National Cancer Institute
Last Modified: October 23, 2012
Aggressive treatment of malignant disease may produce unavoidable toxicities to normal cells. The mucosal lining of the gastrointestinal tract, including the oral mucosa, is a prime target for treatment-related toxicity by virtue of its rapid rate of cell turnover. The oral cavity is highly susceptible to direct and indirect toxic effects of cancer chemotherapy and ionizing radiation. 1 This risk results from multiple factors, including high rates of cellular turnover for the lining mucosa, a diverse and complex microflora, and trauma to oral tissues during normal oral function. 2 Although changes in soft tissue structures within the oral cavity presumably reflect the changes that occur throughout the gastrointestinal tract, this summary focuses on oral complications of antineoplastic drugs and radiation therapies.
It is essential that a multidisciplinary approach be used for oral management of the cancer patient before, during, and after cancer treatment. A multidisciplinary approach is warranted because the medical complexity of these patients affects dental treatment planning, prioritization, and timing of dental care. In addition, selected cancer patients (e.g., status posttreatment with high-dose head-and-neck radiation) are often at lifelong risk for serious complications such as osteoradionecrosis of the mandible. Thus, a multidisciplinary oncology team that includes oncologists, oncology nurses, and dental generalists and specialists as well as dental hygienists, social workers, dieticians, and related health professionals can often achieve highly effective preventive and therapeutic outcomes relative to oral complications in these patients.
While oral complications may mimic selected systemic disorders, unique oral toxicities emerge in the context of specific oral anatomic structures and their functions.
|Complication||Reference Citation||Weighted Prevalence|
|Bisphosphonate osteonecrosis||6.1% for all studies (mean)|
|Studies with documented follow-up = 13.3%|
|Studies with undocumented follow-up = 0.7%|
|Epidemiological studies = 1.2%|
|Dysgeusia||CT only = 56.3% (mean)|
|RT only = 66.5% (mean)|
|Combined CT and RT = 76% (mean)|
|Oral fungal infection||Of clinical oral fungal infection (all oral candidiasis):|
|Pretreatment = 7.5%|
|During treatment = 39.1%|
|Posttreatment = 32.6%|
|Of oral candidiasis clinical infection by cancer treatment:|
|During HNC RT = 37.4%|
|During CT = 38%|
|Oral viral infection||In patients treated with CT for hematologic malignancies:|
|Patients with oral ulcerations/sampling oral ulcerations = 49.8%|
|Patients sampling oral ulcerations = 33.8%|
|Patients sampling independently of the presence of oral ulcerations = 0%|
|In patients treated with RT:|
|Patients with RT only/sampling oral ulcerations = 0%|
|Patients with RT and adjunctive CT/sampling oral ulcerations = 43.2%|
|Dental disease||For dental caries in patients treated with cancer therapy:|
|All studies = 28.1%|
|CT only = 37.3%|
|Post-RT = 24%|
|Post-CT and -RT = 21.4%|
|Of severe gingivitis in patients undergoing CT = 20.3%|
|Of dental infection/abscess in patients undergoing CT = 5.8%|
|Osteoradionecrosis||In conventional RT = 7.4%|
|In IMRT = 5.2%|
|In RT and CT = 6.8%|
|In brachytherapy = 5.3%|
|Trismus||For conventional RT = 25.4%|
|For IMRT = 5%|
|For combined RT and CT = 30.7%|
|Oral paina||VAS pain level (0100) in HNC patients:|
|Pretreatment = 12/100|
|Immediately posttreatment = 33/100|
|1 mo posttreatment = 20/100|
|EORTC QLQ-C30 pain level (0100) in HNC patients:|
|Pretreatment = 27/100|
|3 mo posttreatment = 30/100|
|6 mo posttreatment = 23/100|
|12 mo posttreatment = 24/100|
|Salivary gland hypofunction and xerostomia||Of xerostomia in HNC patients by type of RT:|
|Pre-RT = 6%|
|During RT = 93%|
|13 mo post-RT = 74%|
|36 mo post-RT = 79%|
|612 mo post-RT = 83%|
|12 y post-RT = 78%|
|>2 y post-RT = 85%|
|Pre-RT = 10%|
|During RT = 81%|
|13 mo post-RT = 71%|
|36 mo post-RT = 83%|
|612 mo post-RT = 72%|
|12 y post-RT = 84%|
|>2 y post-RT = 91%|
|Pre-RT = 12%|
|During RT = 100%|
|13 mo post-RT = 89%|
|36 mo post-RT = 73%|
|612 mo post-RT = 90%|
|12 y post-RT = 66%|
|>2 y post-RT = 68%|
|CT = chemotherapy; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; HNC = head and neck cancer; IMRT = intensity-modulated radiation therapy; MASCC/ISOO = Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology; RT = radiation therapy; VAS = visual analog scale.|
The most common oral complications related to cancer therapies are mucositis, infection, salivary gland dysfunction, taste dysfunction, and pain. These complications can lead to secondary complications such as dehydration, dysgeusia, and malnutrition. In myelosuppressed cancer patients, the oral cavity can also be a source of systemic infection. Radiation of the head and neck can irreversibly injure oral mucosa, vasculature, muscle, and bone, resulting in xerostomia, rampant dental caries, trismus, soft tissue necrosis, and osteonecrosis.
