#50683: Oral Cancer and Complications of Cancer Therapies

Most patients with oral cancer have used tobacco products for prolonged periods of time [4]. Cigarettes, with their multitude of carcinogens, are the most frequent form of tobacco used. However, cigars, pipes, and smokeless tobacco also contain carcinogens; these should not be considered safe alternatives to cigarettes.

Although many more people smoke than develop oral cancer, the majority of oral cancers may be attributed to tobacco and/or alcohol use, either individually or together [4,5]. The use of alcoholic beverages by those who use tobacco products may enhance the negative effect upon the oral tissues [4]. The desiccating effects of alcohol provide a prolonged exposure of the carcinogens within tobacco on these tissues. This additional contact time increases the risk of the development of an oral malignancy, such as squamous cell carcinoma, 100 fold [4]. Factors such as immunosuppression and immunocompromise, a family history of cancer, nutritional considerations, alcohol abuse, systemic disease, and the duration and amount of tobacco used are possible reasons some tobacco users develop oral cancer and others do not. Because the majority of patients with oral cancer have a history of tobacco use, the implication of this product's carcinogens as agents that can cause malignant transformation in the oral tissues is strongly correlated.

Increasing age is another risk factor in the development of oral cancer, with a peak incidence in individuals 63 years of age; however, it is now occurring more frequently in younger individuals [2,6]. The exact causes for this are not yet clear, but there appear to be associations between young men and women who use conventional "smokeless" chewing or spit tobacco [2]. Historically, the incidence of oral cancer in the African American population has been twice that of the white population, but 2020 data from the National Cancer Institute indicates that the incidence in the white population has surpassed that of the African American population for both men and women [2,3]. A strong gender differentiation has also been noted historically, as men developed oral cancer with a frequency that was more than six times that of women. The ratio is now one woman to every three men, likely due to the increase in women who smoke since the 1950s [2]. It is thought that lifestyle choices (e.g., tobacco use, particularly in combination with the consumption of alcohol), rather than genetics, are responsible for these various disparities.

Chronic tissue trauma from ill-fitting prostheses, such as dentures or partial dentures, may predispose tissues to malignant change, though as a whole, there is no heightened risk for those with dentures [4]. However, patients who utilize these devices should be educated that any area of irritation should be examined and the corresponding adjustment should be made by a dentist. Sore spots that cannot be eliminated after adjustments, relines of the existing prosthesis, or the fabrication of a completely new prosthesis should be monitored very closely. If the prosthesis is not worn and the sore spot remains, a biopsy of the area is indicated.

In one study, HPV type 16 (HPV16) was found to account for approximately 55% of oral cancer cases in the absence of any other risk factors [7]. While HPV16 and HPV18 infections are widely recognized as a main cause of cervical cancers in women, they are also increasingly linked to oral cancer in those younger than 40 years of age [3,4]. The increase of oral cancer cases in this population is associated with the spread of HPV and is strongly correlated to having multiple oral sex partners [2,3,7]. Autoimmune factors, complex genetic mechanisms (individually or collectively), and other viral agents, such as herpes simplex virus, may also be etiologic risk factors in this group (Table 1).

Excessive, chronic ultraviolet light exposure has been linked to cancers of the lip, particularly in individuals who work outdoors [4]. Other documented or researched causes include poor nutrition (i.e., lack of fruits/vegetables), lichen planus, and graft-versus-host disease. Oral cancer may also develop in the absence of known risk factors. Approximately 25% of patients with oral cancer have no identified risk factors for the disease [10]. Most of these patients are younger than 40 years of age, well below the age distribution for this disease [2,11].

A discussion of the histologic basis for normal, healthy oral mucosa is required before an understanding of the stages that lead to the development of an oral malignancy can be appreciated. Also, some of the problems that develop after radiotherapy and chemotherapy have a cellular basis in these tissues.

