References

1. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. Mosby Elsevier, 2011, pp 782-98.
2. 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]
3. Migliorati CA, Woo SB, Hewson I, et al.: A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support Care Cancer 18 (8): 1099-106, 2010. [PubMed: 20411279]
4. 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]
5. Lalla RV, Latortue MC, Hong CH, et al.: A systematic review of oral fungal infections in patients receiving cancer therapy. Support Care Cancer 18 (8): 985-92, 2010. [PMC free article: PMC2914797] [PubMed: 20449755]
6. 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]
7. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010. [PMC free article: PMC2914291] [PubMed: 20449756]
8. Peterson DE, Doerr W, Hovan A, et al.: Osteoradionecrosis in cancer patients: the evidence base for treatment-dependent frequency, current management strategies, and future studies. Support Care Cancer 18 (8): 1089-98, 2010. [PubMed: 20526784]
9. Bensadoun RJ, Riesenbeck D, Lockhart PB, et al.: A systematic review of trismus induced by cancer therapies in head and neck cancer patients. Support Care Cancer 18 (8): 1033-8, 2010. [PubMed: 20213237]
10. Epstein JB, Hong C, Logan RM, et al.: A systematic review of orofacial pain in patients receiving cancer therapy. Support Care Cancer 18 (8): 1023-31, 2010. [PubMed: 20544225]
11. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010. [PubMed: 20237805]

Chemotherapy-induced Complications

Risk factors for oral complications (see Table 2) derive from both direct damage to oral tissues secondary to chemotherapy and indirect damage due to regional or systemic toxicity. For example, therapy-related toxicity to oral mucosa can be exacerbated by colonizing oral microflora when local and systemic immune function is concurrently compromised. Frequency and severity of oral complications are directly related to extent and type of systemic compromise.

Ulcerative oral mucositis occurs in approximately 40% of patients receiving chemotherapy. In approximately 50% of these patients, the lesions are severe and require medical intervention including modification of their cytotoxic cancer therapy. Normal oral mucosal epithelium is estimated to undergo complete replacement every 9 to 16 days. Intensive chemotherapy can cause ulcerative mucositis that initially emerges approximately 2 weeks after initiation of high-dose chemotherapy.[2-4]

Chemotherapy directly impairs replication of basal epithelial cells; other factors, including proinflammatory cytokines and metabolic products of bacteria, may also play a role. The labial mucosa, buccal mucosa, tongue, floor of mouth, and soft palate are more severely affected by chemotherapy than are the attached, heavily keratinized tissues such as the hard palate and gingiva; this may be caused by relative rate of epithelial cell turnover among high-risk versus low-risk oral mucosal tissues. Topical cryotherapy may ameliorate mucositis caused by agents such as 5-fluorouracil (5-FU) by reducing vascular delivery of these toxic agents to replicating oral epithelium.[5]

It is difficult to predict whether a patient will develop mucositis strictly on the basis of the classes of drugs that are administered. Several drugs are associated with a propensity to damage oral mucosa:

• Methotrexate.
• Doxorubicin.
• 5-FU.
• Busulfan.
• Bleomycin.
• The platinum coordination complexes, including cisplatin and carboplatin.
• Mammalian target of rapamycin (mTOR) inhibitors (a new class of targeted cancer therapeutic agents).[6,7]

Anecdotal evidence suggests that patients who experience mucositis with a specific chemotherapy regimen during the first cycle will typically develop comparable mucositis during subsequent courses of that regimen.

Other oral complications typically include infections of the mucosa, dentition/periapices, and periodontium. Prevalence of these infections has been substantiated in multiple studies.[8-11] Specific criteria for determining risk of infectious flare during myelosuppression have not been developed. Guidelines for assessment primarily address both degree of severity of the chronic lesion and whether acute symptoms have recently (i.e., <90 days) developed. However, chronic asymptomatic periodontitis may also represent a focus for systemic infectious complications since bacteria, bacterial cell wall substances, and inflammatory cytokines may translocate into the circulation via ulcerated pocket epithelium.[10] In addition, poor oral hygiene and periodontitis seem to increase the prevalence of pulmonary infections in high-risk patients.[12]

Resolution of oral toxicity, including mucositis and infection, generally coincides with granulocyte recovery. This relationship may be temporally but not causally related. For example, oral mucosal healing in hematopoietic stem cell transplantation patients is only partially dependent on rate of engraftment, especially neutrophils.

Head/Neck Radiation–induced Complications

Head and neck radiation can cause a wide spectrum of oral complications (refer to the list of Oral Complications of Radiation Therapy). Ulcerative oral mucositis is a virtually universal toxicity resulting from this treatment; there are clinically significant similarities as well as differences compared with oral mucositis caused by chemotherapy.[2] In addition, oral mucosal toxicity can be increased by use of head and neck radiation together with concurrent chemotherapy.

Head and neck radiation can also induce damage that results in permanent dysfunction of vasculature, connective tissue, salivary glands, muscle, and bone. Loss of bone vitality occurs:

• Secondary to injury to osteocytes, osteoblasts, and osteoclasts.
• From a relative hypoxia due to reduction in vascular supply.

These changes can lead to soft tissue necrosis and osteonecrosis that result in bone exposure, secondary infection, and severe pain.[11]

Oral Complications of Radiation Therapy

• Acute complications:

  -

  Oral mucositis.

  -

  Infection:

  • Fungal.
  • Bacterial.

  -

  Salivary gland dysfunction:

  • Sialadenitis.
  • Xerostomia.

  -

  Taste dysfunction.

• Chronic complications:

  -

  Mucosal fibrosis and atrophy.

  -

  Xerostomia.

  -

  Dental caries.

  -

  Soft tissue necrosis.

  -

  Osteonecrosis.

  -

  Taste dysfunction:

  • Dysgeusia.
  • Ageusia.

  -

  Muscular/cutaneous fibrosis.

  -

  Infections:

  • Fungal.
  • Bacterial.

Unlike chemotherapy, however, radiation damage is anatomically site-specific; toxicity is localized to irradiated tissue volumes. Degree of damage depends on treatment regimen-related factors, including type of radiation utilized, total dose administered, and field size/fractionation. Radiation-induced damage also differs from chemotherapy-induced changes in that irradiated tissue tends to manifest permanent damage that places the patient at continual risk for oral sequelae. The oral tissues are thus more easily damaged by subsequent toxic drug or radiation exposure, and normal physiologic repair mechanisms are compromised as a result of permanent cellular damage.

References

1. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998. [PubMed: 9691508]
2. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998. [PubMed: 9659518]
3. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. Mosby Elsevier, 2011, pp 782-98.
4. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Wiley-Blackwell, 2009, pp 1589-1607.
5. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72 (7): 2234-8, 1993. [PubMed: 8374882]
6. Pilotte AP, Hohos MB, Polson KM, et al.: Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs 15 (5): E83-9, 2011. [PubMed: 21951751]
7. de Oliveira MA, Martins E Martins F, Wang Q, et al.: Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol 47 (10): 998-1003, 2011. [PubMed: 21890398]
8. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001.
9. Akintoye SO, Brennan MT, Graber CJ, et al.: A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (5): 581-8, 2002. [PubMed: 12424452]
10. Raber-Durlacher JE, Epstein JB, Raber J, et al.: Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer 10 (6): 466-73, 2002. [PubMed: 12353125]
11. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990. [PubMed: 1692972]
12. Paju S, Scannapieco FA: Oral biofilms, periodontitis, and pulmonary infections. Oral Dis 13 (6): 508-12, 2007. [PMC free article: PMC2258093] [PubMed: 17944664]

Chemotherapy Patients

Oral evaluation and management of patients scheduled to undergo myeloablative chemotherapy should occur as early as possible before initiation of therapy (refer to the list on Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplantation). To maximize outcomes, the oncology team should clearly advise the dentist as to the patient’s medical status and oncology treatment plan. In turn, the dental team should delineate and communicate a plan of care for oral disease management before, during, and after cancer therapy.[5]

Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplantation

• Data provided by oncology team to dental providers:

  -

  Underlying disease:

  • Cancer: type, stage, prognosis.
  • Aplastic anemia status, complete blood count (CBC).
  • Other.

  -

  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 status and immunologic status.

  -

  Present medications.

  -

  Other medical considerations:

  • Cardiac disease (including murmurs).
  • Pulmonary disease.
  • Indwelling venous access line.
  • Coagulation status.
  • Splenectomy.

• Data provided by dental providers to oncology team:

  -

  Dental caries (number of teeth and severity, including designation of 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.

  -

  Other urgent care required.

  -

  Time necessary to complete stabilization of oral disease.

The overall goal is to complete a comprehensive oral care plan that eliminates or stabilizes oral disease that could otherwise produce complications during or following chemotherapy. Achieving this goal will most likely reduce risk of oral toxicities with resultant reduced risk for systemic sequelae, reduced cost of patient care, and enhanced quality of life. If the patient is unable to receive the medically necessary oral care in the community, the oncology team should assume responsibility for oral management.

It is important to realize that dental treatment plans need to be realistic relative to type and extent of dental disease and how long it could be before resumption of routine dental care. For example, teeth with minor caries may not need restoration before cancer treatment begins, especially if more conservative disease stabilization strategies can be used (e.g., aggressive topical fluoride protocols, temporary restorations, or dental sealants).

Specific interventions are directed to:

• Mucosal lesions.
• Dental caries and endodontic disease.
• Periodontal disease.
• Ill-fitting dentures.
• Orthodontic appliances.
• Temporomandibular dysfunction.
• Salivary abnormalities.

Guidelines for dental extractions, endodontic management, and related interventions (see Table 3) can be used as appropriate.[6,7] Antibiotic prophylaxis prior to invasive oral procedures may be warranted in the context of central venous catheters; the current American Heart Association (AHA) protocol for infective endocarditis and oral procedures is frequently used for these patients.

Assessment of Hematopoietic Stem Cell Transplant Patients

Stages of assessment have been described relative to the hematopoietic stem cell transplant patient (see Table 4).[5] This model provides a useful classification for neutropenic cancer patients in general. Type, timing, and severity of oral complications represent the interaction of local and systemic factors that culminate in clinical expression of disease. Correlating oral status with systemic condition of the patient is thus critically important.

Selected conditioning regimens characterized by reduced intensity for myelosuppression have been used in patients. These regimens have generally been noted to significantly reduce the severity of oral complications early posttransplant, especially for mucositis and infection risk. The guidelines listed in Table 4 can be adjusted to reflect these varying degrees of risk, based on the specific conditioning regimen to be used.

Phase I: Before Chemotherapy

Oral complications are related to current systemic and oral health, oral manifestations of underlying disease, and oral complications of recent cancer or other medical therapy. During this period, oral trauma and clinically significant infections, including dental caries, periodontal disease, and pulpal infection, should be eliminated. Additionally, patients should be educated relative to the range and management of oral complications that may occur during subsequent phases. Baseline oral hygiene instructions should be provided. It is especially important to note whether patients have been treated with bisphosphonates (e.g., patients with multiple myeloma) and to plan their care accordingly.

Phase II: Neutropenic Phase

Oral complications arise primarily from direct and indirect stomatotoxicities associated with high-dose chemotherapy or chemoradiotherapy and their sequelae. Mucositis, xerostomia, and those lesions related to myelosuppression, thrombocytopenia, and anemia predominate. This phase is typically the period of high prevalence and severity of oral complications.

Oral mucositis usually begins 7 to 10 days after initiation of cytotoxic therapy and remains present for approximately 2 weeks after cessation of that therapy. Viral, fungal, and bacterial infections may arise, with incidence dependent on the use of prophylactic regimens, oral status prior to chemotherapy, and duration/severity of neutropenia. Frequency of infection declines upon resolution of mucositis and regeneration of neutrophils. This phenomenon appears to be more a temporal relation than a causative one, based on the predominant evidence. Despite the initial marrow recovery, however, the patient may remain at risk for infection, depending on status of overall immune reconstitution.

