INTRODUCTION — For most cancer survivors there are no specific oral health considerations or expected late complications. However, cancer survivors prescribed bone-modifying or anti-angiogenic agents, survivors of head and neck cancer, childhood cancer survivors, and patients treated on protocols involving high-dose chemotherapy and stem cell transplantation (HCT-SCT) constitute high-risk groups for oral health complications. These patients may require long-term dental follow-up well after completion of cancer therapy . An overview of oral complications is shown in the table (table 1).
Since most patients are usually followed and managed by their local community dentists, communication between medical and dental providers is critical prior, during, and after cancer therapy, in order to minimize or prevent oral health complications [2,3].
This topic will review oral health considerations in cancer survivors at high risk for complications. Because head and neck cancer survivors, patients treated with hematopoietic cell transplantation who develop chronic graft-versus-host disease (GVHD), and patients taking bone-modifying and anti-angiogenic agents are at significant risk for oral health complications, a detailed discussion of these patients is covered separately.
Use of bone-modifying and anti-angiogenic agents — Patients who are currently being treated with or have been treated in the past with bone-modifying agents (ie, bisphosphonates or denosumab) or anti-angiogenic agents (ie, bevacizumab) are at risk for developing osteonecrosis of the jaw, which can be associated with long-term pain and discomfort. Those at risk include survivors of more common cancers, such as prostate and breast cancer. (See 'Osteonecrosis' below and "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Osteoclast inhibitor therapy'.)
Use of checkpoint inhibitor immunotherapy — Some patients with specific types of advanced or relapsed cancers (eg, melanoma, non-small cell carcinoma, head and neck squamous cell carcinoma) may receive immunotherapy agents, such as checkpoint inhibitors as part of their cancer treatment . This group of patients is at risk of potentially severe immune-related adverse events (irAEs), which can affect the oral cavity as lichenoid inflammation, erythema multiforme-like inflammation, pemphigoid, and salivary gland dysfunction [5,6]. These oral complications can potentially persist even if the immunotherapy has been discontinued.
The management of irAEs involving the oral cavity are discussed separately. (See 'Immune-related adverse events' below and "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Dermatologic and mucosal toxicity'.)
Head and neck cancer — Oral and dental complications are common in head and neck cancer survivors because the treatment field often includes, by their proximity, organs required for breathing, eating, and communicating. As a result, a number of complications can arise that impact the oral cavity directly and the surrounding organs (eg, thyroid gland) and structures. These include facial disfigurement, salivary gland hypofunction, osteoradionecrosis, and trismus. In addition, these patients are at risk for both recurrence and a second primary lesion. (See 'Facial disfigurement' below and 'Chronic salivary gland hypofunction' below and 'Due to radiation therapy' below and 'Trismus' below and 'Malignancy' below and "Management of late complications of head and neck cancer and its treatment" and "Management and prevention of complications during initial treatment of head and neck cancer".)
Childhood cancer — Although cancer is the second leading cause of death in children [7,8], childhood cancer survivors constitute a small proportion of cancer survivors. For these patients, chemotherapy and radiation therapy (RT) to the head and neck region can have an adverse impact on normal growth and development of teeth and surrounding structures.
Abnormal findings include smaller than normal teeth (microdontia) and failure of the teeth to develop (hypodontia) [9,10]. In one study involving 150 children, the prevalence of microdontia and hypodontia were 19 and 9 percent (compared with 0 and 4 percent among 193 age-matched controls) . (See 'Abnormal dental development' below.)
Treatment-related risk factors for oral complications were identified in a report from the Childhood Cancer Survivor Study . In this study, 8522 cancer survivors and 2831 of their siblings responded to questionnaires and an interview about oral health. The median age at cancer diagnosis was six years and median time from diagnosis to interview was 22 years. The majority of cancer survivors reported prior treatment with chemotherapy (76 percent) and/or radiation therapy (64 percent). Risk factors associated with at least one dental problem included the following:
●RT dose to the jaw – A total dose <20 Gy was associated with a 1.3-fold higher risk (odds ratio [OR] 1.3, 95% CI 1.2-1.5), while a total dose ≥20 Gy was associated with a nearly sixfold increase in risk (OR 5.6, 95% CI 3.7-8.5).
