients underwent allogenic hematopoietic stem cell transplantation conditioned with myeloablative regimen. Int J Dent Hyg 11 (2): 84-90, 2013.
31. Barasch A, Cunha-Cruz J, Curro F, et al.: Dental risk factors for osteonecrosis of the jaws: a CONDOR case-control study. Clin Oral Investig 17 (8): 1839-45, 2013.
32. Kato GF, Lopes RN, Jaguar GC, et al.: Evaluation of socket healing in patients undergoing bisphosphonate therapy: experience of a single Institution. Med Oral Patol Oral Cir Bucal 18 (4): e650-6, 2013.
33. Schiodt M, Vadhan-Raj S, Chambers MS, et al.: A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer. Support Care Cancer 26 (6): 1905-1915, 2018.
34. Vidal-Real C, Pérez-Sayáns M, Suárez-Peñaranda JM, et al.: Osteonecrosis of the jaws in 194 patients who have undergone intravenous bisphosphonate therapy in Spain. Med Oral Patol Oral Cir Bucal 20 (3): e267-72, 2015.
35. Tsao C, Darby I, Ebeling PR, et al.: Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 71 (8): 1360-6, 2013.
36. Smith MR, Saad F, Coleman R, et al.: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379 (9810): 39-46, 2012.
37. Gabbert TI, Hoffmeister B, Felsenberg D: Risk factors influencing the duration of treatment with bisphosphonates until occurrence of an osteonecrosis of the jaw in 963 cancer patients. J Cancer Res Clin Oncol 141 (4): 749-58, 2015.
38. Rabelo GD, Assunção JN, Chavassieux P, et al.: Bisphosphonate-Related Osteonecrosis of the Jaws and Its Array of Manifestations. J Maxillofac Oral Surg 14 (3): 699-705, 2015.
39. Fusco V, Galassi C, Berruti A, et al.: Decreasing frequency of osteonecrosis of the jaw in cancer and myeloma patients treated with bisphosphonates: the experience of the oncology network of piedmont and aosta valley (north-Western Italy). ISRN Oncol 2013: 672027, 2013.

Special Considerations in Pediatric Populations

There has been a marked increase in the survival rates of childhood cancers because of advances in cancer therapy. However, this progress has resulted in an increase in the number of the late effects from antineoplastic therapy observed in children.[1] Approximately 60% to 80% of childhood cancer survivors develop at least one chronic condition caused by previous cancer treatment.[1] Altered dental growth and craniofacial development is a frequent complication in childhood cancer survivors who received high-dose chemotherapy and/or head and neck radiation.[2,3] For more information, see Late Effects of Treatment for Childhood Cancer.

The severity and location of dental and craniofacial abnormalities are typically associated with the type of cancer modality used and the age at which cancer therapy began.

Dental Abnormalities

The reported incidence and types of dental abnormalities, such as hypodontia, may also alter craniofacial development and lead to malocclusion.

The following cancer modalities have been associated with higher incidence and more severe dental defects:

• High-dose chemotherapy, especially that involving alkylating agents (e.g., cyclophosphamide) and anthracyclines.[4,5][Level of evidence: II];[6][Level of evidence: II]
• Multimodality cancer regimens.[7][Level of evidence: II];[8][Level of evidence: III][9]
• Hematopoietic stem cell transplant conditioning regimens.[10]
• Head and neck radiation.[11][Level of evidence: II] For doses of 20 Gy or more, the odds ratio (OR) of developing at least one dental abnormality has been reported to be 5.6 (confidence interval [CI], 3.7–8.5) versus 1.3 (CI, 1.2–1.5) for radiation doses of 0 to 19 Gy.[4] Even though modern conformal intensity-modulated radiation therapy (IMRT) has been suggested to minimize these effects, reports have shown that IMRT still results in both dental and craniofacial developmental abnormalities.[12][Level of evidence: II];[13][Level of evidence: III]

The association between risk of dental abnormalities and age at time of cancer therapy ranges between age 3 years or younger to age 8 years.[10][Level of evidence: III][14][Level of evidence: II] However, there appear to be more reports documenting that children younger than 5 years at the time of chemotherapy are at increased risk of developing dental abnormalities. For head and neck radiation with doses 20 Gy or higher, the OR of having at least one dental abnormality was 5.6 for those aged 0 to 5 years and 9.6 for those aged 6 to 10 years.[4]

The impact of cancer therapy on dental age is unclear, with one study [15] reporting an advanced dental age and other studies reporting either no difference [16,17] or a delay in dental age.[18][Level of evidence: III];[19][Level of evidence: II]

References:

1. Crowder SL, Douglas KG, Yanina Pepino M, et al.: Nutrition impact symptoms and associated outcomes in post-chemoradiotherapy head and neck cancer survivors: a systematic review. J Cancer Surviv 12 (4): 479-494, 2018.
2. Effinger KE, Migliorati CA, Hudson MM, et al.: Oral and dental late effects in survivors of childhood cancer: a Children's Oncology Group report. Support Care Cancer 22 (7): 2009-19, 2014.
3. Gawade PL, Hudson MM, Kaste SC, et al.: A systematic review of dental late effects in survivors of childhood cancer. Pediatr Blood Cancer 61 (3): 407-16, 2014.
4. Kaste SC, Goodman P, Leisenring W, et al.: Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study. Cancer 115 (24): 5817-27, 2009.
5. Hsieh SG, Hibbert S, Shaw P, et al.: Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy. Cancer 117 (10): 2219-27, 2011.
6. Nishimura S, Inada H, Sawa Y, et al.: Risk factors to cause tooth formation anomalies in chemotherapy of paediatric cancers. Eur J Cancer Care (Engl) 22 (3): 353-60, 2013.
7. Maciel JC, de Castro CG, Brunetto AL, et al.: Oral health and dental anomalies in patients treated for leukemia in childhood and adolescence. Pediatr Blood Cancer 53 (3): 361-5, 2009.
8. Kaste SC, Hopkins KP, Jones D, et al.: Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia 11 (6): 792-6, 1997.
9. Cubukcu CE, Sevinir B, Ercan I: Disturbed dental development of permanent teeth in children with solid tumors and lymphomas. Pediatr Blood Cancer 58 (1): 80-4, 2012.
10. Hölttä P, Hovi L, Saarinen-Pihkala UM, et al.: Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT. Cancer 103 (7): 1484-93, 2005.
11. Jaffe N, Toth BB, Hoar RE, et al.: Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: effects of treatment with chemotherapy and radiation to the head and neck. Pediatrics 73 (6): 816-23, 1984.
12. Owosho AA, Brady P, Wolden SL, et al.: Long-term effect of chemotherapy-intensity-modulated radiation therapy (chemo-IMRT) on dentofacial development in head and neck rhabdomyosarcoma patients. Pediatr Hematol Oncol 33 (6): 383-392, 2016.
13. Paulino AC, Simon JH, Zhen W, et al.: Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 48 (5): 1489-95, 2000.
14. Hutton A, Bradwell M, English M, et al.: The oral health needs of children after treatment for a solid tumour or lymphoma. Int J Paediatr Dent 20 (1): 15-23, 2010.
15. Vasconcelos NP, Caran EM, Lee ML, et al.: Dental maturity assessment in children with acute lymphoblastic leukemia after cancer therapy. Forensic Sci Int 184 (1-3): 10-4, 2009.
16. Flores AP, Monti CF, Brunotto M: Dental and chronological age in children under oncological treatment. J Forensic Sci 60 (2): 453-6, 2015.
17. Martin MB, Li CS, Rowland CC, et al.: Correlation of bone age, dental age, and chronological age in survivors of childhood acute lymphoblastic leukaemia. Int J Paediatr Dent 18 (3): 217-23, 2008.
18. Bagattoni S, D'Alessandro G, Prete A, et al.: Oral health and dental late adverse effects in children in remission from malignant disease. A pilot case-control study in Italian children. Eur J Paediatr Dent 15 (1): 45-50, 2014.
19. Purdell-Lewis DJ, Stalman MS, Leeuw JA, et al.: Long term results of chemotherapy on the developing dentition: caries risk and developmental aspects. Community Dent Oral Epidemiol 16 (2): 68-71, 1988.

Special Considerations in Geriatric Populations

An aging population is living with more chronic diseases, comorbidities, multidrug use, and cancers. The special care needs of the geriatric population should be assessed and considered in the development of cancer treatment protocols.

Oncologists need to promote oral health in frail older adults when they are about to undergo a cancer therapy that could have permanent or temporary impacts on oral/dental health. Pretherapy oral/dental evaluation is mandatory, and the follow-up of an older adult with frailty involves close monitoring (face to face or telehealth) and education of caregivers regarding oral and dental hygiene.

Quality-of-life (QOL) considerations should be a fundamental component in cancer management, whatever a patient's age. In the field of oncology, it is apparent that the geriatric cancer population has special oral/dental needs. Special precautions are advised for this patient group. Dental professionals need to be part of the geriatric oncology team for better support of QOL.

Latest Updates to This Summary (02 / 16 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was renamed from Oral Complications of Chemotherapy and Head/Neck Radiation.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of oral complications of cancer therapies. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Oral Complications of Cancer Therapies are:

• Megan Reimann, PharmD, BCOP (Total CME)
• Andrea Ruskin, MD (VA Connecticut Healthcare System)

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PDQ® Supportive and Palliative Care Editorial Board. PDQ Oral Complications of Cancer Therapies. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/mouth-throat/oral-complications-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389320]

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Last Revised: 2024-02-16