Salivary gland hypofunction/xerostomia secondary to anticholinergic drugs and taste dysfunction is initially detected in this phase; the toxicity typically resolves within 2 to 3 months.

In allogeneic transplant patients, while uncommon, hyperacute graft-versus-host disease (GVHD) can occur and can result in significant oral mucosal inflammation and breakdown that can complicate the oral course for patients. Clinical presentation will often not be sufficiently distinct to diagnosis this lesion. The clinical assessment is typically based on the patient experiencing more-severe-than-expected mucositis that will often not heal within the time line for mucosal recovery associated with oral mucositis caused by chemotherapy.

Phase III: Hematopoietic Recovery

Frequency and severity of acute oral complications typically begin to decrease approximately 3 to 4 weeks after cessation of chemotherapy. Healing of ulcerative oral mucositis in the setting of marrow regeneration contributes to this dynamic. Although immune reconstitution is developing, oral mucosal immune defenses may not be optimal. Generally stated, immune reconstitution will take between 6 and 9 months for autologous transplant patients and between 9 and 12 months for allogeneic transplant patients not developing chronic GVHD. Thus, the patient remains at risk for selected infection, including candidal and herpes simplex virus infections.

Mucosal bacterial infections during this phase occur less frequently unless engraftment is delayed or the patient has acute GVHD or is receiving GVHD therapy. Most centers will use systemic infection prophylaxis throughout this period (and, in many instances, longer) to reduce the risk of infections in general, a practice that positively influences the rate and severity of both systemic and local oral infections.

The hematopoietic stem cell transplant patient represents a unique cohort at this point. For example, risk for acute oral GVHD typically emerges during this time in allogeneic graft recipients.

Phase IV: Immune Reconstitution/Recovery from Systemic Toxicity

Oral lesions are principally related to chronic conditioning regimen–associated (chemotherapy with or without radiation therapy) toxicity and, in the allogeneic patient, GVHD. Late viral infections and xerostomia predominate. Mucosal bacterial infections are infrequent unless the patient remains neutropenic or has severe chronic GVHD.

Risk exists for graft failure, cancer relapse, and second malignancies. The hematopoietic stem cell transplant patient may develop oral manifestations of chronic GVHD during this period.

Phase V: Long-term Survival

Long-term survivors of cancer treated with high-dose chemotherapy alone or chemoradiotherapy will generally have few significant permanent oral complications.

Risk for radiation-induced chronic complications is related to the total dose and schedule of radiation therapy. Regimens that incorporate total body irradiation may result in permanent salivary gland hypofunction/xerostomia,[8] which is the most frequently reported late oral complication. Permanent salivary gland dysfunction can occur in autologous transplant patients in addition to nonautologous recipients. Other significant complications include craniofacial growth and developmental abnormalities in pediatric patients, and emergence of second malignancies of the head/neck region.

References

1. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990. [PubMed: 2342592]
2. Epstein JB: Infection prevention in bone marrow transplantation and radiation patients. NCI Monogr (9): 73-85, 1990. [PubMed: 2111470]
3. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010. [PMC free article: PMC2914291] [PubMed: 20449756]
4. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. Mosby Elsevier, 2011, pp 782-98.
5. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Wiley-Blackwell, 2009, pp 1589-1607.
6. Williford SK, Salisbury PL, Peacock JE, et al.: The safety of dental extractions in patients with hematologic malignancies. J Clin Oncol 7 (6): 798-802, 1989. [PubMed: 2523958]
7. Overholser CD, Peterson DE, Bergman SA, et al.: Dental extractions in patients with acute nonlymphocytic leukemia. J Oral Maxillofac Surg 40 (5): 296-8, 1982. [PubMed: 6211528]
8. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010. [PubMed: 20237805]

References

1. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Wiley-Blackwell, 2009, pp 1589-1607.

Chemoradiotherapy and Hematopoietic Stem Cell Transplantation Patients

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998. [PubMed: 9659518]
2. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. Mosby Elsevier, 2011, pp 782-98.
3. Sonis ST, Elting LS, Keefe D, et al.: Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100 (9 Suppl): 1995-2025, 2004. [PubMed: 15108222]
4. Barasch A, Peterson DE: Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol 39 (2): 91-100, 2003. [PubMed: 12509961]
5. Ezzeldin HH, Diasio RB: Predicting fluorouracil toxicity: can we finally do it? J Clin Oncol 26 (13): 2080-2, 2008. [PubMed: 18299611]
6. Schwab M, Zanger UM, Marx C, et al.: Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26 (13): 2131-8, 2008. [PubMed: 18299612]
7. Werbrouck J, De Ruyck K, Duprez F, et al.: Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys 73 (4): 1187-95, 2009. [PubMed: 19251090]
8. Hahn T, Zhelnova E, Sucheston L, et al.: A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biol Blood Marrow Transplant 16 (6): 801-8, 2010. [PubMed: 20074657]
9. Spielberger R, Stiff P, Bensinger W, et al.: Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351 (25): 2590-8, 2004. [PubMed: 15602019]
10. Peterson DE, Barker NP, Akhmadullina LI, et al.: Phase II, randomized, double-blind, placebo-controlled study of recombinant human intestinal trefoil factor oral spray for prevention of oral mucositis in patients with colorectal cancer who are receiving fluorouracil-based chemotherapy. J Clin Oncol 27 (26): 4333-8, 2009. [PubMed: 19636011]
11. Peterson DE, Bensadoun RJ, Roila F, et al.: Management of oral and gastrointestinal mucositis: ESMO clinical recommendations. Ann Oncol 20 (Suppl 4): 174-7, 2009. [PubMed: 19454447]
12. Schubert MM, Williams BE, Lloid ME, et al.: Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 69 (10): 2469-77, 1992. [PubMed: 1568168]
13. Sonis ST, Eilers JP, Epstein JB, et al.: Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer 85 (10): 2103-13, 1999. [PubMed: 10326686]
14. McGuire DB, Peterson DE, Muller S, et al.: The 20 item oral mucositis index: reliability and validity in bone marrow and stem cell transplant patients. Cancer Invest 20 (7-8): 893-903, 2002. [PubMed: 12449720]
15. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998. [PubMed: 9691508]
16. Schubert MM: Oro-pharyngeal mucositis. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge University Press, 2000, pp 812-20.
17. 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]
18. Elting LS, Cooksley C, Chambers M, et al.: The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 98 (7): 1531-9, 2003. [PubMed: 14508842]
19. Elting LS, Cooksley CD, Chambers MS, et al.: Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 68 (4): 1110-20, 2007. [PubMed: 17398022]
20. Lalla RV, Sonis ST, Peterson DE: Management of oral mucositis in patients who have cancer. Dent Clin North Am 52 (1): 61-77, viii, 2008. [PMC free article: PMC2266835] [PubMed: 18154865]
21. Peterson DE, Lalla RV: Oral mucositis: the new paradigms. Curr Opin Oncol 22 (4): 318-22, 2010. [PMC free article: PMC3716390] [PubMed: 20485169]
22. Rosenthal DI: Consequences of mucositis-induced treatment breaks and dose reductions on head and neck cancer treatment outcomes. J Support Oncol 5 (9 Suppl 4): 23-31, 2007. [PubMed: 18046995]
23. Sonis ST, Oster G, Fuchs H, et al.: Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 19 (8): 2201-5, 2001. [PubMed: 11304772]
24. Sonis ST: Regimen-related gastrointestinal toxicities in cancer patients. Curr Opin Support Palliat Care 4 (1): 26-30, 2010. [PubMed: 20040879]
25. Trotti A, Bellm LA, Epstein JB, et al.: Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 66 (3): 253-62, 2003. [PubMed: 12742264]
26. Pillitteri LC, Clark RE: Comparison of a patient-controlled analgesia system with continuous infusion for administration of diamorphine for mucositis. Bone Marrow Transplant 22 (5): 495-8, 1998. [PubMed: 9733274]
27. 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]
28. Clarkson JE, Worthington HV, Furness S, et al.: Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev (8): CD001973, 2010. [PMC free article: PMC6669240] [PubMed: 20687070]
29. Worthington HV, Clarkson JE, Bryan G, et al.: Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 12: CD000978, 2010. [PubMed: 21154347]
30. Rosen LS, Abdi E, Davis ID, et al.: Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol 24 (33): 5194-200, 2006. [PubMed: 17075109]
31. Vadhan-Raj S, Trent J, Patel S, et al.: Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. Ann Intern Med 153 (6): 358-67, 2010. [PubMed: 20855800]
32. Henke M, Alfonsi M, Foa P, et al.: Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial. J Clin Oncol 29 (20): 2815-20, 2011. [PubMed: 21670447]
33. Le QT, Kim HE, Schneider CJ, et al.: Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. J Clin Oncol 29 (20): 2808-14, 2011. [PubMed: 21670453]
34. Kuhn A, Porto FA, Miraglia P, et al.: Low-level infrared laser therapy in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in children. J Pediatr Hematol Oncol 31 (1): 33-7, 2009. [PubMed: 19125084]
35. Schubert MM, Eduardo FP, Guthrie KA, et al.: A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Support Care Cancer 15 (10): 1145-54, 2007. [PubMed: 17393191]
36. National Institutes of Health Consensus Development Conference on Oral Complications of Cancer Therapies: Diagnosis, Prevention, and Treatment. Bethesda, Maryland, April 17-19, 1989. NCI Monogr (9): 1-184, 1990. [PubMed: 2188147]
37. Bavier AR: Nursing management of acute oral complications of cancer. NCI Monogr (9): 123-8, 1990. [PubMed: 2188149]
38. Takahashi A, Aoshiba K, Nagai A: Apoptosis of wound fibroblasts induced by oxidative stress. Exp Lung Res 28 (4): 275-84, 2002. [PubMed: 12042030]
39. Bennett LL, Rosenblum RS, Perlov C, et al.: An in vivo comparison of topical agents on wound repair. Plast Reconstr Surg 108 (3): 675-87, 2001. [PubMed: 11698839]
40. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Wiley-Blackwell, 2009, pp 1589-1607.
41. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72 (7): 2234-8, 1993. [PubMed: 8374882]
42. Mori T, Yamazaki R, Aisa Y, et al.: Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer 14 (4): 392-5, 2006. [PubMed: 16633843]
43. Ohbayashi Y, Imataki O, Ohnishi H, et al.: Multivariate analysis of factors influencing oral mucositis in allogeneic hematopoietic stem cell transplantation. Ann Hematol 87 (10): 837-45, 2008. [PubMed: 18553082]
44. Lugliè PF, Mura G, Mura A, et al.: [Prevention of periodontopathy and oral mucositis during antineoplastic chemotherapy. Clinical study] Minerva Stomatol 51 (6): 231-9, 2002. [PubMed: 12147975]
45. Cheng KK, Molassiotis A, Chang AM, et al.: Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients. Eur J Cancer 37 (16): 2056-63, 2001. [PubMed: 11597384]
46. Wardley AM, Jayson GC, Swindell R, et al.: Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 110 (2): 292-9, 2000. [PubMed: 10971384]

Orofacial Pain due to Cancer

Acute and chronic pain in cancer can result from several factors, including the following:

• Pain due to malignant disease:

  -

  Local/regional cancer.

  -

  Oral involvement in systemic/hematopoietic cancer.

  -

  Metastatic disease.

• Pain due to treatment:

  -

  Surgery.

  -

  Radiation.

  -

  Chemotherapy.

• Pain unrelated to malignancy.

Pain at diagnosis is often low intensity but typically becomes more frequent and severe with advancing disease. Cancer pain may be caused by local and distant tumor effects. Direct invasion by cancer may cause pain and may result from inflammatory and neuropathic mechanisms. Effective prevention and management of pain in cancer requires knowledge of the factors and mechanisms involved.

It is estimated that 45% to 80% of all cancer patients have inadequate pain management. Seventy-five percent to 90% of patients with terminal or advanced cancer may have pain. Pain may be present in up to 85% of patients with head and neck cancers (HNCs) at diagnosis.