●Total dose of alkylating agents – The risk increased with increasing cumulative dose of alkylating drugs administered. There was a twofold higher risk for those who had the highest exposure to alkylating agents compared with those who were not treated with alkylating agents (OR 2.0, 95% CI 1.6-2.4).
In general, treatment at a younger age is associated with a greater potential for long-term effects . When there are complications affecting growth and development, patients may require the expertise of oral and maxillofacial surgeons, orthodontists, and prosthodontists for comprehensive management.
Chronic graft-versus-host disease — Although patients who undergo autologous hematopoietic cell transplantation are at risk for acute complications (eg, mucositis and infection) immediately following transplantation, following immune reconstitution, there are no specific associated late oral complications. (See 'Oral chronic graft-versus-host disease' below.)
In contrast, patients treated with allogeneic hematopoietic cell transplantation are at an increased risk for oral health complications if they develop chronic graft-versus-host disease (GVHD), particularly for the development of dental caries [12-14]. Oral complications affect more than 80 percent of patients with GVHD .
Patients with GVHD often require extended immunosuppressive therapy, putting them at long-term risk of oral infections . These patients are also at an increased risk for squamous cell carcinoma of the oral cavity, likely due to a combination of chronic inflammation associated with GVHD, as well as long-term immunosuppression. In addition, patients with a history of allogeneic hematopoietic cell transplantation who experience relapse and are subsequently managed with immune checkpoint inhibitor therapy may experience reactivation of GVHD (acute or chronic) as a potential irAEs. (See 'Oral candidiasis' below and 'Recurrent herpes simplex virus infection' below and "Cutaneous manifestations of graft-versus-host disease (GVHD)".)
PREVENTING ORAL COMPLICATIONS — We suggest that newly diagnosed cancer patients be referred for a thorough oral examination prior to initiation of therapy, particularly if treatment will be administered to the head and neck region or if profound and prolonged immunosuppression is anticipated. The primary objective is to identify any actively infected teeth so that they can be treated definitively prior to the initiation of cancer-related therapy [17-19]. This is especially important for high risk patients as discussed above because dental extractions are a well-recognized risk factor for complications including osteonecrosis of the jaw in patients being treated with bone-modifying agents and osteoradionecrosis following radiation therapy (RT) in head and neck cancer survivors. (See 'Osteonecrosis' below and 'Due to radiation therapy' below.)
In addition, dental screening and counseling will reinforce the importance of oral hygiene and the maintenance of an infection-free oral cavity to reduce the risk of developing localized and/or systemic infection during anticipated periods of neutropenia . (See "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Dental issues' and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Oral lesions' and "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Prevention'.)
Abnormal dental development — Childhood cancer survivors are at risk for multiple developmentally-related dental complications as a consequence of radiation therapy (RT) and/or chemotherapy. In the Childhood Cancer Study discussed above, cancer survivors had a higher risk of dental complications compared with their siblings including [9,11]:
●Abnormal dental roots (5 percent in cancer survivors versus 3 percent in their siblings, odds ratio [OR] 3.0, 95% CI 2.2-4.0)
●Microdontia (9 versus 3 percent, OR 3.0, 95% CI 2.4-3.8)
●Loss of six or more teeth (5 versus 2 percent, OR 2.6, 95% CI 1.9-3.6)
Facial disfigurement — Head and neck surgery may result in significant disfigurement, despite careful treatment planning, due to surgical excision involving the anatomic locations of the vital organs of speech, swallowing, and respiration [21-23]. Even relatively minor surgical defects can have a tremendous impact on social interaction, self-image, and psychological well-being. (See "Overview of treatment for head and neck cancer", section on 'Reconstruction and rehabilitation'.)