The oral mucous membrane does not have the same surface consistency throughout the oral cavity. The oral mucosa is classified into three types:

Common to all three mucosal types is an outermost cellular layer composed of stratified squamous epithelium. Some of the stratified squamous epithelium, specifically the masticatory mucosa, may be keratinized. All of these surface cells are produced from a deeper layer of cells called basal cells. This cellular layer consists of cells that are active in deoxyribonucleic acid (DNA) synthesis and undergo mitosis. The cells that replace the outer squamous layer every three to four days originate here. When radiotherapy or chemotherapy causes ulcerations anywhere in the oral mucosa, it is because the mitotic sequence of the basal cells has been interrupted. A small membrane beneath the basal cells, called the basement membrane, is what malignant cells perforate to invade the underlying tissue and begin the growth of a malignant lesion [12].

Premalignant Lesions

The National Guideline Alliance recommends considering an urgent referral (for an appointment within two weeks) for assessment for possible oral cancer by a dentist in people who have either a lump on the lip or in the oral cavity or a red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia.

(https://www.nice.org.uk/guidance/ng12 Last Accessed: February 1, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

The earliest deviation from normal cellular arrangement is dysplasia. Dysplasia is characterized by atypical cellular formation and arrangement without any malignant transformation. Dysplastic cells can progress to carcinoma in situ, in which actual malignant transformation has occurred to one layer of cells. At this point, there is no invasion into the underlying tissue. The potential for continued growth and metastasis continues to be very high [13]. Both dysplasia and carcinoma in situ can only be diagnosed by histologic analysis. Lesions of varying sizes, shapes, colors, and surface textures cannot be discerned by visual means to possess any of these cellular alterations. Patients with premalignant lesions do not experience symptoms that would prompt them to seek medical or dental care.

There is no universal appearance of malignant lesions. It is recommended that an oral lesion of unknown origin that does not heal within two weeks should be submitted for an expedited referral [2]. Patients should be advised that lesions that appear harmless may be malignant, while those that appear aggressive may be benign. Whether benign or malignant, oral lesions span a remarkable array of clinical presentations.

Ultimately, histologic analysis is the only standard by which an oral lesion can be classified (Table 2) [8]. However, only 25% of intraoral leukoplakic lesions are submitted for histopathic examination via traditional biopsy procedures [15].

Traditional biopsy techniques are either incisional or excisional in nature. Larger lesions that cannot be removed completely usually undergo an incisional biopsy. This procedure features the removal of a small portion of the lesion along with a continuous band of healthy tissue. If a lesion plus some adjacent healthy tissue is small enough to be removed in its entirety, this process is essentially an excisional biopsy.

If a general dentist does not provide this service, the patient should be referred to an oral or maxillofacial surgeon or an otolaryngologist. Lesions located on the soft palate or the tonsillar pillar area may be difficult to biopsy due to a strong gag reflex. These patients may need sedation to accomplish the procedure.

The American Dental Association does not recommend autofluorescence, tissue reflectance, or vital staining adjuncts for the evaluation of potentially malignant disorders among adult patients with clinically evident, seemingly innocuous, or suspicious lesions.

(https://jada.ada.org/article/S0002-8177(17)30701-8/fulltext Last Accessed: February 1, 2023)

Level of Evidence: Low or very low

Correspondence from any specialist to which the patient has been referred should be monitored closely for the diagnosis and the treatment plan. It should not be assumed that the patient will go to the specialist or follow his or her recommendations; a follow-up with the patient is necessary. In the event a malignancy is detected, the patient should be made aware of his or her treatment options, and those options should be pursued. Similarly, a patient's refusal to seek specialty care when it is recommended should be documented in the chart for medicolegal reasons. The patient should clearly be informed that the risks of refusing a biopsy procedure may allow for the formation of a malignant lesion that is capable of metastasizing with possible fatal consequences. Ideally, the patient should sign this informed refusal with at least two staff members witnessing it. Legal counsel may be necessary to prepare the appropriate forms.

Diagnostic tools that precede traditional biopsy procedures have been developed. Toluidine blue, ViziLite, and computer-assisted brush biopsy analysis are such adjunctive techniques. These screening tools do not replace the traditional biopsy procedures but provide an initial assessment of a questionable lesion [8].