Orofacial pain associated with cancer management is a well-recognized adverse effect of treatment. Pain due to oral mucositis is the most frequently reported patient-related complaint during cancer therapy. Severe and painful mucositis is associated with additional hospital admissions and prolonged periods in hospital, leading to delayed, interrupted, or altered cancer therapy protocols that may affect prognosis, QOL, and cost of care. Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT), occurring in 25% to 70% of patients; oral lesions are often painful.

In addition to HNCs, oral manifestations of leukemia and lymphoma may cause pain and loss of function. Lymphomas and leukemias may induce pain by infiltration of pain-sensitive structures and if secondary oral infection occurs. Multiple myeloma frequently presents with pain and, when associated with teeth, presents a diagnostic challenge. Intracranial malignancies may give rise to orofacial pain and headache. Even in diagnosed cancer patients, the prediction of intracranial metastases with new or changed headache is difficult.

Pain may present similarly to classical trigeminal neuralgia. Jaw pain may be caused by metastatic cancer, and tumors arising from the breast, prostate, thyroid, lung, and kidney have a propensity to spread to bone in the head and neck, most commonly seen in the posterior mandible. Metastasis in the oral region may be the first indication of a distant undiscovered malignancy in up to 60% of patients. Patients with nasopharyngeal cancer report pain that may be referred to the temporomandibular joint region and masquerade as temporomandibular disorder. Orofacial pain has been reported in patients with a distant nonmetastasized cancer, most commonly in the lungs.

The mechanism of pain is thought to be involvement of the vagus or phrenic nerve. Paraneoplastic processes may present with peripheral neuropathies, particularly in patients with lung cancer and lymphoma. Neuropathies are commonly reported in patients with malignancy (1.7%–5.5%) because of the direct effects of the tumor, paraneoplastic syndromes, and treatment-related toxicities.

Orofacial Pain due to Cancer Management

The most common acute oral side effect of radiation therapy and/or cancer chemotherapy is oral mucositis. Oral mucositis and associated pain are the most distressing symptoms reported by patients receiving head and neck radiation therapy and aggressive neutropenia-inducing chemotherapy regimens. Combined chemotherapy and radiation therapy results in increased frequency, severity, and duration of mucositis. (Refer to the Oral Mucositis section of this summary for more information.)

Mucositis pain may interfere with daily activities in approximately one-third of patients, interfering with social activities and mood in more than half. Mucosal pain may persist long after the mucositis resolves. Reports of mucosal sensitivity at 1-year follow-up are common, suggesting that chronic symptoms may be related to tissue change, including epithelial atrophy and/or neuropathy.

Orofacial pain after HNC therapy can be caused by musculoskeletal syndromes, including temporomandibular disorders associated with muscular fibrosis, scar formation, and discontinuity of the jaw. Ablative surgery may lead to tissue defects that may cause significant loss of orofacial function. Resection of the maxilla and mandible leads to sensory impairment, and more than half of patients experience regional hyperalgesia or allodynia. Pain scores after surgery for HNCs are highest for oral cavity cancers, followed by cancers of the larynx and oropharynx.

At more than 6 months postsurgery, impairment due to moderate to severe pain may be seen in approximately one-third of patients. Analgesics and physiotherapy are commonly used in pain management in these patients. Long-term HNC survivors (>3 years) continue to suffer from more pain and functional problems. Surgery-related pain involves inflammatory and neuropathic pain mechanisms.

Postradiation osteonecrosis and bisphosphonate-associated osteonecrosis are recognized oral complications that may cause pain; clinical presentation may include pain, swelling, and bone exposure. Oral GVHD represents a local manifestation of a systemic disease post-HCT that may result in mucosal and arthritic pain. Viral reactivation of herpes viruses may cause pain. Postherpetic neuralgia may result in chronic pain causing painful dysesthesias in the affected area that may persist for years.

Treatment of Pain in Cancer Patients

Pain management should be directed at the diagnoses of etiologic factors, pain mechanisms involved, and pain severity. (Refer to the PDQ summary on Cancer Pain for more information.) Pain mechanisms in cancer include the following:

• Inflammation.

  -

  Malignant disease.

  -

  Complications of treatment.

  -

  Infection.

• Tumor invasion, pressure on structures, or ulceration of mucosal surface.
• Nociceptive pain.
• Neuropathic pain.

Orofacial Pain Summary

Orofacial pain is common in cancer patients and may be caused by the cancer or its treatment. Orofacial pain is frequently associated with locoregional cancer, but it can also be a sign of systemic and distant cancer.

Pain management requires diagnosis of the various causes and mechanisms of pain in cancer patients. Practitioners must obtain regular pain ratings during the treatment of patients with cancer-related pain. Because pain is frequently multifactorial, addressing each of the dimensions of a patient’s pain can improve pain control. Attention should be paid to the patient’s overall medical status and oral status.

It is important to recognize and manage the side effects of analgesic therapy, especially those induced by opioids and adjuvant medications. Use of effective topical pain therapy with the initial mucosal injury may allow for reduced duration or reduced doses of systemic medications. Awareness of adjuvant approaches to management is essential; both medications and complementary management with evidence of effect should be considered.

References

1. Epstein JB, Elad S, Eliav E, et al.: Orofacial pain in cancer: part II--clinical perspectives and management. J Dent Res 86 (6): 506-18, 2007. [PubMed: 17525349]
2. Kazemian A, Kamian S, Aghili M, et al.: Benzydamine for prophylaxis of radiation-induced oral mucositis in head and neck cancers: a double-blind placebo-controlled randomized clinical trial. Eur J Cancer Care (Engl) 18 (2): 174-8, 2009. [PubMed: 19267733]
3. Berger A, Henderson M, Nadoolman W, et al.: Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J Pain Symptom Manage 10 (3): 243-8, 1995. [PubMed: 7629418]
4. Meuser T, Pietruck C, Radbruch L, et al.: Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93 (3): 247-57, 2001. [PubMed: 11514084]
5. Eisenberg E, Marinangeli F, Birkhahn J, et al.: Time to modify the WHO analgesic ladder? Pain: Clinical Updates 13 (5): 1-4, 2005. Also available online. Last accessed January 28, 2021.
6. Benedetti C, Brock C, Cleeland C, et al.: NCCN Practice Guidelines for Cancer Pain. Oncology (Williston Park) 14 (11A): 135-50, 2000. [PubMed: 11195407]
7. Ripamonti C, Dickerson ED: Strategies for the treatment of cancer pain in the new millennium. Drugs 61 (7): 955-77, 2001. [PubMed: 11434451]
8. Rankin KV, Jones DL, Redding SW, eds.: Oral Health in Cancer Therapy: A Guide for Health Care Professionals. 3rd ed. Dental Oncology Education Program, 2008.
9. Mercadante S, Arcuri E, Tirelli W, et al.: Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study. Tumori 88 (3): 239-42, 2002 May-Jun. [PubMed: 12195763]
10. Mercadante S, Fulfaro F, Casuccio A: A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis. Eur J Cancer 38 (10): 1358-63, 2002. [PubMed: 12091067]
11. Epstein JB, Hong C, Logan RM, et al.: A systematic review of orofacial pain in patients receiving cancer therapy. Support Care Cancer 18 (8): 1023-31, 2010. [PubMed: 20544225]

Bacterial Infection

Changes in infection profiles in myelosuppressed cancer patients have occurred over the past three decades. This evolving epidemiology has been caused by multiple factors, including the use of prophylactic and therapeutic antimicrobial regimens and decreased depth and duration of myelosuppression via growth factor therapy.[17] 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 of concern.

Myeloablated cancer patients with chronic periodontal disease may develop acute periodontal infections, with associated systemic sequelae.[3,9-12] Extensive ulceration of sulcular epithelium associated with periodontal disease is not directly observable yet may represent a source of disseminated infection by a wide variety of organisms. Inflammatory signs may be masked by the underlying myelosuppression. Thus, neutropenic mouth care protocols that reduce microbial colonization of the dentition and periodontium are important during myelosuppression. Topical therapy may include the following:

• Oral rinses with 0.12% chlorhexidine digluconate.
• Irrigation with effervescent (peroxide) agents, which may affect anaerobic bacteria colonizing the periodontal pocket.
• Gentle mechanical plaque removal, including dental brushing and flossing.

Pulpal/periapical infections of dental origin can cause complications for the chemotherapy patient.[14] Such lesions should be eliminated before chemotherapy begins. Prechemotherapy endodontic therapy should be completed at least 10 days before chemotherapy begins. Teeth with poor prognoses should be extracted, using the 10-day window as a guide. Specific management guidelines are delineated in the NIH Consensus Conference statement.[14,15]

Ill-fitting, removable prosthetic appliances can traumatize oral mucosa and increase the risk of microbial invasion into deeper tissues. Denture-soaking cups can readily become colonized with a variety of pathogens, including P. aeruginosa, E. coli, Enterobacter species, Staphylococcus aureus, Klebsiella species, and Candida albicans. Dentures should be evaluated before chemotherapy begins and adjusted as necessary to reduce risk of trauma. Denture-cleansing solutions should be changed daily. In general, dentures should not be worn when the patient has ulcerative mucositis and is neutropenic (i.e., absolute neutrophil count <500 cells/mm³).