Chronic salivary gland hypofunction — Salivary gland hypofunction is common in patients with chronic graft-versus-host disease (GVHD) and patients treated with RT to the head and neck . This may also occur in solid tumor patients as a result of chemotherapy, but is a temporary phenomenon that resolves within one year of the completion of treatment . (See "Management of late complications of head and neck cancer and its treatment", section on 'Salivary gland damage and xerostomia'.)
Hyposalivation is defined as a resting whole saliva flow rate of ≤0.1 mL/min and/or a stimulated whole saliva flow rate of ≤0.5 mL/min. Hyposalivation results in dry mouth (xerostomia), although qualitative changes in the composition of saliva can result in xerostomia without a significant decrease in flow [26-28].
Xerostomia can negatively impact normal functions, including eating, speaking, and swallowing. It is associated with alterations in taste and can cause symptoms of burning within the oral cavity. Xerostomia also increases the risk of oral candidiasis and dental caries, which can impact tooth failure , nutritional status, social interactions, and overall quality of life [30-33].
The management of salivary gland hypofunction is discussed in detail separately, but relies upon frequent water sipping, use of moisturizing and saliva stimulating agents, and prescription sialogogue therapy (ie, pilocarpine or cevimeline). (See "Management of late complications of head and neck cancer and its treatment".)
Oral candidiasis — Under normal conditions, candida coexist with the other microorganisms of the oral flora in humans and do not cause disease . However, alterations in the oral environment and/or systemic immunosuppression can result in fungal overgrowth, leading to clinical oral fungal infection or candidiasis. For cancer survivors, the primary risk factors for recurrent candidiasis are salivary gland hypofunction and long-term immunosuppression . (See "Overview of Candida infections", section on 'Oropharyngeal candidiasis'.)
Patients with oral candidiasis can be asymptomatic or can present with a range of symptoms that include burning, sensitivity, and taste changes. When symptomatic, oral candidiasis can have a significant impact on quality of life and may impair nutritional intake . Multiple presentations of oral candidiasis in cancer survivors have been described including :
●Pseudomembranous candidiasis – Typically presents as patchy white papules and plaques throughout the oral cavity (picture 1)
●Erythematous candidiasis – Characterized by mucosal erythema only and may be more challenging to diagnose as the presentation features may be more subtle
●Hyperplastic candidiasis – Hyperplastic candidiasis presents as a distinct area of leukoplakia and requires biopsy for diagnosis
The majority of cases of oral candidiasis respond readily to topical and/or systemic antifungal therapy. The Infectious Diseases Society of America (IDSA) guidelines recommend the use of clotrimazole troches or nystatin suspension/pastilles as first-line therapy for the management of mild oropharyngeal candidiasis . It should be noted that most formulations of troches/pastilles require saliva to dissolve and contain sugar for flavoring, which may exacerbate the risk for dental caries, especially in patients with hyposalivation. Further discussion of treatment is covered separately. (See "Oropharyngeal candidiasis in adults".)
Recurrent herpes simplex virus infection — Patients with chronic GVHD who require long-term immunosuppressive therapy are at risk for reactivation of herpes simplex virus (HSV). Pain and discomfort are common with active HSV infection, and can lower intake of fluid and nutrients, which in severe cases can lead to dehydration and malnutrition, requiring hospitalization . Although the risk of viral outbreaks can be reduced with antiviral prophylaxis, patients are still at risk for "breakthrough" infections. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Immunocompromised hosts'.)
HSV lesions generally appear as solitary or crop-like groupings of shallow mucosal ulcerations that are typically highly painful, even when the size is very small; a crusted appearance is generally only encountered on the lips (picture 2) . The diagnosis of oral HSV infection can often be made clinically based on the history and presenting features. Confirmatory laboratory diagnosis with viral culture can be helpful in cases of breakthrough infection, or when the diagnosis is unclear.
For patients with recurrent HSV infections, management is similar to the treatment of immunocompetent patients with HSV reactivation disease. This may entail episodic treatment using oral antiviral agents (acyclovir, famciclovir, or valacyclovir) during outbreaks, and chronic antiviral therapy as a means to suppress outbreaks. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults", section on 'Recurrent infections'.)