The principle upon which ViziLite works is based on the cell physiology of abnormal cells. These cells have a nuclear content and mitochondrial matrix that is denser than normal cells. The patient rinses with a special ViziLite solution for 60 seconds and expectorates the excess. This acetic acid rinse removes the adherent mucosal glycoprotein layer and increases the nuclear/cytoplasmic ratio via osmosis. A disposable handheld ViziLite is then passed over the oral tissues. Normal cells will absorb the light and appear dark. Abnormal cells, given the increased density of the nucleus and the mitochondrial matrix, will reflect the light and appear bright [20]. This reflection pattern from ViziLite provides for the detection beneath the epithelial surface. If a suspicious lesion is detected at or below the epithelial surface, the clinician should perform a biopsy or refer the patient to a specialist who is able to perform this procedure. Further study is needed to determine what role, if any, this test should play in oral cancer screening [8]. The ultimate diagnosis of the lesion is still dependent on a biopsy procedure.

Toluidine blue is a metachromatic dye that stains abnormal DNA, thereby identifying appropriate tissue for biopsy. Studies have proven its efficacy as a diagnostic adjunct in detecting the presence of potential malignant lesions, particularly in the early stages [8,21,22]. A Taiwanese study found a 79% increase in the detection of oral submucous fibrosis when using the dye compared to standard visual screening [23].

Sections suspected of being malignant lesions should be deparaffinized and hydrated with distilled water. Then, the sections may be stained with toluidine blue solution for two to three minutes, after which the section should be thoroughly rinsed and dehydrated. Malignant cells will appear as violet or red purple against a blue background.

The Oral CDx brush biopsy system is another means of attaining an initial assessment for suspect oral lesions [8]. The Oral CDx kit contains a sterile brush biopsy instrument, a precoded glass slide, a tissue fixative pouch, a requisition form, and a pre-addressed container into which the slide and requisition form are placed [24]. The brush biopsy instrument is a small, circular wire brush that is rotated several times over the lesion surface until the tissue is slightly pink or is just beginning to bleed. This slight degree of lesion penetration is usually done without topical or local anesthesia. The tissue sample on the brush biopsy instrument is then applied to the precoded glass slide, which is bathed in the tissue fixative. This sample undergoes analysis by the Oral CDx computer.

One of four classifications is possible for all submitted samples. An inadequate category indicates that not enough of a tissue sample for a meaningful classification has been obtained. A negative classification means that no epithelial abnormality has been detected. An atypical sample is one that has some epithelial abnormalities whose diagnostic meaning is unclear. A positive classification indicates positive evidence of epithelial dysplasia or carcinoma [25]. Treatment from this point depends on the lesion classification. This is an expedient addition to the armamentarium of oral cancer screening devices. Of note, screening should be done by the clinician who has adequate illumination, visualization, and knowledge of how the tissues of the oral and maxillofacial complex appear in a healthy state.

The oral malignancy responsible for more than 90% of the total cases of oral cancer is squamous cell carcinoma [26]. Squamous cell carcinoma is the result of uncontrolled differentiation of surface squamous cells of the oral mucosa into malignant cells. This is an aggressive lesion whose nests of malignant cells penetrate the basement membrane and the underlying connective tissue. Infiltration into the vascular and lymphatic circulation may occur early and facilitate metastasis. Continued proliferation can extend into the musculature and the supporting bone, with the capacity to destroy both. Upon histologic confirmation of a squamous cell carcinoma, surgery and radiotherapy should be scheduled as quickly as possible, because growth of the primary lesion and metastasis both occur rapidly; combined therapy may also include chemotherapy in later stages [26].

Squamous cell carcinoma can occur anywhere in the oral cavity. However, there are some areas of the mouth where these lesions occur more frequently than others. As noted, the most common sites of involvement are the tongue, lip, and floor of the mouth [21]. Many squamous cell carcinomas are located in areas that preclude visualization by the patient and can grow to larger sizes asymptomatically (Image 1).

A gingival squamous cell carcinomatous lesion in a patient with HIV.

Image 1

Source : CDC/Sol Silverman, Jr., DDS

The remaining types of oral malignancies affect tissues within the oral cavity or the adjacent salivary glands. Kaposi sarcoma, mainly associated with late-stage human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), is one such malignancy. A rarity in the United States until the AIDS epidemic, Kaposi sarcoma has been identified as an AIDS-defining illness.