Fungal Infection

Viral Infections

References

1. Squier CA, Kremer MJ: Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr (29): 7-15, 2001. [PubMed: 11694559]
2. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. Mosby Elsevier, 2011, pp 782-98.
3. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Wiley-Blackwell, 2009, pp 1589-1607.
4. De Pauw BE, Donnelly JP: Infections in the immunocompromised host: general principles. In: Mandell GL, Bennett JE, Dolin R, eds.: Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 5th ed. Churchill Livingstone, 2000, pp 3079-90.
5. Kennedy HF, Morrison D, Kaufmann ME, et al.: Origins of Staphylococcus epidermidis and Streptococcus oralis causing bacteraemia in a bone marrow transplant patient. J Med Microbiol 49 (4): 367-70, 2000. [PubMed: 10755632]
6. Rolston KVI, Bodey GP: Infections in patients with cancer. In: Hong WK, Bast RC Jr, Hait WN, et al., eds.: Holland-Frei Cancer Medicine. 8th ed. People's Medical Publishing House-USA, 2010, pp 1921-40.
7. Giamarellou H, Antoniadou A: Infectious complications of febrile leukopenia. Infect Dis Clin North Am 15 (2): 457-82, 2001. [PubMed: 11447706]
8. Zambelli A, Montagna D, Da Prada GA, et al.: Evaluation of infectious complications and immune recovery following high-dose chemotherapy (HDC) and autologous peripheral blood progenitor cell transplantation (PBPC-T) in 148 breast cancer patients. Anticancer Res 22 (6B): 3701-8, 2002 Nov-Dec. [PubMed: 12552979]
9. Peterson DE, Minah GE, Overholser CD, et al.: Microbiology of acute periodontal infection in myelosuppressed cancer patients. J Clin Oncol 5 (9): 1461-8, 1987. [PubMed: 3625260]
10. Graber CJ, de Almeida KN, Atkinson JC, et al.: Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 27 (5): 537-42, 2001. [PubMed: 11313689]
11. Akintoye SO, Brennan MT, Graber CJ, et al.: A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (5): 581-8, 2002. [PubMed: 12424452]
12. Raber-Durlacher JE, Epstein JB, Raber J, et al.: Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer 10 (6): 466-73, 2002. [PubMed: 12353125]
13. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010. [PMC free article: PMC2914291] [PubMed: 20449756]
14. Peterson DE: Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr (9): 61-71, 1990. [PubMed: 2111469]
15. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990. [PubMed: 2342592]
16. Peters E, Monopoli M, Woo SB, et al.: Assessment of the need for treatment of postendodontic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 76 (1): 45-8, 1993. [PubMed: 8351120]
17. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990. [PubMed: 1692972]
18. Böhme A, Karthaus M, Hoelzer D: Antifungal prophylaxis in neutropenic patients with hematologic malignancies. Antibiot Chemother 50: 69-78, 2000. [PubMed: 10874456]
19. Lalla RV, Latortue MC, Hong CH, et al.: A systematic review of oral fungal infections in patients receiving cancer therapy. Support Care Cancer 18 (8): 985-92, 2010. [PMC free article: PMC2914797] [PubMed: 20449755]
20. Nicolatou-Galitis O, Athanassiadou P, Kouloulias V, et al.: Herpes simplex virus-1 (HSV-1) infection in radiation-induced oral mucositis. Support Care Cancer 14 (7): 753-62, 2006. [PubMed: 16402233]
21. Nicolatou-Galitis O, Velegraki A, Sotiropoulou-Lontou A, et al.: Effect of fluconazole antifungal prophylaxis on oral mucositis in head and neck cancer patients receiving radiotherapy. Support Care Cancer 14 (1): 44-51, 2006. [PubMed: 15947956]
22. Epstein JB, Vickars L, Spinelli J, et al.: Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol 73 (6): 682-9, 1992. [PubMed: 1437036]
23. Ellis ME, Clink H, Ernst P, et al.: Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients. Eur J Clin Microbiol Infect Dis 13 (1): 3-11, 1994. [PubMed: 8168557]
24. Schubert MM: Oral manifestations of viral infections in immunocompromised patients. Curr Opin Dent 1 (4): 384-97, 1991. [PubMed: 1666308]
25. 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]
26. Bergmann OJ, Ellermann-Eriksen S, Mogensen SC, et al.: Acyclovir given as prophylaxis against oral ulcers in acute myeloid leukaemia: randomised, double blind, placebo controlled trial. BMJ 310 (6988): 1169-72, 1995. [PMC free article: PMC2549556] [PubMed: 7767151]
27. Warkentin DI, Epstein JB, Campbell LM, et al.: Valacyclovir versus acyclovir for HSV prophylaxisin neutropenic patients. Ann Pharmacother 36 (10): 1525-31, 2002. [PubMed: 12243600]
28. Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation: Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 49 (RR-10): 1-125, CE1-7, 2000. [PubMed: 11718124]
29. Sullivan KM, Dykewicz CA, Longworth DL, et al.: Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond. Hematology Am Soc Hematol Educ Program : 392-421, 2001. [PubMed: 11722995]
30. Krüger WH, Bohlius J, Cornely OA, et al.: Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the infectious diseases working party (AGIHO) of the german society of haematology and oncology. Ann Oncol 16 (8): 1381-90, 2005. [PubMed: 15905309]
31. Apperley J, Carreras E, Gluckman E, et al., eds.: The EBMT Handbook: Haematopoietic Stem Cell Transplantation. 6th ed. European School of Haemtology and European Group for Blood and Marrow Transplantation, 2012. Also available online. Last accessed January 5, 2018.
32. Leflore S, Anderson PL, Fletcher CV: A risk-benefit evaluation of aciclovir for the treatment and prophylaxis of herpes simplex virus infections. Drug Saf 23 (2): 131-42, 2000. [PubMed: 10945375]
33. Reusser P: Management of viral infections in immunocompromised cancer patients. Swiss Med Wkly 132 (27-28): 374-8, 2002. [PubMed: 12428191]
34. Naesens L, De Clercq E: Recent developments in herpesvirus therapy. Herpes 8 (1): 12-6, 2001. [PubMed: 11867011]
35. Jubelt B: Valacyclovir and famciclovir therapy in herpes zoster. Curr Neurol Neurosci Rep 2 (6): 477-8, 2002. [PubMed: 12359099]
36. Burns LJ, Miller W, Kandaswamy C, et al.: Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation. Bone Marrow Transplant 30 (12): 945-51, 2002. [PubMed: 12476289]
37. Zaia JA: Prevention of cytomegalovirus disease in hematopoietic stem cell transplantation. Clin Infect Dis 35 (8): 999-1004, 2002. [PubMed: 12355388]
38. Kanegane H, Nomura K, Miyawaki T, et al.: Biological aspects of Epstein-Barr virus (EBV)-infected lymphocytes in chronic active EBV infection and associated malignancies. Crit Rev Oncol Hematol 44 (3): 239-49, 2002. [PubMed: 12467964]
39. Kumar S, Wairagkar NS, Mahanta J: Demonstration of Epstein-Barr virus antibodies in serum of patients with nasopharyngeal carcinoma. Indian J Cancer 38 (2-4): 72-5, 2001 Jun-Dec. [PubMed: 12593442]

References

1. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Wiley-Blackwell, 2009, pp 1589-1607.

References

1. Schubert MM, Sullivan KM: Recognition, incidence, and management of oral graft-versus-host disease. NCI Monogr (9): 135-43, 1990. [PubMed: 2188151]
2. Demarosi F, Bez C, Sardella A, et al.: Oral involvement in chronic graft-vs-host disease following allogenic bone marrow transplantation. Arch Dermatol 138 (6): 842-3, 2002. [PubMed: 12056980]
3. Abdelsayed RA, Sumner T, Allen CM, et al.: Oral precancerous and malignant lesions associated with graft-versus-host disease: report of 2 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93 (1): 75-80, 2002. [PubMed: 11805779]
4. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Wiley-Blackwell, 2009, pp 1589-1607.
5. Schima W, Pokieser P, Forstinger C, et al.: Videofluoroscopy of the pharynx and esophagus in chronic graft-versus-host disease. Abdom Imaging 19 (3): 191-4, 1994 May-Jun. [PubMed: 8019340]
6. Jacobsohn DA, Margolis J, Doherty J, et al.: Weight loss and malnutrition in patients with chronic graft-versus-host disease. Bone Marrow Transplant 29 (3): 231-6, 2002. [PubMed: 11859395]
7. Loughran TP, Sullivan K, Morton T, et al.: Value of day 100 screening studies for predicting the development of chronic graft-versus-host disease after allogeneic bone marrow transplantation. Blood 76 (1): 228-34, 1990. [PubMed: 2194590]
8. Yamada H, Chihara J, Hamada K, et al.: Immunohistology of skin and oral biopsies in graft-versus-host disease after bone marrow transplantation and cytokine therapy. J Allergy Clin Immunol 100 (6 Pt 2): S73-6, 1997. [PubMed: 9440549]
9. Epstein JB, Nantel S, Sheoltch SM: Topical azathioprine in the combined treatment of chronic oral graft-versus-host disease. Bone Marrow Transplant 25 (6): 683-7, 2000. [PubMed: 10734307]

Osteonecrosis of the Jaw Associated With Medications (ONJ)

The first reported cases of osteonecrosis of the jaw associated with medications (ONJ) were seen in patients taking bisphosphonates.[1-3] Bisphosphonates are potent inhibitors of osteoclasts. They are used in cancer patients with skeletal metastasis, including breast, prostate, or lung cancer; and in patients with multiple myeloma. Bisphosphonates are also used to treat hypercalcemia of malignancy. Bisphosphonates reduce the risk of fracture and skeletal pain, improving the quality of life of patients with malignant bone disease.[4] (Refer to the PDQ summary on Cancer Pain for more information.)

Evidence in the medical and dental literature reveals several cases of ONJ reported with the use of drugs other than bisphosphonates, including the following:[5,6]

• Denosumab, a human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL).
• The antiangiogenic drugs being tested in advanced cancer cases, including bevacizumab, sunitinib, and possibly sorafenib.

With the approval of a new antiresorptive medication, denosumab, a fully humanized monoclonal antibody that targets RANKL and that has indications similar to those of the bisphosphonates, additional reports confirmed that this new drug can also cause ONJ. Subsequently, the introduction of antiangiogenic medications in clinical trials in oncology revealed that these agents can also be associated with ONJ development, either as single drugs or when used in combination with antiresorptives. When antiangiogenics are used in combination with bisphosphonates, the risk of ONJ increases significantly.[7]

Thus, 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, it is proposed that the nomenclature that refers to this pathology be changed to ONJ, meaning osteonecrosis of the jaw that is associated with medications.

ONJ is an oral complication of antiresorptive therapy in cancer patients.[8] First reported in 2003,[1-3] ONJ is defined as the unexpected appearance of exposed necrotic bone anywhere in the oral cavity of an individual who is receiving drugs that have been associated with ONJ (bisphosphonates, denosumab, and antiangiogenics) and who has not received radiation therapy to the head and neck. The exposed bone persists for at least 6 to 8 weeks, despite the provision of standard dental care. It is also possible that symptoms of dental disease, periodontal disease, or both may be present, without visible exposed bone.[9] The occurrence of ONJ is based on cases reported in the literature, and occurrence ranges from between 1% and 10% for patients receiving the intravenous formulation (pamidronate and zoledronic acid) to less than 1% for patients taking oral bisphosphonates.[10,11]

A study evaluating the literature until December 2008 found that the prevalence of ONJ can vary according to study design and the type of bisphosphonate used. For example, studies in which patient evaluation and follow-up are conducted by dental professionals have an overall prevalence of 7.3%, whereas survey studies of large populations of patients have a prevalence of less than 1%. If the prevalence is calculated on the basis of type of bisphosphonate used, then the prevalence of cases of ONJ in which a combination of zoledronic acid and pamidronate is used over the course of therapy can be as high as 24.5%.[12] The mandible is affected in approximately 68% of cases, the maxilla in about 28% of cases, and both jawbones in approximately 4% of cases.[13] However, there have been reports of evidence of ONJ in other parts of the head and neck and skeleton.[14-16]

ONJ incidence, risk factors, and outcomes were assessed in an analysis of three phase III trials in patients who had metastatic bone disease secondary to solid tumors or myeloma and who were receiving antiresorptive therapies.[17] Patients were assigned to receive either subcutaneous injections of denosumab (120 mg) or intravenous administration of zoledronic acid (4 mg) every 4 weeks. Oral examinations were performed at baseline and every 6 months. Oral adverse events were adjudicated by a panel of dental experts. Of 5,723 patients enrolled, 89 (1.6%) were diagnosed with ONJ; 37 received zoledronic acid, and 52 received denosumab. Tooth extraction was reported for two-thirds of patients with ONJ. As of October 2010, ONJ resolved in 36% of patients (29.7% for zoledronic acid and 40.4% for denosumab). A combined analysis of these trials found that ONJ was an infrequent event, management was mostly conservative, and healing occurred in more than one-third of the patients. Bone-targeted therapy may help reduce the rate of ONJ and improve outcomes.[17]

When denosumab was compared to placebo in a study of men with nonmetastatic, high-risk, castration-resistant prostate cancer in which patients received treatment for at least 24 months, ONJ incidence was 4.6% in patients treated with denosumab; there were no cases of ONJ in the placebo group.[18] Therefore, time on medication can be a factor in the development of ONJ.