Severe oral toxicities can compromise delivery of optimal cancer therapy protocols. For example, dose reduction or treatment schedule modifications may be necessary to allow for resolution of oral lesions. In cases of severe oral morbidity, the patient may no longer be able to continue cancer therapy; treatment is then usually discontinued. These disruptions in dosing caused by oral complications can directly affect patient survivorship.
Management of oral complications of cancer therapy includes identification of high-risk populations, patient education, initiation of pretreatment interventions, and timely management of lesions. Assessment of oral status and stabilization of oral disease before cancer therapy are critical to overall patient care. Care should be both preventive and therapeutic to minimize risk for oral and associated systemic complications.
Development of new technologies to prevent cancer therapyinduced complications, especially oral mucositis, could substantially reduce the risk of oral pain, oral and systemic infections, and number of days in the hospital; and could improve quality of life and reduce health care costs. New technologies could also provide a setting in which novel classes of chemotherapeutic drugs, used at increased doses, could lead to enhanced cancer cure rates and durability of disease remission.
As has been noted, it is essential that a multidisciplinary approach be used for oral management of the cancer patient before, during, and after cancer treatment. This collaboration is pivotally important for the advancement of basic, clinical, and translational research associated with oral complications of current and emerging cancer therapies. The pathobiologic complexity of oral complications and the ever-expanding science base of clinical management require this comprehensive interdisciplinary approach.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Oral complications associated with cancer chemotherapy and radiation result from complex interactions among multiple factors. The most prominent contributors are direct lethal and sublethal damage to oral tissues, attenuation of immune and other protective systems, and interference with normal healing. Principal causes can be attributed to both direct stomatotoxicity and indirect stomatotoxicity. Direct toxicities are initiated via primary injury to oral tissues. Indirect toxicities are caused by nonoral toxicities that secondarily affect the oral cavity, including the following:
Understanding of mechanisms associated with oral complications continues to increase. Unfortunately, there are no universally effective agents or protocols to prevent toxicity. Elimination of preexisting dental/periapical, periodontal, and mucosal infections; institution of comprehensive oral hygiene protocols during therapy; and reduction of other factors that may compromise oral mucosal integrity (e.g., physical trauma to oral tissues) can reduce frequency and severity of oral complications in cancer patients (refer to the Oral and Dental Management Prior to Cancer Therapy and the Management Following Cancer Therapy sections for further information). 1
Complications can be acute (developing during therapy) or chronic (developing months to years after therapy). In general, cancer chemotherapy causes acute toxicities that resolve following discontinuation of therapy and recovery of damaged tissues. In contrast, radiation protocols typically cause not only acute oral toxicities, but induce permanent tissue damage that result in lifelong risk for the patient.
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.
|Complication||Direct Risk Factor||Indirect Risk Factors|
|Oral mucositis||Mucosal cytotoxicity||Decreased local/systemic immunity: local infections, reactivation of HSV|
|Viral||Decreased systemic immunity|
|Fungal||Decreased oral mucosal and/or systemic immunity|
|Salivary gland dysfunction|
|Altered oral flora (decreased bacterial flora)|
|Bacterial||Inadequate oral hygiene||Decreased oral mucosal and/or systemic immunity|
|Mucosal breakdown||Salivary gland dysfunction|
|Taste dysfunction||Taste receptor toxicity|
|Xerostomia||Salivary gland toxicity||Anticholinergic drugs|
|Neuropathies||Vinca alkaloid, thalidomide, bortezomib drug use; risk for specific drug toxicity varies||Anemia, dental hypersensitivity, temporomandibular dysfunction/myofascial pain|
|Dental and skeletal growth and development (pediatric patients)||Specific drug toxicity||Stage of dental and skeletal maturation|
|Gastrointestinal mucositis causing secondary changes in oral status including taste, hygiene, and dietary intake||Mucosal cytotoxicity: radiation, chemotherapy||Nausea and vomiting|
|Physical trauma||Decreased clotting factors (e.g., DIC)|
|Infections (e.g., HSV)|
|DIC = disseminated intravascular coagulation; HSV = herpes simplex virus.|
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 3 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:
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 9 10 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 and neck radiation can cause a wide spectrum of oral complications (refer to the list of Oral Complications of Radiation Therapy below). 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.