The initial presentation of these lesions is usually on the skin, but oral manifestations occur frequently. The palate, gingiva, and tongue are the primary sites of the appearance of these lesions; however, they may occur anywhere in the mouth. The human herpesvirus-8 (HHV-8) is considered to be the etiologic agent of this malignancy [9]. The lesions of Kaposi sarcoma may be red, violet, dark blue, or black-blue and usually begin asymptomatically. This vascular malignancy is typically flat at its onset but progresses to form nodules that develop a spongy consistency. Their growth can interfere with swallowing and eating, and larger lesions bleed easily. Treatment is usually a combination of surgery and radiation therapy, which is taxing for patients with an advanced stage of immunosuppression (Image 2).

Kaposi sarcoma in the mouth of a patient with AIDS.

Image 2

Source : National Cancer Institute

Other types of cancers that may occur in the oral cavity include lymphomas, melanomas, and cancer of the minor salivary glands. These cancers are rare; nonetheless, they should be considered as a part of differential diagnosis when a patient presents with oral lesions of unknown etiology.

When the diagnosis of oral squamous cell carcinoma is confirmed, plans for surgery and radiotherapy are initiated. Surgery includes the removal of the lesion and its extension into the neighboring hard and soft tissue. Surgical extension into the neck (neck dissection) is usually required to evaluate the extent of the tumor and its spread into local and regional lymph nodes. Areas where surgical deficits are created should be stabilized prior to surgical closure. Muscle from sites such as the pectoralis major muscle may be grafted to repair the surgical wound. Vascular grafts may also be needed to provide adequate circulation for the new muscle grafts. Larger lesions can intertwine around nerves of varying sizes. The removal of these lesions may cause permanent loss of sensation and loss of motor function for many structures in the oral cavity. The loss of hard and soft tissue is commensurate with the size of the lesion. Many patients require the use of maxillofacial prostheses to restore form, function, cosmetics, and self-esteem after these extensive surgical procedures. If a large portion of the tongue is removed, speaking, swallowing, eating, and drinking become arduous functions.

Surgery may not eliminate all squamous cell carcinoma cells. Radiotherapy is utilized to eliminate the cancer cells that may have persisted beyond surgical measures. A common modality used postsurgically, radiotherapy may be rarely used presurgically to decrease the size of larger lesions [34].

The current unit of absorbed radiation is the gray (Gy) or the centigray (cGy). Tumor size, location, and metastasis will determine the required cumulative dosage of radiation.

Radiation in adequate doses is cytotoxic to malignant cells because it causes free radical damage to the cellular components that are required for cell division and replication. Unfortunately, healthy tissues in the area of the radiation beam will undergo the same cellular damage. So, the goal is to destroy the malignant cells with as little damage to healthy cells as possible.

The amount of radiation required to destroy all affected cells is too large to be administered in only one dose. Modified fractionation is used to make doses smaller and more tolerable. Most patients receive the same dose of radiation five days a week, over a five-to seven-week period [35,36]. Because salivary glands are particularly radiosensitive, relatively small doses or irradiation may result in damage [37]. Most radiotherapy is given in fractionated doses of 150–200 cGy per day [35]. Once a cumulative dose of 4,500 cGy has been absorbed, long-term deleterious side effects are encountered. Because most radiotherapy regimens for squamous cell carcinoma patients range between 5,000 and 7,000 cGy, most patients will encounter undesirable side effects [38]. The area at which the radiation is targeted will influence the types of side effects experienced by the patient.

Concurrent antibody therapy with cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, may be considered for patients in whom chemotherapy is contraindicated, as many oral squamous cell carcinomas show moderate to high levels of EGFR expression [39,40]. It has been suggested that side effects may be minimized if the agent is administered between the hours of 11 a.m. and 3 p.m., due to the circadian rhythm of the oral mucosa [41,42]. This time frame is hypothesized as being ideal for maximum therapeutic effect and reduced toxicity of both cetuximab and radiotherapy treatments.