Risk factors for ONJ include the following:

• Dental extractions.[19][Level of evidence: II][20]
• Ill-fitting dentures.[19]
• Intravenous bisphosphonate (zoledronic acid, denosumab).[19,20][Level of evidence: I][12];[21][Level of evidence: I]
• Time on medication.[12,18,20]
• Multiple myeloma.[12]

The incidence of ONJ may be reduced by the implementation of dental preventive measures before bisphosphonate therapy is initiated in solid-tumor patients with bone metastases.[22,23]

References

1. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al.: Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62 (5): 527-34, 2004. [PubMed: 15122554]
2. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61 (9): 1115-7, 2003. [PubMed: 12966493]
3. Migliorati CA: Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 21 (22): 4253-4, 2003. [PubMed: 14615459]
4. 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]
5. Migliorati CA, Covington JS: New oncology drugs and osteonecrosis of the jaw (ONJ). J Tenn Dent Assoc 89 (4): 36-8; quiz 38-9, 2009. [PubMed: 20102031]
6. Yarom N, Elad S, Madrid C, et al.: Osteonecrosis of the jaws induced by drugs other than bisphosphonates - a call to update terminology in light of new data. Oral Oncol 46 (1): e1, 2010. [PubMed: 19932046]
7. 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]
8. Migliorati CA, Siegel MA, Elting LS: Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 7 (6): 508-14, 2006. [PubMed: 16750501]
9. Ruggiero SL, Dodson TB, Fantasia J, et al.: Medication-Related Osteonecrosis of the Jaw—2014 Update. Rosemont, Ill: American Association of Oral and Maxillofacial Surgeons, 2014. Available online. Last accessed January 5, 2018.
10. Woo SB, Hellstein JW, Kalmar JR: Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144 (10): 753-61, 2006. [PubMed: 16702591]
11. Khosla S, Burr D, Cauley J, et al.: Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22 (10): 1479-91, 2007. [PubMed: 17663640]
12. Migliorati CA, Woo SB, Hewson I, et al.: A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support Care Cancer 18 (8): 1099-106, 2010. [PubMed: 20411279]
13. Marx RE, Sawatari Y, Fortin M, et al.: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63 (11): 1567-75, 2005. [PubMed: 16243172]
14. Polizzotto MN, Cousins V, Schwarer AP: Bisphosphonate-associated osteonecrosis of the auditory canal. Br J Haematol 132 (1): 114, 2006. [PubMed: 16371027]
15. Khan AM, Sindwani R: Bisphosphonate-related osteonecrosis of the skull base. Laryngoscope 119 (3): 449-52, 2009. [PubMed: 19235747]
16. Longo R, Castellana MA, Gasparini G: Bisphosphonate-related osteonecrosis of the jaw and left thumb. J Clin Oncol 27 (35): e242-3, 2009. [PubMed: 19858386]
17. Saad F, Brown JE, Van Poznak C, et al.: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23 (5): 1341-7, 2012. [PubMed: 21986094]
18. 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]
19. 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]
20. Hoff AO, Toth BB, Altundag K, et al.: Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23 (6): 826-36, 2008. [PMC free article: PMC2677083] [PubMed: 18558816]
21. Stopeck AT, Lipton A, Body JJ, et al.: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28 (35): 5132-9, 2010. [PubMed: 21060033]
22. Ripamonti CI, Maniezzo M, Campa T, et al.: Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20 (1): 137-45, 2009. [PubMed: 18647964]
23. 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]
24. Migliorati CA, Schubert MM, Peterson DE, et al.: Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 104 (1): 83-93, 2005. [PubMed: 15929121]
25. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102 (4): 433-41, 2006. [PubMed: 16997108]
26. Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (5 Suppl): 85-95, 2009. [PubMed: 19371819]
27. Stockmann P, Vairaktaris E, Wehrhan F, et al.: Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer 18 (4): 449-60, 2010. [PubMed: 19609572]
28. Williamson RA: Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg 39 (3): 251-5, 2010. [PubMed: 20015614]
29. Gander T, Obwegeser JA, Zemann W, et al.: Malignancy mimicking bisphosphonate-associated osteonecrosis of the jaw: a case series and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 117 (1): 32-6, 2014. [PubMed: 24332325]
30. Vescovi P, Manfredi M, Merigo E, et al.: Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci 25 (1): 101-13, 2010. [PubMed: 19543768]
31. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, et al.: Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 65 (7): 1321-7, 2007. [PubMed: 17577496]
32. Freiberger JJ: Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (5 Suppl): 96-106, 2009. [PubMed: 19371820]
33. Pautke C, Bauer F, Tischer T, et al.: Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (3): 471-6, 2009. [PubMed: 19231768]
34. Ruggiero SL, Dodson TB, Assael LA, et al.: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw - 2009 update. Aust Endod J 35 (3): 119-30, 2009. [PubMed: 19961450]
35. Dickinson M, Prince HM, Kirsa S, et al.: Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment. Intern Med J 39 (5): 304-16, 2009. [PubMed: 19220531]
36. Berenson JR, Yellin O, Crowley J, et al.: Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid. Am J Hematol 86 (1): 25-30, 2011. [PubMed: 21120861]
37. Chaudhry AN, Ruggiero SL: Osteonecrosis and bisphosphonates in oral and maxillofacial surgery. Oral Maxillofac Surg Clin North Am 19 (2): 199-206, vi, 2007. [PubMed: 18088878]
38. Yarom N, Yahalom R, Shoshani Y, et al.: Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 18 (10): 1363-70, 2007. [PubMed: 17598065]

Preradiation Dental Evaluation and Oral Disease Stabilization

Elimination of oral disease and implementation of oral care protocols designed to maintain maximum oral health must be components of patient assessment and care before radiation therapy begins. During and after radiation therapy, oral management will be dictated by the following:

• Specific needs of the patient.
• Specifics of the radiation therapy.
• Chronic complications caused by radiation therapy.

Ongoing oral assessment and treatment of complications are essential because radiation to oral tissues typically conveys a lifelong risk of oral complications. In addition, invasive oral procedures can cause additional sequelae. Dental care typically needs to be altered because of underlying chronic radiation-induced tissue damage.

Patients should receive a comprehensive oral evaluation several weeks before high-dose upper-mantle radiation begins. This timing provides an appropriate interval for tissue healing in the event that invasive oral procedures, including dental extractions, dental scaling/polishing, and endodontic therapy, are necessary. The goal of this evaluation is to identify teeth at significant risk of infection and/or breakdown that would ultimately require aggressive or invasive dental treatment during or after the radiation that increases the risk of soft tissue necroses and osteonecroses. The likelihood of these lesions occurring postradiation increases over the patient’s lifetime as the risk of significant dental disease (restorative, periodontal, and endodontic) increases. Salivary gland hypofunction and xerostomia frequently occur postradiation. It is thus especially important that preradiation dental care strategies are instituted to reduce the impact of the complications of severely decreased saliva secretion and the associated high risk of dental caries.

In addition, three radiation-specific issues emerge:

1. Radiation injury is oral tissue–specific and dependent on dosage and portals of therapy.
2. Radiation-induced oral mucositis typically lasts 6 to 8 weeks, versus the approximate 5 to 14 days observed in chemotherapy patients. The extended radiation treatment protocols are chiefly responsible for this difference.
3. The primary cause of oral cancer is tobacco use; alcohol abuse further escalates risk. It is therefore critical that head/neck cancer patients permanently cease tobacco use.

   • Most patients with smoking-related cancer appear motivated to quit smoking at the time of cancer diagnosis.
   • Continued smoking substantially increases the likelihood of recurrence or occurrence of a second cancer in survivors, particularly in those who previously received radiation therapy.
   • A stepped-care approach to tobacco cessation is recommended, including direct physician advice to quit and provision of basic information to all patients at each contact during the first month of diagnosis, followed by more intensive pharmacologic treatment or counseling for those having difficulty quitting or remaining abstinent.

Oral Complications of Head and Neck Radiation

The oral complications of head and neck radiation can be divided into two groups on the basis of the usual time of their occurrence:

• Acute complications occurring during therapy.
• Late complications occurring after radiation therapy has ended.

Acute complications include the following:

• Oropharyngeal mucositis.[1]
• Sialadenitis and xerostomia.
• Infections (primarily candidiasis).
• Taste dysfunction.

Occasionally, tissue necrosis can be seen late during therapy, but this is relatively rare.

Chronic complications include the following:

• Mucosal fibrosis and atrophy.
• Decreased saliva secretion and xerostomia.[1]
• Accelerated dental caries related to compromised saliva secretion.
• Infections (primarily candidiasis).
• Tissue necrosis (soft tissue necrosis and osteonecrosis).
• Taste dysfunction (dysgeusia/ageusia).
• Muscular and cutaneous fibrosis.[1]
• Dysphagia.[2]

References

1. Vera-Llonch M, Oster G, Hagiwara M, et al.: Oral mucositis in patients undergoing radiation treatment for head and neck carcinoma. Cancer 106 (2): 329-36, 2006. [PubMed: 16342066]
2. Caudell JJ, Schaner PE, Meredith RF, et al.: Factors associated with long-term dysphagia after definitive radiotherapy for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 73 (2): 410-5, 2009. [PubMed: 18635320]
3. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998. [PubMed: 9659518]
4. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001.
5. Barasch A, Peterson DE: Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol 39 (2): 91-100, 2003. [PubMed: 12509961]
6. Demarosi F, Bez C, Carrassi A: Prevention and treatment of chemo- and radiotherapy-induced oral mucositis. Minerva Stomatol 51 (5): 173-86, 2002. [PubMed: 12070468]
7. Shih A, Miaskowski C, Dodd MJ, et al.: A research review of the current treatments for radiation-induced oral mucositis in patients with head and neck cancer. Oncol Nurs Forum 29 (7): 1063-80, 2002. [PubMed: 12183755]
8. Bar Ad V, Weinstein G, Dutta PR, et al.: Gabapentin for the treatment of pain related to radiation-induced mucositis in patients with head and neck tumors treated with intensity-modulated radiation therapy. Head Neck 32 (2): 173-7, 2010. [PubMed: 19572284]
9. Wong PC, Dodd MJ, Miaskowski C, et al.: Mucositis pain induced by radiation therapy: prevalence, severity, and use of self-care behaviors. J Pain Symptom Manage 32 (1): 27-37, 2006. [PubMed: 16824982]
10. Lin LC, Que J, Lin LK, et al.: Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. Int J Radiat Oncol Biol Phys 65 (3): 745-50, 2006. [PubMed: 16751063]
11. Madan PD, Sequeira PS, Shenoy K, et al.: The effect of three mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies: a randomized control trial. J Cancer Res Ther 4 (1): 3-8, 2008 Jan-Mar. [PubMed: 18417894]
12. Lalla RV, Latortue MC, Hong CH, et al.: A systematic review of oral fungal infections in patients receiving cancer therapy. Support Care Cancer 18 (8): 985-92, 2010. [PMC free article: PMC2914797] [PubMed: 20449755]
13. Nelson GM: Biology of taste buds and the clinical problem of taste loss. Anat Rec 253 (3): 70-8, 1998. [PubMed: 9700392]
14. Zheng WK, Inokuchi A, Yamamoto T, et al.: Taste dysfunction in irradiated patients with head and neck cancer. Fukuoka Igaku Zasshi 93 (4): 64-76, 2002. [PubMed: 12048909]
15. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. BC Decker Inc, 2003, pp 113-28.
16. Ripamonti C, Zecca E, Brunelli C, et al.: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 82 (10): 1938-45, 1998. [PubMed: 9587128]

Mucosal Lesions

Mucosal lesions include epithelial atrophy, reduced vascularization, and submucosal fibrosis. These changes lead to an atrophic, friable barrier. Fibrosis involving muscle, dermis, and the temporomandibular joint results in compromised oral function. Salivary tissue changes include loss of acinar cells, alteration in duct epithelium, fibrosis, and fatty degeneration. Compromised vascularization and remodeling capacity of bone leads to risk of osteonecrosis.

Salivary Gland Hypofunction and Xerostomia

Ionizing radiation to salivary glands results in inflammatory and degenerative effects on salivary gland parenchyma, especially serous acinar cells. The early salivary gland tissue response to irradiation results in decreased salivary flow rates within the first week of treatment, and xerostomia (the subjective feeling of oral dryness) becomes apparent when doses exceed 10 Gy.

The degree of dysfunction is related to the radiation dose and volume of glandular tissue in the radiation field. Doses larger than 54 Gy are generally considered to induce irreversible dysfunction. Serous parotid glands may be more susceptible to radiation effects than are nonserous submandibular, sublingual, and minor salivary gland tissues. Management strategies described for late salivary gland complications are generally applicable to the acute complications in the head/neck radiation patient. (Refer to the Oral and dental management of the xerostomic patient section of this summary for more information.)