Oral chronic graft-versus-host disease — For patients with chronic GVHD, involvement of the oral mucosa is common, with upwards of 80 percent of patients affected . These patients are at an increased risk for dental caries due to chronic treatment-related salivary gland hypofunction. Despite systemic therapies, patients often require intensive localized ancillary measures to control symptoms [16,41-43]. (See 'Chronic salivary gland hypofunction' above and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Oral lesions'.)
The primary symptom associated with oral mucosal chronic GVHD is sensitivity, such that normally tolerated foods and drinks become painful, potentially affecting nutrition and quality of life. As a result, patients need to modify their diets to avoid foods that are no longer tolerated. In rare cases, long-standing oral chronic GVHD inflammation can result in band-like fibrosis of the buccal mucosa leading to trismus. (See 'Trismus' below.)
Lacy or reticulated white plaques that resemble Wickham striae of lichen planus may occur on the tongue, buccal mucosa, lips, or palate (picture 3). Hyperkeratotic plaques, mucosal erythema, erosions, and ulceration can also occur. Associated pain may inhibit oral intake . Criteria to make the diagnosis of oral chronic GVHD have been defined by a 2014 consensus panel of the National Institutes of Health (table 2).
Management of oral mucosal chronic GVHD is largely driven by symptoms, with the primary goals directed at diminishing pain and sensitivity and maintaining the patient's ability to eat. Although patients may be on systemic immunosuppressive therapy for management of chronic GVHD, aggressive ancillary measures such as topical corticosteroids or tacrolimus may be necessary to provide symptomatic relief [45-50]. Management of salivary gland cGVHD is already summarized above. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Management'.)
Immune-related adverse events — Immune-related adverse events (irAEs) are a group of adverse effects associated with immunotherapy, such as checkpoint inhibitors . Cancer survivors receiving immunotherapy may develop irAEs in the oral cavity involving the mucosa (eg, lichenoid lesions, erythema multiforme-like features, pemphigoid, and acute GVHD reactivation) and salivary glands (eg, sicca-like syndrome) [5,52,53]. The median onset of such irAEs from initiation of immunotherapy is approximately three months [5,52]. (See "Mucocutaneous toxicities associated with immune checkpoint inhibitors", section on 'Mucosal toxicities'.)
Oral mucosal inflammation may respond well to topical corticosteroid therapy; however, systemic corticosteroids and discontinuation of immunotherapy may be required. Salivary gland dysfunction is managed as described above, and similarly may also be managed with systemic corticosteroids and discontinuation of immunotherapy. (See 'Chronic salivary gland hypofunction' above and "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Dermatologic and mucosal toxicity'.)
Osteonecrosis — Osteonecrosis can occur as a complication of specific therapeutic agents or as a consequence of RT to the head and neck. These are discussed below.
Due to bone-modifying agents or anti-angiogenic agents — Cancer survivors taking bone-modifying or anti-angiogenic agents are at risk for medication-associated osteonecrosis of the jaw (MRONJ), which is characterized by the presence of exposed bone in the oral cavity that persists for greater than eight weeks . (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Clinical presentation'.)
Patients suffering from MRONJ may experience a substantial deterioration in their quality of life due to chronic pain, difficulty eating, and facial deformation . Secondary infection of the surrounding soft tissue is common, presenting with painful erythema, swelling, and purulence. Some patients with MRONJ may also present with complaints of dysesthesia or paresthesia in the affected area due to inflammatory or infectious involvement of the neurovascular bundle around the necrotic bone, or due to increased bone deposition and narrowing of the nerve canal. A clinical staging system for MRONJ developed by the American Association of Oral and Maxillofacial Surgeons can be helpful in categorizing patients based on severity of symptoms and need for treatment. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Staging and treatment'.)