For patients with oral cancer, chemotherapy is recommended only as an adjunct to radiation and/or surgical therapy [2]. Chemotherapy alone has not been shown to have the same efficacy against oral cancer as with other cancers. Chemotherapy is recommended as an adjunct in the treatment of oral cancer in order to [2,14]:

Additional research to determine the most effective use of chemotherapy as part of the overall treatment plan for oral cancer is necessary.

Normal oral epithelium regenerates every three to four days. The outer squamous cells are replenished by cells made anew at the basal layer. The cellular regeneration corresponds with a high level of mitotic activity. Radiotherapy cannot distinguish the mitotic activity between malignant cells and those needed to replenish the oral epithelium; it is cytotoxic to both groups of cells, resulting in mucositis.

A Cochrane Review found that oral cryotherapy leads to large reductions in oral mucositis of all severities in adults receiving 5FU for solid cancers.

(https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011552.pub2/full Last Accessed: February 1, 2023)

Level of Evidence: Meta-Analysis

Oral mucositis is the most common intraoral side effect of radiotherapy and usually has an onset in the second week of therapy [43,44]. Mucositis affects nearly 80% of all patients who undergo head and neck radiotherapy and occurs in four phases [43]. The inflammatory phase is begun as ionizing radiation causes the generation of free radicals. The disruption of the normal sequence of turnover and stratification from the basal cell layer is a continuum into the epithelial phase. The ulcerative phase features ulcerations of varied dimensions on any mucosal surface. The consequent pain can be so intense that patients may have difficulty eating at a time when adequate nutrition is life sustaining. Patients with removable complete or partial dentures may be unable to wear them, further complicating their ability to masticate and swallow. The denuded mucosal surfaces also are a portal of entry for organisms of an altered oral microflora. This, coupled with a host whose immunocompetence is challenged, can lead to systemic bacterial or fungal infections that may be fatal. Severe mucositis mandates that radiotherapy be postponed until adequate healing of the epithelium occurs. The healing phase may take several weeks after the last radiotherapy treatment [45].

The National Cancer Institute has developed a Mucositis Scale to allow for the basic categorization of the mucositis lesions according to severity [46]. Grade 1 is defined as the absence of symptomatic mucositis or mild symptoms. Minimal mucositis, grade 2, involves moderate pain that does not greatly interfere with food intake but may necessitate a slightly altered diet. A grade 3 (severe) reaction is present when extreme pain causes feeding to become difficult. At this grade, the patient can only tolerate a liquid diet. When the mucosal ulcerations are deep or necrotic and bleed spontaneously, a grade 4 level has been attained. This level of mucositis is considered life-threatening. Patients with grade 4 mucositis may require intravenous fluids, analgesics, and antibiotics in a hospital setting until they are medically stabilized. Even if radiotherapy has been completed, the patient should still be followed closely to assure complete healing of all lesions. If radiotherapy has been interrupted because of the severity of mucositis, the cumulative dose of radiation that remains may be fractionated into smaller daily doses. Grade 5 is death [46].

Management of less severe grades of mucositis consist of palliative relief of pain, the monitoring and treatment of localized infections that may develop, and monitoring the patient's ability to maintain an oral care regimen and an adequate nutrition level. Liquid forms of systemic analgesics and antibiotics may be easier for the patient to swallow. Topical liquid anesthetics such as 2% viscous lidocaine may provide temporary analgesia. Because these patients may be taking medications for other conditions, care should be taken to avoid any adverse drug interactions. Prednisone, 40 mg to 80 mg per day prescribed for one week or less, may help to resolve some of the inflammation [47]. Varied rinses of sodium chloride and sodium bicarbonate may allow for tissue cleansing, moistening, and lubricating and are well tolerated. These rinses, along with proper oral hygiene and hydration, are mainstays of prevention and treatment. Chlorhexidine 0.12% rinses are useful but have a tendency to cause discomfort and nausea. Evidence supporting their use is generally inadequate and/or conflicting [48].