Salivary gland hypofunction (decreased salivary gland secretion) and xerostomia are among the most frequent and severe long-term side effects of radiation therapy to the head and neck region. The adverse effects will have a significant impact on a patient’s quality of life in a lifelong perspective after radiation treatment.[5]

Xerostomia is caused by salivary gland hypofunction. Saliva is necessary for the normal execution of oral functions such as taste, swallowing, and speech. Unstimulated whole salivary flow rates lower than 0.1 mL per minute are considered pathologic low (normal salivary flow rate = 0.3–0.5 mL/min).[6]

Late salivary tissue changes induced by radiation therapy include loss of acinar cells, alteration in duct epithelium, fibrosis, and fatty degeneration. The early response to irradiation resulting in markedly decreased salivary flow rates within the first week of treatment is followed by a further decline in saliva secretion and worsening of xerostomia after radiation therapy (1–3 months posttreatment), whereafter salivary secretion and xerostomia gradually recover over time (maximum recovery, 1–2 years posttherapy), depending on the total radiation dose to the gland tissue.[6] Recovery of salivary gland function is usually incomplete, and the overall degree of dryness can range from mild to severe.

It should be noted that salivary gland hypofunction and xerostomia may also be sequelae of other radiation regimens, e.g., radioactive iodine treatment of thyroid cancer and preconditioning total body irradiation in hematopoietic stem cell transplantation for the treatment of hematologic malignancies—although to a much lesser severity.[7,8]

Symptoms and signs of salivary gland hypofunction include the following:

• Xerostomia.
• Lip dryness/crusting.
• Fissures at lip commissures.
• Atrophy of dorsal tongue surface.
• Atrophic and fragile oral mucosa.
• Difficulties in speech, chewing, and swallowing.
• Difficulty in wearing dentures (edentulous patients).
• Oral burning sensation.
• Taste disturbances.
• Increased thirst.
• Sensitivity/pain in response to spicy foods and strong flavorings.

Salivary gland tissues that have been excluded from the radiation portal may become hyperplastic, partially compensating for the nonfunctional glands at other oral sites.

Salivary gland hypofunction also alters the mechanical cleansing ability and the buffer capacity of the mouth, thereby contributing to a high risk of accelerated dental caries (cavities) and periodontal disease. Also, the progression of dental caries is accelerated by the reduction in antimicrobial proteins normally contained in saliva.

In summary, salivary gland hypofunction produces the following changes in the mouth that collectively cause patient discomfort and increased risk of oral lesions:

• Increase in salivary viscosity, with resultant impaired lubrication of oral tissues.
• Decrease in flushing/clearance of acid production after sugar exposure, resulting in demineralization of the teeth and leading to dental decay.
• Compromise of buffering capacity and salivary pH, with increased risk for dental caries and erosion.
• Increase in pathogenicity of oral flora.
• Accumulated bacterial plaque levels caused by patient difficulty in maintaining oral hygiene (caused by soreness of oral mucosa and/or muscular fibrosis/trismus).

Caries

The risk of dental caries increases secondary to a number of factors, including shifts to a cariogenic flora, reduced concentrations of salivary antimicrobial proteins, and loss of mineralizing components.[3] (Refer to the Conditions Affected By Both Chemotherapy and Head/Neck Radiation section of this summary for more information.) As reported in a systematic review, the overall count of decayed, missing, or filled teeth (DMFT) in patients who were post–antineoplastic therapy was 9.19 (standard deviation [SD], 7.98; n = 457). The DMFT for patients who were post–radiation therapy was 17.01 (SD, 9.14; n = 157), which was much higher than that in patients who were postchemotherapy (DMFT, 4.5).[27]

Treatment strategies must be directed to each component of the caries process. Optimal oral hygiene must be maintained. Xerostomia should be managed whenever possible via salivary substitutes or replacements. Caries resistance can be enhanced with the use of topical fluorides and/or remineralizing agents. Efficacy of topical products may be enhanced by increased contact time on the teeth by application using vinyl carriers. Patients unable to effectively comply with use of fluoride trays should be instructed to use brush-on gels and rinses.

Increased colonization with Streptococcus mutans and Lactobacillus species increases caries risk. Culture data can be useful in defining level of risk in relation to colonization patterns. Topical fluorides or chlorhexidine rinses may lead to reduced levels of S. mutans but not Lactobacilli. Because of adverse drug interactions, fluoride and chlorhexidine dosing should be separated by several hours.

Remineralizing agents, which are high in calcium phosphate and fluoride, have demonstrated salutary in vitro and clinical effects. The intervention may be enhanced by delivering the drug via customized vinyl carriers. This approach extends the contact time of active drug with tooth structure, which leads to increased uptake into enamel.

A systematic review of managing dental caries in post–radiation therapy patients produced the following conclusions:[27,28]

• Fluoride: The use of fluoride products reduces caries activity in patients who are post–radiation therapy. The type of fluoride gel or fluoride delivery system used did not significantly influence caries activity.
• Chlorhexidine: The use of chlorhexidine rinse reduces plaque scores and oral streptococcus mutans scores. This reduction was not seen with lactobacillus counts.
• Dental restorative materials: There is evidence suggesting that conventional glass ionomer restorations performed more poorly than did resin-modified glass ionomer, composite resin, and amalgam restorations in patients who had been treated with radiation therapy.

Osteoradionecrosis

Risk of osteoradionecrosis (ORN) is directly related to radiation dose and volume of tissue irradiated. The unilateral vascular supply to each half of the mandible results in postradiation ORN most frequently involving the mandible, compared with the maxilla. Presenting clinical features include:

• Pain.
• Diminished or complete loss of sensation.
• Fistula.
• Infection.

Pathologic fracture can occur because the compromised bone is unable to appropriately undergo repair at the involved sites. Risk of tissue necrosis is in part related to trauma or oral infection; however, idiopathic cases can also occur. Patients who have received high-dose radiation to the head and neck are at lifelong risk for ORN, with an overall risk of approximately 15%.

Ideally, postradiation management or ORN is based on prevention that begins with comprehensive oral and dental care before radiation therapy begins. The dentition, periodontium, periapices, and mucosa should be thoroughly examined to identify oral disease, which could lead to serious odontogenic, periodontal, or mucosal infections that could necessitate surgical therapy postradiation. Oral disease should be eliminated pretreatment. Dentition that exhibits poor prognosis and is within high-dose fields should be extracted before radiation therapy begins. Ideally, at least 7 to 14 days should be allowed for healing before initiation of radiation; some have suggested allowing up to 21 days. Surgical technique should be as atraumatic as possible and use primary wound closure.

Patients who develop ORN should be comprehensively managed to:

• Eliminate trauma.
• Avoid removable dental prosthesis if the denture-bearing area is within the osteonecrotic field.
• Ensure adequate nutritional intake.
• Discontinue tobacco and alcohol use.

Topical antibiotics (e.g., tetracycline) or antiseptics (e.g., chlorhexidine) may contribute to wound resolution. Wherever possible, coverage of the exposed bone with mucosa should be achieved. Analgesics for pain control are often effective. Local resection of bone sequestra may be possible.

Hyperbaric oxygen therapy (HBO) is recommended for management of ORN, although it has not been universally accepted. HBO has been reported to increase oxygenation of irradiated tissue, promote angiogenesis, and enhance osteoblast repopulation and fibroblast function. HBO is usually prescribed as 20 to 30 dives at 100% oxygen and 2 to 2.5 atmospheres of pressure. If surgery is needed, ten dives of postsurgical HBO are recommended. Unfortunately, HBO technology is not always accessible to patients who might otherwise benefit because of lack of available units and the high price of care.

A systematic review regarding treatment-dependent frequency, current management strategies, and future studies has been published.[29] A total of 43 articles published between 1990 and 2008 were reviewed. The weighted prevalence for ORN included the following:

• Conventional radiation therapy, 7.4%.
• IMRT, 5.1%.
• Chemoradiation therapy, 6.8%.
• Brachytherapy, 5.3%.

HBO may contribute a role in management of ORN. However, no clear recommendations for the prevention or treatment of ORN could be established on the basis of the literature reviewed. The review concluded that new cancer treatment modalities such as IMRT and concomitant chemoradiation therapy have had minimal effect on prevalence of ORN. No studies have systematically addressed the impact of ORN on either quality of life or cost of care. Research addressing these collective issues is needed.

Partial mandibulectomy may be necessary in severe cases of ORN. The mandible can be reconstructed to provide continuity for esthetics and function. A multidisciplinary cancer team that includes oncologists, oncology nurses, maxillofacial prosthodontists, general dentists, hygienists, and physical therapists is appropriate for management of these patients.

Tissue Necrosis

Necrosis and secondary infection of previously irradiated tissue is a serious complication for patients who have undergone radiation therapy for head and neck tumors.[3] Acute effects typically involve oral mucosa. Chronic changes involving bone and mucosa are a result of the process of vascular inflammation and scarring that in turn result in hypovascular, hypocellular, and hypoxic changes. Infection secondary to tissue injury and osteonecrosis confounds the process.

Soft tissue necrosis can involve any mucosal surface in the mouth, though nonkeratinized surfaces appear to be at moderately higher risk. Trauma and injury are often associated with nonhealing soft tissue necrotic lesions, though spontaneous lesions are also reported. Soft tissue necrosis begins as an ulcerative break in the mucosal surface and can spread in diameter and depth. Pain will generally become more prominent as soft tissue necrosis becomes worse. Secondary infection is a risk.

Mandibular Dysfunction

Musculoskeletal syndromes may develop secondary to radiation therapy and surgery. Lesions include soft tissue fibrosis, surgically induced mandibular discontinuity, and parafunctional habits associated with emotional stress caused by cancer and its treatment. Patients can be instructed in physical therapy interventions such as mandibular stretching exercises and the use of prosthetic aids designed to reduce the severity of fibrosis. It is important that these approaches be instituted before trismus develops. If clinically significant changes develop, several approaches can be considered, including the following:

• Stabilization of occlusion.
• Use of trigger-point injection and other pain management strategies.
• Use of muscle relaxants.
• Use of tricyclic medications.

Trismus

Trismus has been associated with significant morbidity post–radiation therapy, with significant health implications, including reduced nutrition due to impaired mastication, difficulty in speaking, and compromised oral hygiene.[30] Limitations in jaw opening have been reported in 6% to 86% of patients who received radiation to the temporomandibular joint and/or masseter/pterygoid muscles, with frequency and severity that are somewhat unpredictable.[31]

The loss of function and range of mandibular motion from radiation therapy appears to be related to fibrosis in and damage to the muscles of mastication. Studies have demonstrated that an abnormal proliferation of fibroblasts is an important initial event in these reactions. Additionally, there may be scar tissue from radiation therapy or surgery, nerve damage, or a combination of these factors. Regardless of the immediate cause, mandibular hypomobility will ultimately result in degeneration of both muscle and temporomandibular joint.

Radiation therapy involving the temporomandibular joint, the pterygoid muscles, or the masseter muscle is most likely to result in trismus.[30] Tumors related to this type of radiation can appear in the following locations:

• Nasopharynx.
• Oral cavity.
• Oropharynx.
• Base of tongue.
• Salivary gland.
• Maxilla or mandible.

The prevalence of trismus increases with increasing doses of radiation, and levels in excess of 60 Gy are more likely to cause trismus.[5] Patients who have been previously irradiated and who are being treated for a recurrence appear to be at higher risk of trismus than those who are receiving their first treatment.[32,33] This suggests that the effects of radiation are cumulative, even over many years. Radiation-induced trismus may begin toward the end of radiation therapy or at any time during the subsequent 24 months. Limitations in opening the mouth often increase slowly over several weeks or months. The condition may worsen over time or remain the same, or the symptoms may reduce over time, even in the absence of treatment.

Limited mouth opening frequently results in reduced nutritional status. These patients may experience significant weight loss and nutritional deficits.[34] It is generally accepted that weight loss of more than 10% of initial body weight is considered significant. This is of particular importance at a time when the patient is recovering from surgery, chemotherapy, and/or radiation therapy. Additionally, it lowers the ability for social eating and thereby increases the risk of social isolation and decrease in quality of life in patients with HNC.