The diagnosis of MRONJ is based primarily upon clinical signs of ulceration of the mucosa (ie, complete loss of overlying mucosa) with exposure of necrotic bone. Radiographic features of MRONJ include mixed radiopaque/radiolucent lesions, often with a mottled appearance. In more advanced cases, osteolytic changes can extend to the inferior border of the mandible. In most cases intraoral and panoramic radiography are sufficient; however, in cases of suspected pathological fractures, computed tomography (CT) scans may be indicated . (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Clinical presentation' and "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Imaging studies'.)
In patients receiving anti-resorptive therapy, it remains unclear whether or not discontinuation of therapy (bisphosphonate "holidays") reduces the risk of developing MRONJ. Given the long half-life of bisphosphonates, discontinuation of treatment likely does not significantly impact on the course of MRONJ [54,56]. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Cessation of at-risk medication prior to invasive dental procedures'.)
The majority of symptomatic cases of MRONJ are associated with secondary soft tissue infection; therefore, management includes topical and systemic antimicrobial agents. Patients should be instructed to gently brush exposed bone to reduce plaque accumulations. Other treatment for established MRONJ is discussed separately. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Treatment of established MRONJ'.)
Due to radiation therapy — The development of exposed bone in a previously irradiated field in the absence of recurrent or residual tumor is defined as osteoradionecrosis (ORN). It is commonly precipitated by an injury (surgery, dental extractions, poor dentition, or infection) to hypoxic bone tissue.
Symptoms of ORN can include pain, bad breath, dysgeusia, dysesthesia or anesthesia, trismus, difficulty with chewing and swallowing, speech difficulties, fistula formation, pathologic fracture, and infection. In some cases, it may be diagnosed shortly after completion of RT, while in other patients it may not be diagnosed for years after the original cancer treatment . (See "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis'.)
The mandible is the most frequently affected bone, because a large part of the mandible is exposed to high doses of radiation in the majority of patients treated for head and neck cancer . Maxillary ORN is rare and seen most often in the setting of irradiation for nasopharyngeal cancer . For any patient with ORN, recurrent cancer must always be considered in the differential diagnosis of exposed mandible or maxilla.
The management of ORN is largely similar to approaches for MRONJ. For mild cases of ORN, conservative debridement and antibiotics are usually successful . However, when bone and soft tissue necrosis are extensive, resection of the mandible with immediate microvascular reconstruction may provide better results [60-62]. Although many clinicians prescribe hyperbaric oxygen to treat or prevent ORN, its use is generally governed by institutional guidelines . Further details on these management strategies for ORN are discussed separately. (See "Management of late complications of head and neck cancer and its treatment", section on 'Treatment'.)
Trismus — Trismus is the inability to fully open the mouth and is a common complication of treatment for head and neck cancer. Clinically, trismus is defined as a maximum interincisal opening <35 mm, which is measured using a specialized device . Trismus can result in reduced nutrition due to impaired mastication, poor oral hygiene, pain and myospasms, and an overall reduced quality of life [64,65]. (See "Management of late complications of head and neck cancer and its treatment", section on 'Trismus'.)
The management of trismus requires lifelong physical therapy, which involves self-directed passive range of motion exercises [66,67]. The most basic approaches involve using two hands to stretch the jaw passively (completely relaxed) or stacking tongue depressors into the oral cavity. Physical therapy devices engineered specifically for the management of trismus are available by prescription and should be considered in patients with more severe trismus [68,69]. Maintenance of oral hygiene is of particular importance as dental care is difficult in patients with limited ability to fully open their mouth.
Malignancy — The risk of a new malignancy involving the oral cavity is related to the type of initial cancer, prior treatment received, and underlying personal risk factors such as smoking or family history [70-72]. In general, patients with head and neck squamous cell carcinoma, those with GVHD, and those previously treated with high-dose chemotherapy (HCT) are at particular risk of a new primary and for recurrence involving the oral cavity [73,74]. (See "Management of late complications of head and neck cancer and its treatment", section on 'Second malignancies'.)