There is increasing evidence that severe oral mucositis due to radiotherapy may be pre-empted with palifermin, a recombinant human keratinocyte growth factor, though this use is an off-label use [49]. Palifermin is approved by the U.S. Food and Drug Administration for the treatment of severe oral mucositis in patients with hematologic malignancies undergoing total body irradiation, stem-cell transplantation, and chemotherapy [50]. Though the agent is expensive, oral mucositis is often reported to be the most torturous side effect of cancer treatment and may necessitate the cessation of radiotherapy even with advanced-stage malignancies. Evidence supporting the use of palifermin is conflicting [48].

The prophylactic palifermin regimen begins with one 60 mcg/kg IV dose three days prior to treatment and three days following treatment up to a maximum of six doses [51]. The most common side effect is skin rash/erythema [51,52]. A 2011 study examined its use in patients with head and neck cancer undergoing postoperative radiochemotherapy and found a modest reduction in the incidence of severe mucositis in those given palifermin (51%) versus placebo (67%), but the primary outcome was the reduction in duration of severe mucositis (4.5 days versus 22 days, respectively) [53]. A phase 3 clinical trial to determine safety and efficacy as an adjuvant treatment for those with head and neck cancers undergoing radiochemotherapy was completed in 2016, but the results of the study have not been published [54].

Palifermin use should be carefully considered for patients at increased risk of developing severe mucositis [51,52]. Pediatric patients and the elderly are at an increased risk; other risk factors include existing periodontal disease, poor diet, alcohol use, tobacco use, certain medications, oxygen therapy, and changes in breathing [55].

The Oral Assessment Guide (OAG), developed by Eilers, may be used in the staging of mucositis and when creating a management plan (Table 5) [56]. Using the OAG, the patient is assigned a number of points, from 1 to 3, in each of eight categories, with a total score of 8 indicating no change and a total score of 24 indicating severe mucositis. The OAG has been shown to be effective and reasonably easy to use in several studies [57,58]. It provides for objective assessment (as it omits pain as a measure of severity) and is able to identify subtle changes in status when used daily, thus ensuring rapid intervention. Another assessment tool is the World Health Organization scale, which despite its simplicity, is regarded as the most effective instrument used worldwide (followed by the OAG) [56,58]. Whichever tool is implemented, daily evaluation using a standardized assessment instrument is considered to be an integral part of oral mucositis management and should also be used at every patient contact [55,56,57,58]. Self-assessment using the OAG can also be taught for closer observations.

While mucositis usually resolves after radiotherapy is completed, other radiotherapy-induced problems may be long-term or permanent. These include changes in the salivary glands, caries due to radiation, and osteoradionecrosis.

Saliva has several critical functions in the oral environment. Its chemical composition allows it to function as a lubricant, a buffer in the modulation of acidity (pH) levels, an initiator in the enzymatic process of digestion, and as part of the immune system. The immune function is not readily apparent but is critical in maintaining the delicate balance of the oral microflora. Certain salivary proteins inhibit microbial growth. Lysozyme, a salivary enzyme, can hydrolyze and thus destroy certain components of the bacterial cell wall. Immunoglobulin (Ig) is also secreted into saliva, with IgA being the predominant secretion. Small amounts of IgG and IgM are also secreted. These substances may exert their action by decreasing bacterial adherence to hard and soft tissue. The pH of saliva ranges from 6.7 (a weak acid) to 7.4 (a weak base) [59]. Alteration of this range toward either spectrum promotes certain forms of microbial growth over others. Lactobacillus and Streptococcus mutans, two cariogenic resident bacterial species, favor a more acidic environment. This situation occurs when salivary output decreases secondary to radiation therapy [60].

The parotid, submandibular, and sublingual glands compromise the major salivary glands. Scattered throughout the remainder of the oral mucosa are minor salivary glands. Location of the radiation portal will determine which gland or glands will be susceptible to damage. Because the secretory product of each gland varies, postradiation salivary composition will be determined by which gland or glands are damaged and which are spared.