Finally, limited mouth opening can result in compromised oral hygiene. Patients who have undergone radiation therapy involving the salivary glands must maintain excellent oral hygiene to prevent dental caries. Deficits in oral hygiene can aggravate mucosal and dental problems, with the subsequent risk of mandibular ORN. Also, dental work and other professional oral care measures such as surgery can be made more difficult, which might even result in compromised oncologic follow-up.

The weighted prevalence of trismus with conventional radiation is estimated to be 25%, but 5% with IMRT only. Trismus prevalence in studies of chemoradiation is approximately 30%.[35]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990. [PubMed: 1692972]
2. Epstein JB, Wong FL, Stevenson-Moore P: Osteoradionecrosis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 45 (2): 104-10, 1987. [PubMed: 3468211]
3. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. BC Decker Inc, 2003, pp 113-28.
4. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010. [PubMed: 20237805]
5. Teguh DN, Levendag PC, Voet P, et al.: Trismus in patients with oropharyngeal cancer: relationship with dose in structures of mastication apparatus. Head Neck 30 (5): 622-30, 2008. [PubMed: 18213726]
6. Jellema AP, Slotman BJ, Doornaert P, et al.: Impact of radiation-induced xerostomia on quality of life after primary radiotherapy among patients with head and neck cancer. Int J Radiat Oncol Biol Phys 69 (3): 751-60, 2007. [PubMed: 17560735]
7. Hyer S, Kong A, Pratt B, et al.: Salivary gland toxicity after radioiodine therapy for thyroid cancer. Clin Oncol (R Coll Radiol) 19 (1): 83-6, 2007. [PubMed: 17305259]
8. Dahllöf G, Bågesund M, Ringdén O: Impact of conditioning regimens on salivary function, caries-associated microorganisms and dental caries in children after bone marrow transplantation. A 4-year longitudinal study. Bone Marrow Transplant 20 (6): 479-83, 1997. [PubMed: 9313881]
9. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 18 (8): 1061-79, 2010. [PubMed: 20333412]
10. Seikaly H, Jha N, Harris JR, et al.: Long-term outcomes of submandibular gland transfer for prevention of postradiation xerostomia. Arch Otolaryngol Head Neck Surg 130 (8): 956-61, 2004. [PubMed: 15313866]
11. Jha N, Seikaly H, Harris J, et al.: Phase III randomized study: oral pilocarpine versus submandibular salivary gland transfer protocol for the management of radiation-induced xerostomia. Head Neck 31 (2): 234-43, 2009. [PubMed: 19107948]
12. Buentzel J, Micke O, Adamietz IA, et al.: Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled phase III study. Int J Radiat Oncol Biol Phys 64 (3): 684-91, 2006. [PubMed: 16243440]
13. Sasse AD, Clark LG, Sasse EC, et al.: Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys 64 (3): 784-91, 2006. [PubMed: 16198504]
14. Wasserman TH, Brizel DM, Henke M, et al.: Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial. Int J Radiat Oncol Biol Phys 63 (4): 985-90, 2005. [PubMed: 16253773]
15. Brizel DM, Overgaard J: Does amifostine have a role in chemoradiation treatment? Lancet Oncol 4 (6): 378-81, 2003. [PubMed: 12788413]
16. Rieke JW, Hafermann MD, Johnson JT, et al.: Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized clinical trials. Int J Radiat Oncol Biol Phys 31 (3): 661-9, 1995. [PubMed: 7852133]
17. Scarantino C, LeVeque F, Swann RS, et al.: Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients. J Support Oncol 4 (5): 252-8, 2006. [PubMed: 16724649]
18. Burlage FR, Roesink JM, Kampinga HH, et al.: Protection of salivary function by concomitant pilocarpine during radiotherapy: a double-blind, randomized, placebo-controlled study. Int J Radiat Oncol Biol Phys 70 (1): 14-22, 2008. [PubMed: 17869018]
19. Chambers MS, Jones CU, Biel MA, et al.: Open-label, long-term safety study of cevimeline in the treatment of postirradiation xerostomia. Int J Radiat Oncol Biol Phys 69 (5): 1369-76, 2007. [PubMed: 17855005]
20. Jham BC, Teixeira IV, Aboud CG, et al.: A randomized phase III prospective trial of bethanechol to prevent radiotherapy-induced salivary gland damage in patients with head and neck cancer. Oral Oncol 43 (2): 137-42, 2007. [PubMed: 16798061]
21. Blom M, Lundeberg T: Long-term follow-up of patients treated with acupuncture for xerostomia and the influence of additional treatment. Oral Dis 6 (1): 15-24, 2000. [PubMed: 10673783]
22. O'Sullivan EM, Higginson IJ: Clinical effectiveness and safety of acupuncture in the treatment of irradiation-induced xerostomia in patients with head and neck cancer: a systematic review. Acupunct Med 28 (4): 191-9, 2010. [PubMed: 21062848]
23. Cho JH, Chung WK, Kang W, et al.: Manual acupuncture improved quality of life in cancer patients with radiation-induced xerostomia. J Altern Complement Med 14 (5): 523-6, 2008. [PubMed: 18532895]
24. Strietzel FP, Martín-Granizo R, Fedele S, et al.: Electrostimulating device in the management of xerostomia. Oral Dis 13 (2): 206-13, 2007. [PubMed: 17305624]
25. Strietzel FP, Lafaurie GI, Mendoza GR, et al.: Efficacy and safety of an intraoral electrostimulation device for xerostomia relief: a multicenter, randomized trial. Arthritis Rheum 63 (1): 180-90, 2011. [PubMed: 20882668]
26. Lafaurie G, Fedele S, López RM, et al.: Biotechnological advances in neuro-electro-stimulation for the treatment of hyposalivation and xerostomia. Med Oral Patol Oral Cir Bucal 14 (2): E76-80, 2009. [PubMed: 19179954]
27. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010. [PMC free article: PMC2914291] [PubMed: 20449756]
28. Brennan MT, Elting LS, Spijkervet FK: Systematic reviews of oral complications from cancer therapies, Oral Care Study Group, MASCC/ISOO: methodology and quality of the literature. Support Care Cancer 18 (8): 979-84, 2010. [PubMed: 20306090]
29. Peterson DE, Doerr W, Hovan A, et al.: Osteoradionecrosis in cancer patients: the evidence base for treatment-dependent frequency, current management strategies, and future studies. Support Care Cancer 18 (8): 1089-98, 2010. [PubMed: 20526784]
30. Dijkstra PU, Kalk WW, Roodenburg JL: Trismus in head and neck oncology: a systematic review. Oral Oncol 40 (9): 879-89, 2004. [PubMed: 15380165]
31. Louise Kent M, Brennan MT, Noll JL, et al.: Radiation-induced trismus in head and neck cancer patients. Support Care Cancer 16 (3): 305-9, 2008. [PubMed: 17965892]
32. Dijkstra PU, Huisman PM, Roodenburg JL: Criteria for trismus in head and neck oncology. Int J Oral Maxillofac Surg 35 (4): 337-42, 2006. [PubMed: 16280237]
33. Yeh SA, Tang Y, Lui CC, et al.: Treatment outcomes and late complications of 849 patients with nasopharyngeal carcinoma treated with radiotherapy alone. Int J Radiat Oncol Biol Phys 62 (3): 672-9, 2005. [PubMed: 15936544]
34. Hsiung CY, Huang EY, Ting HM, et al.: Intensity-modulated radiotherapy for nasopharyngeal carcinoma: the reduction of radiation-induced trismus. Br J Radiol 81 (970): 809-14, 2008. [PubMed: 18591201]
35. Bensadoun RJ, Riesenbeck D, Lockhart PB, et al.: A systematic review of trismus induced by cancer therapies in head and neck cancer patients. Support Care Cancer 18 (8): 1033-8, 2010. [PubMed: 20213237]
36. Chua DT, Lo C, Yuen J, et al.: A pilot study of pentoxifylline in the treatment of radiation-induced trismus. Am J Clin Oncol 24 (4): 366-9, 2001. [PubMed: 11474263]
37. Grandi G, Silva ML, Streit C, et al.: A mobilization regimen to prevent mandibular hypomobility in irradiated patients: an analysis and comparison of two techniques. Med Oral Patol Oral Cir Bucal 12 (2): E105-9, 2007. [PubMed: 17322796]
38. Hartl DM, Cohen M, Juliéron M, et al.: Botulinum toxin for radiation-induced facial pain and trismus. Otolaryngol Head Neck Surg 138 (4): 459-463, 2008. [PubMed: 18359354]
39. Melchers LJ, Van Weert E, Beurskens CH, et al.: Exercise adherence in patients with trismus due to head and neck oncology: a qualitative study into the use of the Therabite. Int J Oral Maxillofac Surg 38 (9): 947-54, 2009. [PubMed: 19414238]
40. Shulman DH, Shipman B, Willis FB: Treating trismus with dynamic splinting: a cohort, case series. Adv Ther 25 (1): 9-16, 2008. [PubMed: 18227979]

Salivary Gland Hypofunction and Xerostomia

Radiation therapy can damage salivary glands, causing salivary hypofunction and xerostomia. (Refer to the Oral Complications of Head and Neck Radiation section of this summary for more information.) In addition, selected chemotherapeutic agents (singly or in combination) have been implicated in causing salivary dysfunction and xerostomia.[1] However, it has not been possible to draw consistent conclusions about the effects of cancer chemotherapy on salivary gland function.[2]

Dysphagia

Dysphagia and odynophagia are common in cancer patients and can exist before, during, and after treatment:

• Dysphagia predisposes to aspiration and potentially life-threatening pulmonary complications.[3]
• Swallowing disorders may lead to unfavorable dietary changes and decreased oral intake, which may result in dehydration, malnutrition, delayed wound healing, and decreased resistance to infection.
• Tube feeding may become necessary, which may further compromise swallowing.
• Opioids administered for the management of odynophagia may cause xerostomia and constipation.
• Difficulties with speaking, eating and drinking, or drooling may affect mental health and put patients and family members in social isolation.

All of these problems, plus the patient perception of swallowing difficulties, significantly decrease health-related quality of life.[3,4]

Dysphagia is most prominent in patients with head and neck cancers but may also develop in patients with other malignancies as a symptom of oropharyngeal or esophageal mucositis or infection. In addition, dysphagia can be associated with graft-versus-host disease.

The prevalence and severity of pretreatment dysphagia associated with head and neck tumors depend on tumor stage and localization.[5] Pretreatment dysphagia is most prevalent in patients with pharyngeal and laryngeal cancers.[6] Surgical interventions for head and neck tumors result in anatomic or neurologic insults with site-specific patterns of dysphagia.[7] In general, the larger the resection, the more swallowing function will be impaired.

The severity of radiation-induced dysphagia depends on the following:[8]

• Total radiation dose.
• Fraction size and schedule.
• Target volumes.
• Treatment delivery techniques.
• Concurrent chemotherapy.
• Genetic factors.
• Feeding status (via percutaneous endoscopic gastrostomy [PEG] tube or nil per os [NPO, nothing by mouth]).
• Smoking status.
• Psychological coping factors.

Intensified schedules and the use of chemoradiation therapy have been shown to improve locoregional control and survival but come at the cost of more severe acute and chronic side effects. Intensity-modulated radiation therapy (IMRT) has emerged as an effective technique to deliver the full radiation dose to the tumor and regions at risk while reducing exposure of surrounding healthy tissues. However, the preservation of anatomy does not necessarily translate into the preservation of swallowing function.[9]

Mucositis induced by chemoradiation therapy or chemotherapy alone, edema, pain, thickened mucous saliva and hyposalivation, radiation dermatitis, and infection may all contribute to acute dysphagia. The use of epidermal growth factor inhibitors seems not to be associated with increased mucositis and acute dysphagia.[10]

By 3 months posttreatment, acute clinical effects have largely resolved, and normal swallowing function starts to return in most patients. Unfortunately, in head and neck cancer patients treated with chemoradiation, a continuing cascade of inflammatory cytokines triggered by oxidative stress and hypoxia may damage exposed tissues, and dysphagia may develop even years after the completion of treatment. Late sequelae that may contribute to chronic dysphagia include the following:

• Reduced capillary flow.
• Atrophy and necrosis.
• Lymphedema.
• Neuromuscular fibrosis leading to trismus and stricture formation.
• Hyposalivation.
• Infection.