Metastatic cancer to the oral cavity from other solid tumors is rare, accounting for approximately 1 to 2 percent of all oral malignancies . The most frequent cancers that metastasize to the oral cavity include lung (22.5 percent), breast (18 percent), kidney (12 percent), and liver (8.6 percent) [76,77]. Routes of metastasis include arterial, venous, and lymphatic circulation, and lesions can involve soft tissue and bone . Management depends on the underlying primary diagnosis, whether the oral lesion is the only area of metastasis, and symptoms.
APPROACH TO THE CANCER PATIENT — All cancer survivors, regardless of their level of risk for developing oral and dental complications, require routine dental care including recall visits and scaling/prophylaxis. For patients at high risk, we suggest evaluation at least twice a year [79-81]. All patients should receive thorough soft tissue examinations.
Further details on the diagnosis and management of dental complications, such as odontogenic infections, are discussed separately. (See "Epidemiology, pathogenesis, and clinical manifestations of odontogenic infections" and "Complications, diagnosis, and treatment of odontogenic infections".)
Communication with the dental provider — It is important that the dentist and oncologist maintain communication so that each provider is aware of relevant findings and potential complications of treatment. Dentists should be provided with:
●Information regarding the cancer diagnosis (ie, type of cancer, date of cancer diagnosis, treatment rendered, and current status).
●A history of complications or serious events during cancer therapy or since completion of therapy.
●A list of medications, especially if patients were previously prescribed or continue to take a bone-modifying or anti-angiogenic agent. (See 'Use of bone-modifying and anti-angiogenic agents' above.)
Imaging studies — Intraoral dental radiographs, particularly bitewing radiographs, are required to assess for decay. Whereas these are typically obtained every one to two years in otherwise healthy patients, they may be needed as frequently as every four to six months in patients with a history of significant dental caries developing after completion of cancer therapy . Advanced imaging studies, such as CT and magnetic resonance imaging (MRI), may be indicated to examine suspected lesions in the bone and salivary glands and to evaluate for the presence of possible metastatic lesions (figure 1).
SUMMARY AND RECOMMENDATIONS
●For most cancer survivors, there are no specific oral health considerations or expected late complications. However, cancer survivors prescribed bone-modifying agents or anti-angiogenic agents, survivors of head and neck cancer, childhood cancer survivors, and patients treated on protocols involving high-dose chemotherapy and stem cell transplantation (HCT-SCT) constitute high-risk groups for oral health complications. (See 'Introduction' above.)
●Newly diagnosed cancer patients be referred for a thorough oral examination prior to initiation of therapy to ensure any actively infected teeth are extracted prior to initiation of cancer therapy. (See 'Preventing oral complications' above.)
●Oral health problems in childhood cancer survivors are due to chemotherapy and radiotherapy to the head and neck region, which can have a significant impact on growth and development of the teeth. Oral complications include an increased risk for microdontia, dental caries, and premature loss of teeth. (See 'Childhood cancer' above and 'Abnormal dental development' above.)
●Patients treated with allogeneic hematopoietic cell transplantation are at risk for oral health complications largely related to chronic graft-versus-host disease (cGVHD). Oral cGVHD also places patients at risk for recurrent infections (due to prolonged immunosuppression) and squamous cell carcinoma. (See 'Chronic graft-versus-host disease' above and 'Oral candidiasis' above and 'Recurrent herpes simplex virus infection' above and 'Oral chronic graft-versus-host disease' above.)
●Dental and oral complications are common among head and neck cancer survivors, including facial disfigurement, chronic salivary gland dysfunction, and trismus. They are also at an increased risk for secondary malignancies or cancer recurrence. (See 'Head and neck cancer' above and 'Facial disfigurement' above and 'Chronic salivary gland hypofunction' above and 'Trismus' above and 'Malignancy' above.)
●Patients who are currently being treated with (or were treated with) bone-modifying or anti-angiogenic agents are at risk for developing osteonecrosis of the jaw. (See "Medication-related osteonecrosis of the jaw in patients with cancer".)
●Patients receiving immunotherapy, such as checkpoint inhibitors, may develop immune-related adverse events involving the mucosa and salivary glands. (See 'Immune-related adverse events' above.)