These changes can lead to soft tissue necrosis and osteonecrosis that result in bone exposure, secondary infection, and severe pain. 11
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.
Poor oral health has been associated with increased incidence and severity of oral complications in cancer patients, hence the adoption of an aggressive approach to stabilizing oral care before treatment. 1 2 Primary preventive measures such as appropriate nutritional intake, effective oral hygiene practices, and early detection of oral lesions are important pretreatment interventions.
There is no universally accepted precancer therapy dental protocol because of the lack of clinical trials evaluating the efficacy of a specific protocol. A systematic review of the literature revealed two articles on oral care protocols prior to cancer therapy. 3 One study examined the benefits of a minimal intervention precancer therapy (mostly chemotherapy) dental protocol, and the other examined the impact of an intensive preventive protocol on patients undergoing chemotherapy. Both studies had several flaws, including small sample size or the lack of comparison groups. 3
The involvement of a dental team experienced with oral oncology may reduce the risk of oral complications via either direct examination of the patient or in consultation with the community-based dentist. The evaluation should occur as early as possible before treatment. 4 5 The examination allows the dentist to determine the status of the oral cavity before cancer treatment begins and to initiate necessary interventions that may reduce oral complications during and after that therapy. Ideally, this examination should be performed at least 1 month before the start of cancer treatment to permit adequate healing from any required invasive oral procedures. A program of oral hygiene should be initiated, with emphasis on maximizing patient compliance on a continuing basis.
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 below). 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
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).
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.
|Patients with chronic indwelling venous access lines (e.g., Hickman).||AHA prophylactic antibiotic recommendations (low risk).||There is no clear scientific proof detailing infectious risk for these lines following dental procedures. This recommendation is empiric.|
|Neutrophils||Order CBC with differential.|
|>2,000/mm3||No prophylactic antibiotics.|
|1,0002,000/mm3||AHA prophylactic antibiotic recommendations (low risk).||Clinical judgment is critical. If infection is present or unclear, more aggressive antibiotic therapy may be indicated.|
|<1,000/mm3||Amikacin 150 mg/m2 1 h presurgery; ticarcillin 75 mg/kg IV ½ h presurgery. Repeat both 6 h postoperatively.||If organisms are known or suspected, appropriate adjustments should be based on sensitivities.|
|Plateletsa||Order platelet count and coagulation tests.|
|>60,000/mm3||No additional support needed.|
|30,00060,000/mm3||Platelet transfusions are optional for noninvasive treatment; consider administering preoperatively and 24 h later for surgical treatment (e.g., dental extractions). Additional transfusions are based on clinical course.||Utilize techniques to promote establishing and maintaining control of bleeding (i.e., sutures, pressure packs, minimize trauma).|
|<30,000/mm3||Platelets should be transfused 1 h before procedure; obtain an immediate postinfusion platelet count; transfuse regularly to maintain counts >30,00040,000/mm3 until initial healing has occurred. In some instances, platelet counts >60,000/mm3 may be required.||In addition to above, consider using hemostatic agents (i.e., microfibrillar collagen, topical thrombin). Aminocaproic acid may help stabilize nondurable clots. Monitor sites carefully.|
|CBC = complete blood cell count; IV = intravenous.|
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.
|Transplant Phase||Oral Complication|
|Phase I: Preconditioning||Oral infections: dental caries, endodontic infections, periodontal disease (gingivitis, periodontitis), mucosal infections (i.e., viral, fungal, bacterial).|
|Gingival leukemic infiltrates.|
|Oral ulceration: aphthous ulcers, erythema multiforme.|
|Phase II: Conditioning Neutropenic Phase||Oropharyngeal mucositis.|
|Oral infections: mucosal infections (i.e., viral, fungal, bacterial), periodontal infections.|
|Neurotoxicity: dental pain, muscle tremor (e.g., jaws, tongue).|
|Temporomandibular dysfunction: jaw pain, headache, joint pain.|
|Phase III: Engraftment Hematopoietic Recovery||Oral infections: mucosal infections (i.e., viral, fungal, bacterial).|
|Neurotoxicity: dental pain, muscle tremor (e.g., jaws, tongue).|
|Temporomandibular dysfunction: jaw pain, headache, joint pain.|
|Phase IV: Immune Reconstitution Late Posttransplant||Oral infections: mucosal infections (i.e., viral, fungal, bacterial).|
|Dental/skeletal growth and development alterations (pediatric patients).|
|Relapse-related oral lesions.|
|Phase V: Long-term Survival||Relapse or second malignancies.|
|Dental/skeletal growth and development alterations.|
|GVHD = graft-versus-host disease.|
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 regimenassociated (chemotherapy with or without radiation therapy) toxi