Oral Complications of Cancer Therapies (PDQ®)

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. [PubMed: 31425594]
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. [PubMed: 31425601]
3. Keefe DMK, Bateman EH: Potential Successes and Challenges of Targeted Cancer Therapies. J Natl Cancer Inst Monogr 2019 (53): , 2019. [PubMed: 31425592]
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. [PubMed: 31425602]
5. Epstein JB, Miaskowski C: Oral Pain in the Cancer Patient. J Natl Cancer Inst Monogr 2019 (53): , 2019. [PubMed: 31425595]
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. [PMC free article: PMC6699578] [PubMed: 31425593]
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. [PubMed: 31425591]
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. [PubMed: 31425597]
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. [PubMed: 31425599]
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. [PubMed: 31425600]
11. Migliorati CA, Brennan MT, Peterson DE: Medication-Related Osteonecrosis of the Jaws. J Natl Cancer Inst Monogr 2019 (53): , 2019. [PubMed: 31425596]
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. [PubMed: 31425598]

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).[9-11][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

Table 2. Oral Mucositis Scales.

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

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

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

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

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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2. 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. [PMC free article: PMC5998810] [PubMed: 29910997]
3. 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. [PubMed: 28735355]
4. Hong CHL, Gueiros LA, Fulton JS, et al.: Systematic review of basic oral care for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer 27 (10): 3949-3967, 2019. [PubMed: 31286232]
5. Bowen J, Al-Dasooqi N, Bossi P, et al.: The pathogenesis of mucositis: updated perspectives and emerging targets. Support Care Cancer 27 (10): 4023-4033, 2019. [PubMed: 31286231]
6. 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. [PubMed: 31425601]
7. Mougeot JC, Stevens CB, Morton DS, et al.: Oral Microbiome and Cancer Therapy-Induced Oral Mucositis. J Natl Cancer Inst Monogr 2019 (53): , 2019. [PubMed: 31425594]
8. Sonis ST: Oral mucositis in head and neck cancer: risk, biology, and management. Am Soc Clin Oncol Educ Book : , 2013. [PubMed: 23714511]
9. Elad S: The MASCC/ISOO Mucositis Guidelines 2019 Update: introduction to the first set of articles. Support Care Cancer 27 (10): 3929-3931, 2019. [PubMed: 31286226]
10. Elad S: The MASCC/ISOO mucositis guidelines 2019: the second set of articles and future directions. Support Care Cancer 28 (5): 2445-2447, 2020. [PubMed: 32052136]
11. 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. [PMC free article: PMC4164022] [PubMed: 24615748]
12. Bensinger W, Schubert M, Ang KK, et al.: NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 6 (Suppl 1): S1-21; quiz S22-4, 2008. [PubMed: 18289497]
13. Riley P, Glenny AM, Worthington HV, et al.: Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors. Cochrane Database Syst Rev 11: CD011990, 2017. [PMC free article: PMC6486203] [PubMed: 29181845]
14. Saunders DP, Epstein JB, Elad S, et al.: Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients. Support Care Cancer 21 (11): 3191-207, 2013. [PubMed: 23832272]
15. Logan RM, Al-Azri AR, Bossi P, et al.: Systematic review of growth factors and cytokines for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer 28 (5): 2485-2498, 2020. [PubMed: 32080767]
16. Riley P, Glenny AM, Worthington HV, et al.: Interventions for preventing oral mucositis in patients with cancer receiving treatment: oral cryotherapy. Cochrane Database Syst Rev 2015 (12): CD011552, 2015. [PMC free article: PMC8915172] [PubMed: 26695736]
17. Zadik Y, Arany PR, Fregnani ER, et al.: Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer 27 (10): 3969-3983, 2019. [PubMed: 31286228]
18. Yarom N, Hovan A, Bossi P, et al.: Systematic review of natural and miscellaneous agents for the management of oral mucositis in cancer patients and clinical practice guidelines-part 1: vitamins, minerals, and nutritional supplements. Support Care Cancer 27 (10): 3997-4010, 2019. [PubMed: 31286229]
19. Keefe DM, Schubert MM, Elting LS, et al.: Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109 (5): 820-31, 2007. [PubMed: 17236223]
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.
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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.[2-5]

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

Table 5. Pretransplant Dental Evaluation.