Successful management of dysphagia requires the following:

• Interdisciplinary collaboration.
• Accurate and early diagnostic workup.
• Effective preventative and therapeutic strategies.
• An individual approach geared to unique patient characteristics.

Dysphagia- and aspiration-related structures have been identified, and minimizing radiation to these bystander tissues results in better swallowing outcomes.[11] Because hyposalivation affects swallowing function, strategies aimed at sparing salivary glands such as IMRT and the use of amifostine may improve swallowing outcomes.[12,13]

A predictive model for persistent swallowing dysfunction following chemoradiation therapy for head and neck cancer has been developed.[14] Early involvement of a speech and language therapist is critical to assess swallow function and aspiration risk and to generate a treatment plan that includes patient education and swallow therapy.[15] Cooperation with a dietician is important to ensure adequate and safe nutrition. Prosthodontic interventions may improve swallowing performance, and patients may benefit from psychological support.

Dysgeusia

Dysgeusia can be a prominent symptom in patients who are receiving chemotherapy or head/neck radiation.[16,17] Etiology is likely associated with several factors, including direct neurotoxicity to taste buds, xerostomia, infection, and psychologic conditioning. In addition, taste dysfunction can be associated with damage caused by graft-versus-host disease to the taste perception units. (Refer to the Graft-versus-Host Disease section of this summary for more information.)

Patients receiving chemotherapy may experience unpleasant taste secondary to diffusion of drug into the oral cavity. In addition, chemotherapy patients often describe dysgeusia in the early weeks after cessation of cytotoxic therapy. This symptom in general is reversible, and taste sensation returns to normal in the ensuing months.

By comparison, however, 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 the taste cells has been proposed as the principal mechanism for loss of the sense of taste. In many cases, taste acuity returns in 2 to 3 months after cessation of radiation. However, many other patients develop permanent hypogeusia. Zinc supplementation (zinc sulfate 220 mg 2 times a day) has been reported to be useful in some patients; the overall benefit of this treatment remains unclear.[18];[19][Level of evidence: I]

Nutritional Considerations

Patients with head and neck cancer are at high risk for nutritional problems. Contributing to malnutrition are the following:[20]

• The malignancy itself.
• Poor nutrition before diagnosis.
• Complications of surgery, radiation therapy, and chemotherapy.

In cancer patients, loss of appetite can also occur secondary to mucositis, xerostomia, taste loss, dysphagia, nausea, and vomiting. Quality of life is compromised as eating becomes more problematic. Oral pain with eating may lead to selection of foods that do not aggravate the oral tissues, often at the expense of adequate nutrition. Nutritional deficiencies can be minimized by modifying the texture and consistency of the diet and by adding more frequent meals and snacks to increase calories and protein. Ongoing nutrition assessment and counseling with a registered dietitian should be part of the patient’s treatment plan.[21]

Many patients who receive radiation therapy alone are able to tolerate soft foods; however, as treatment progresses, most patients must transition to liquid diets using high-calorie, high-protein liquid nutritional supplements, and some may require enteral feeding tubes to meet their nutritional needs. Almost all patients receiving concurrent chemotherapy and radiation therapy will become fully dependent on enteral nutritional support within 3 to 4 weeks of therapy. Numerous studies have demonstrated the benefit of enteral feedings initiated at the onset of treatment, before significant weight loss has occurred.[22,23]

Oral nutrition is reinstituted after treatment has concluded and the radiated site has adequately healed. Oral nutrition often requires a team approach. The assistance of a speech and swallowing therapist to assess for any swallowing dysfunction resulting from surgery or treatment is often necessary and beneficial in easing the transition back to solid foods. The number of tube feedings can be decreased as a patient's oral intake increases, with tube feeding being discontinued when 75% of a patient's nutrition needs are being met orally. Although most patients will resume adequate oral intake, many will continue to experience chronic complications such as taste changes, xerostomia, and varying degrees of dysphagia that can affect their nutritional status and quality of life.[20,21]

Fatigue

Cancer patients undergoing high-dose chemotherapy and/or radiation therapy can experience fatigue related to either the disease or its treatment.[24] These processes can produce sleep deprivation or metabolic disorders that collectively contribute to compromised oral status. For example, the fatigued patient will likely have impaired compliance with mouth care protocols designed to otherwise minimize risk of mucosal ulceration, infection, and pain. In addition, biochemical abnormalities are likely involved in many patients. The psychosocial component can also play a major role, with depression contributing to overall fatigue. (Refer to the PDQ summary on Fatigue for more information.)

References

1. Jensen SB, Mouridsen HT, Reibel J, et al.: Adjuvant chemotherapy in breast cancer patients induces temporary salivary gland hypofunction. Oral Oncol 44 (2): 162-73, 2008. [PubMed: 17588802]
2. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010. [PubMed: 20237805]
3. Nguyen NP, Moltz CC, Frank C, et al.: Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol 15 (3): 383-8, 2004. [PubMed: 14998839]
4. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, et al.: Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol 26 (22): 3770-6, 2008. [PubMed: 18669465]
5. Logemann JA, Rademaker AW, Pauloski BR, et al.: Site of disease and treatment protocol as correlates of swallowing function in patients with head and neck cancer treated with chemoradiation. Head Neck 28 (1): 64-73, 2006. [PMC free article: PMC1380204] [PubMed: 16302193]
6. Pauloski BR, Rademaker AW, Logemann JA, et al.: Pretreatment swallowing function in patients with head and neck cancer. Head Neck 22 (5): 474-82, 2000. [PubMed: 10897107]
7. Kronenberger MB, Meyers AD: Dysphagia following head and neck cancer surgery. Dysphagia 9 (4): 236-44, 1994. [PubMed: 7805423]
8. Platteaux N, Dirix P, Dejaeger E, et al.: Dysphagia in head and neck cancer patients treated with chemoradiotherapy. Dysphagia 25 (2): 139-52, 2010. [PubMed: 19711127]
9. Mittal BB, Pauloski BR, Haraf DJ, et al.: Swallowing dysfunction--preventative and rehabilitation strategies in patients with head-and-neck cancers treated with surgery, radiotherapy, and chemotherapy: a critical review. Int J Radiat Oncol Biol Phys 57 (5): 1219-30, 2003. [PubMed: 14630255]
10. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007. [PubMed: 17538164]
11. Eisbruch A, Schwartz M, Rasch C, et al.: Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 60 (5): 1425-39, 2004. [PubMed: 15590174]
12. Sasse AD, Clark LG, Sasse EC, et al.: Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys 64 (3): 784-91, 2006. [PubMed: 16198504]
13. Büntzel J, Glatzel M, Mücke R, et al.: Influence of amifostine on late radiation-toxicity in head and neck cancer--a follow-up study. Anticancer Res 27 (4A): 1953-6, 2007 Jul-Aug. [PubMed: 17649803]
14. Langendijk JA, Doornaert P, Rietveld DH, et al.: A predictive model for swallowing dysfunction after curative radiotherapy in head and neck cancer. Radiother Oncol 90 (2): 189-95, 2009. [PubMed: 19167120]
15. Murphy BA, Gilbert J: Dysphagia in head and neck cancer patients treated with radiation: assessment, sequelae, and rehabilitation. Semin Radiat Oncol 19 (1): 35-42, 2009. [PubMed: 19028344]
16. Bartoshuk LM: Chemosensory alterations and cancer therapies. NCI Monogr (9): 179-84, 1990. [PubMed: 2342591]
17. Garrick R: Neurologic complications. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge University Press, 2000, pp 958-79.
18. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. BC Decker Inc, 2003, pp 113-28.
19. Ripamonti C, Zecca E, Brunelli C, et al.: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 82 (10): 1938-45, 1998. [PubMed: 9587128]
20. Robinson CA: Enteral nutrition in adult oncology. In: Elliott L, Molseed LL, McCallum PD, eds.: The Clinical Guide to Oncology Nutrition. 2nd ed. American Dietetic Association, 2006, pp 138-55.
21. Kagan SH, Sweeney-Cordes E: Head and neck cancers. In: Kogut VJ, Luthringer SL, eds.: Nutritional Issues in Cancer Care. Oncology Nursing Society, 2005, pp 103-16.
22. Beer KT, Krause KB, Zuercher T, et al.: Early percutaneous endoscopic gastrostomy insertion maintains nutritional state in patients with aerodigestive tract cancer. Nutr Cancer 52 (1): 29-34, 2005. [PubMed: 16091001]
23. Tyldesley S, Sheehan F, Munk P, et al.: The use of radiologically placed gastrostomy tubes in head and neck cancer patients receiving radiotherapy. Int J Radiat Oncol Biol Phys 36 (5): 1205-9, 1996. [PubMed: 8985044]
24. Visser MR, Smets EM: Fatigue, depression and quality of life in cancer patients: how are they related? Support Care Cancer 6 (2): 101-8, 1998. [PubMed: 9540167]

References

1. Dodd MJ, Dibble S, Miaskowski C, et al.: A comparison of the affective state and quality of life of chemotherapy patients who do and do not develop chemotherapy-induced oral mucositis. J Pain Symptom Manage 21 (6): 498-505, 2001. [PubMed: 11397608]
2. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, et al.: Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol 26 (22): 3770-6, 2008. [PubMed: 18669465]

References

1. Cohen A, Rovelli R, Zecca S, et al.: Endocrine late effects in children who underwent bone marrow transplantation: review. Bone Marrow Transplant 21 (Suppl 2): S64-7, 1998. [PubMed: 9630330]
2. Dahllöf G, Barr M, Bolme P, et al.: Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 65 (1): 41-4, 1988. [PubMed: 2963247]
3. Dahllöf G: Craniofacial growth in children treated for malignant diseases. Acta Odontol Scand 56 (6): 378-82, 1998. [PubMed: 10066121]
4. Dahllöf G, Forsberg CM, Ringdén O, et al.: Facial growth and morphology in long-term survivors after bone marrow transplantation. Eur J Orthod 11 (4): 332-40, 1989. [PubMed: 2687011]
5. Uderzo C, Fraschini D, Balduzzi A, et al.: Long-term effects of bone marrow transplantation on dental status in children with leukaemia. Bone Marrow Transplant 20 (10): 865-9, 1997. [PubMed: 9404928]
6. Lucas VS, Roberts GJ, Beighton D: Oral health of children undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 22 (8): 801-8, 1998. [PubMed: 9827979]
7. Dahllöf G, Heimdahl A, Bolme P, et al.: Oral condition in children treated with bone marrow transplantation. Bone Marrow Transplant 3 (1): 43-51, 1988. [PubMed: 3048469]
8. Rosenberg SW, Kolodney H, Wong GY, et al.: Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia. A review of 17 cases. Cancer 59 (9): 1640-8, 1987. [PubMed: 3470112]
9. Fromm M, Littman P, Raney RB, et al.: Late effects after treatment of twenty children with soft tissue sarcomas of the head and neck. Experience at a single institution with a review of the literature. Cancer 57 (10): 2070-6, 1986. [PubMed: 3955515]
10. Goho C: Chemoradiation therapy: effect on dental development. Pediatr Dent 15 (1): 6-12, 1993 Jan-Feb. [PubMed: 8233995]
11. Näsman M, Forsberg CM, Dahllöf G: Long-term dental development in children after treatment for malignant disease. Eur J Orthod 19 (2): 151-9, 1997. [PubMed: 9183064]
12. 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]

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 chemotherapy and head/neck radiation. It is intended as a resource to inform and assist clinicians who care for cancer 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.

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Oral Complications of Chemotherapy and Head/Neck Radiation. 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]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.