The parotid gland is a purely serous gland (i.e., it releases a watery secretion without a mucous component). The submandibular gland has both a serous and a thicker mucus secretion, with the serous component being predominant. The sublingual salivary gland features secretions that are more mucus than serous. The minor salivary glands have secretions that are nearly all mucus in origin. Damage to one or both parotid glands will increase the viscosity of the saliva as the watery component of the saliva decreases. The saliva develops a thick, ropy consistency that decreases its function as a lubricating medium. The location of some malignant lesions is such that all of the major salivary glands are damaged. The cells that produce the serous secretions are extremely sensitive to ionizing radiation and can undergo a 50% decrease in output with a cumulative radiotherapy dose of only 1,000 cGy [61]. Salivary glands that are irradiated with a cumulative dose of 4,000 cGy usually have a permanent decrease in output [62].

The resultant condition of xerostomia will usually remain with patients for the remainder of their life. It is the most common persistent radiotherapy side effect [63]. Saliva substitutes and certain cholinergic drugs, such as pilocarpine, may decrease the severity of the xerostomia, but no treatment regimen will return salivary output to the levels prior to radiotherapy [64]. However, a 2011 multicenter randomized controlled trial found that intensity-modulated radiotherapy that spares the parotid glands is significantly less likely to cause severe xerostomia [63].

Xerostomia presents patients with a host of problems that they must confront on a daily basis. Patients who wear complete or partial dentures may have chronic sore spots because the lubrication that saliva produces to lessen the friction against the mucosal tissues is significantly decreased. These prostheses may be difficult to use for mastication and thus complicate the ability to eat. Because the perception of taste is partially dependent on food particles dissolved in a salivary medium, taste perception is altered. Patients often attempt to compensate for this by selecting foods that are very spicy or very sweet, which further compromises their medical and dental health. Swallowing food becomes more difficult as the bolus of food is less lubricated. Patients may need frequent sips of water during meals to alleviate this problem. The oral tissues can become subject to frequent irritation, tissue trauma, and opportunistic infection. The cleansing action that saliva provides for the teeth can be severely compromised. This can lead to a form of multiple caries that occurs after radiotherapy has damaged the salivary glands.

The changes that occur in the oral environment after radiotherapy portals have damaged the salivary glands may cause rapid and widespread destruction of teeth that previously had no dental pathology [65]. It is postulated that radiation alters the organic and inorganic matrix of enamel and the remaining tooth structure [47]. Decalcification may be favored over remineralization as an initiator of the carious process. The decrease in pH levels, which is commensurate with the amount of damage to the salivary glands, begins the creation of a caries-prone oral environment. When the serous component of saliva decreases and the viscosity increases, adherence of cariogenic bacteria to tooth structure increases. These organisms thrive in the more acidic oral environment that develops after radiotherapy.

These factors, coupled with the difficulty patients have with their oral hygiene maintenance amidst sensitive teeth and soft tissues, create a problem known as "radiation caries." This is an aggressive and rapid form of dental decay, targeting parts of the tooth that are usually not prone to decay. The smooth buccal (outer) and lingual (inner) walls of the tooth become involved with rapidly advancing carious lesions. The area of the tooth that is closest to the gingival tissues, the cervical area, is a frequent point of origin. The process can also affect the incisal edges of anterior teeth and the cusp tips of posterior teeth. Within weeks or months, the process renders teeth that were previously devoid of any dental pathology completely destroyed.

Extractions of the teeth should only be done after a consultation with the patient's primary care physician. Oral surgery procedures can produce extensive postsurgical complications, with significant morbidity and even death in patients who have undergone a full course of radiotherapy.

The most serious of the complications postradiotherapy is osteoradionecrosis (ORN), occurring in 3% to 10% of patients [66]. This is defined as necrosis of the bone in areas that have received radiotherapy. Patients who have received doses of radiation for head and neck malignancies in excess of 6,000 cGy have the highest risk of this pathologic entity [66,67]. The blood vessels that supply the bones with oxygen and nutrients become hyalinized, with a subsequent decrease in the ability to perfuse the tissue with enough oxygen-rich blood. Areas of bone supplied by these damaged vessels lack the oxygen and nutrients necessary to sustain the appropriate levels of metabolism. These areas of bone become ischemic and ultimately necrotic. The mandible is affected more frequently because it has less of a blood supply than the maxillary arch [66]. Necrotic pieces of bone may be small fragments or large sections whose loss undermines support for either arch. A pathologic fracture of the affected arch is a possible complication. Three grades of ORN have been categorized [67,68]. Grade I occurs in close proximity to the completion of surgery and radiotherapy. Exposed alveolar bone is observed [67]. Grade II designates ORN that does not respond to hyperbaric oxygen therapy and requires sequestrectomy/saucerization [67]. Grade III is demonstrated by full-thickness involvement and/or pathologic fracture. Patients may demonstrate grade I or III ORN at initial presentation [67].