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.

Oral Health After Transplant

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

Table 6. Graft-Versus-Host Disease Classification.

Table

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

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

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

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

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

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. [PMC free article: PMC4830270] [PubMed: 26256941]
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. [PMC free article: PMC4328129] [PubMed: 25189149]
3. Guideline on Dental Management of Pediatric Patients Receiving Chemotherapy, Hematopoietic Cell Transplantation, and/or Radiation Therapy. Pediatr Dent 38 (6): 334-342, 2016. [PubMed: 27931474]
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. [PMC free article: PMC5486807] [PubMed: 28194493]
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. [PubMed: 29509233]
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. [PMC free article: PMC4164022] [PubMed: 24615748]
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. [PMC free article: PMC5339548] [PubMed: 25818385]
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. [PMC free article: PMC5462992] [PubMed: 28642709]
9. Lee SJ: Classification systems for chronic graft-versus-host disease. Blood 129 (1): 30-37, 2017. [PMC free article: PMC5216262] [PubMed: 27821503]
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. [PubMed: 24979731]
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. [PMC free article: PMC4329079] [PubMed: 25529383]
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. [PMC free article: PMC4821166] [PubMed: 25838185]
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. [PubMed: 16435004]
14. Copelan EA: Hematopoietic stem-cell transplantation. N Engl J Med 354 (17): 1813-26, 2006. [PubMed: 16641398]

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

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

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.[3-5]

Table

Table 11. Oral Toxicities of Cancer Drugs.

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.[14-16]

Table

Table 12. Systemic and Oral Toxicities of Cancer Immunotherapy.

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.[18-21]

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.

References

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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. [PubMed: 22669112]
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. [PubMed: 26765102]
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. [PMC free article: PMC5651530] [PubMed: 29093678]
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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. [PubMed: 27086658]
15. Saw S, Lee HY, Ng QS: Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients. Eur J Cancer 81: 237-239, 2017. [PubMed: 28438440]
16. Salati M, Pifferi M, Baldessari C, et al.: Stevens-Johnson syndrome during nivolumab treatment of NSCLC. Ann Oncol 29 (1): 283-284, 2018. [PubMed: 29045532]
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. [PMC free article: PMC5645209] [PubMed: 28419570]
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. [PubMed: 26633184]
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. [PubMed: 29331748]
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. [PMC free article: PMC6310648] [PubMed: 30195074]
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. [PubMed: 32144002]
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. [PMC free article: PMC6400698] [PubMed: 30847290]
23. Epstein JB, Smutzer G, Doty RL: Understanding the impact of taste changes in oncology care. Support Care Cancer 24 (4): 1917-31, 2016. [PubMed: 26820877]
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. [PubMed: 25417041]
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. [PMC free article: PMC4328129] [PubMed: 25189149]
26. Rapoport BL, van Eeden R, Sibaud V, et al.: Supportive care for patients undergoing immunotherapy. Support Care Cancer 25 (10): 3017-3030, 2017. [PubMed: 28707167]

Orofacial Pain Caused by Cancer Persistence, Recurrence, or Metastasis

Orofacial Pain Caused by Cancer Management

References

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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.[11-13]

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

Viral Infections

References

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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. [PubMed: 33392808]
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. [PMC free article: PMC6726710] [PubMed: 31222393]
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. [PMC free article: PMC5998810] [PubMed: 29910997]
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. [PMC free article: PMC5486807] [PubMed: 28194493]
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. [PubMed: 29509233]
16. Hellstein JW, Marek CL: Candidiasis: Red and White Manifestations in the Oral Cavity. Head Neck Pathol 13 (1): 25-32, 2019. [PMC free article: PMC6405794] [PubMed: 30693459]
17. Lewis MAO, Williams DW: Diagnosis and management of oral candidosis. Br Dent J 223 (9): 675-681, 2017. [PubMed: 29123282]
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. [PubMed: 31177394]
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. [PubMed: 28258917]
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. [PMC free article: PMC6221665] [PubMed: 30383690]
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. [PubMed: 28877386]
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. [PubMed: 20544224]
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.

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.

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. [PubMed: 30582167]
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. [PMC free article: PMC6745868] [PubMed: 31400079]

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. [PubMed: 20495984]
2. Epstein JB, Smutzer G, Doty RL: Understanding the impact of taste changes in oncology care. Support Care Cancer 24 (4): 1917-31, 2016. [PubMed: 26820877]
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. [PubMed: 31345378]

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.[3-6]

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

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

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

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

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

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

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

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

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

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

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.[31-33]
• 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

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

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. [PubMed: 31532726]
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. [PubMed: 16383047]
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. [PubMed: 23642545]
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. [PubMed: 30353228]
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. [PubMed: 30055439]
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. [PubMed: 25234529]
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. [PMC free article: PMC4669370] [PubMed: 26335402]
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. [PubMed: 31329513]
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. [PubMed: 26493811]
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. [PubMed: 20863761]
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. [PubMed: 17804475]
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. [PMC free article: PMC5321662] [PubMed: 28030702]
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. [PubMed: 19805682]
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. [PMC free article: PMC6303395] [PubMed: 30591866]
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. [PMC free article: PMC2653138] [PubMed: 18711172]
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. [PMC free article: PMC4211594] [PubMed: 21324674]
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. [PubMed: 23605142]
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. [PubMed: 23154554]
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. [PubMed: 26040499]
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. [PubMed: 24332520]
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. [PubMed: 25414052]
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. [PubMed: 27956123]
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. [PubMed: 28527518]
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. [PubMed: 28735355]
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. [PubMed: 15641766]
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. [PubMed: 12768464]
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. [PMC free article: PMC4984907] [PubMed: 27002936]
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. [PMC free article: PMC4438737] [PubMed: 25503612]
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. [PubMed: 22487659]
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. [PMC free article: PMC3594331] [PubMed: 23212125]
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. [PMC free article: PMC3731094] [PubMed: 23524435]
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. [PMC free article: PMC5919994] [PubMed: 29275525]
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. [PMC free article: PMC4464912] [PubMed: 25662540]
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. [PubMed: 23582590]
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. [PMC free article: PMC3671878] [PubMed: 22093187]
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. [PubMed: 25319961]
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. [PMC free article: PMC4511882] [PubMed: 26225065]
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. [PMC free article: PMC3600177] [PubMed: 23533811]

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. [PubMed: 29556926]
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. [PMC free article: PMC4118932] [PubMed: 24781353]
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. [PMC free article: PMC4281834] [PubMed: 24424790]
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. [PMC free article: PMC3754878] [PubMed: 19834960]
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. [PubMed: 21523736]
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. [PMC free article: PMC3655612] [PubMed: 23336315]
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. [PubMed: 19484760]
8. Kaste SC, Hopkins KP, Jones D, et al.: Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia 11 (6): 792-6, 1997. [PubMed: 9177429]
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. [PubMed: 21254371]
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. [PubMed: 15739206]
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. [PubMed: 6728583]
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. [PMC free article: PMC5175398] [PubMed: 27689858]
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. [PubMed: 11121653]
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. [PubMed: 20059589]
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. [PubMed: 19147312]
16. Flores AP, Monti CF, Brunotto M: Dental and chronological age in children under oncological treatment. J Forensic Sci 60 (2): 453-6, 2015. [PubMed: 25572724]
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. [PubMed: 18298546]
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. [PubMed: 24745592]
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. [PubMed: 3162858]

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.

Reviewers and Updates

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).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Oral Complications of Cancer Therapies are:

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

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

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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