Given the tumoricidal doses of radiation used, the 6,000 cGy threshold is easily reached for most patients with head and neck malignancies. Changes within the bone marrow include fibrous and fatty degeneration. The cells responsible for the production of bone, the osteocytes, are greatly diminished in number secondary to radiotherapy. The cells whose function is the resorption of bone, the osteoclasts, have fewer losses after radiotherapy. Thus, the dynamics of bone metabolism now favor bone resorption rather than bone apposition [60]. When this is combined with the damage to the blood vessels, the risk of ORN will be present for the remainder of the patient's life. Unfortunately, the passage of time does little to reverse the damage and the subsequent risk of ORN.

Treatment for ORN is variable. Small pieces of necrotic bone may migrate through the tissue and can be removed under local anesthesia. Larger segments of bone may require hospitalization for their removal. The risk of osteomyelitis, an infection of the bone, is increased in the patient who has undergone radiotherapy. The bony segments that perforate the mucosal tissues create a portal of entry for microbial organisms of the oral flora. Aggressive surgical and antibiotic treatment is needed to debride the area and resolve the infection. Hyperbaric oxygen treatments may help in the regeneration of new blood vessels with a resultant increase in the oxygen supply to the affected bone [69]. There is also evidence to suggest that hyperbaric oxygen treatments may be helpful as a therapy for soft tissue injury caused by radiation, as well as restoring tissues and cells damaged by chemotherapy and radiation treatments [66]. However, routine use is not recommended, and clinicians should assess any potential benefit to the patient on a case-by-case basis [67,70]. Any oral surgery procedure increases the risk of the development of spontaneous ORN, even if it is performed years after the last radiotherapy treatment. Trauma to the soft tissue by any means also causes a localized area of inflammation and infection that can extend to the bone and cause ORN. Bone that has been irradiated can undergo dire consequences from seemingly minor events.

Patients can experience a wide range of undesirable effects from any treatment modality, and radiotherapy is no exception. One such experience common to many patients undergoing radiotherapy is hypogeusia, the partial loss of the sensation of taste, or ageusia, the complete loss of this sensory function. Taste buds are very sensitive to ionizing radiation and begin to experience damage when a cumulative dosage of 1,000 cGy has been given. When the cumulative dose of 6,000 cGy has been reached, damage to the taste buds is usually permanent with the sensation of taste being lost [71]. Thus, if the oral malignancy being irradiated is in the area of the taste buds, the extent of damage and the ability to regain the sensation of taste will depend on the cumulative dose of radiation and the number of taste buds involved. The lower the dose and exposure, the better the chance that the sensation of taste will be restored. Patients should be counseled about the problems associated with the overcompensation of this loss by eating foods that are high in sugar content or excessively spicy.

A resident oral fungal organism with pathogenic capabilities, Candida albicans, causes a common opportunistic infection in the oral tissues of patients receiving radiotherapy. The normal competitive mechanisms among the microbial species of the oral environment and the immunocompetence of the host are usually sufficient to prevent infection of the mucosal tissues by this fungal organism. After radiotherapy, both of these protective mechanisms are altered, which can result in candidiasis in the oral tissues. This may be especially painful and even difficult to diagnose if it is superimposed on areas of mucositis.

The most significant concern is that a Candida infection superimposed over an area of mucositis could be a source of a regional or systemic fungal infection, which could have fatal consequences in a patient already weakened by illness, surgery, radiotherapy, and/or chemotherapy. Treatments for these infections consist of antifungal oral suspensions, such as nystatin, that follow a swish-and-swallow protocol (used with varying degrees of efficacy), or systemic fluconazole (highly effective for prophylaxis and treatment) [72]. Antifungal lozenges are difficult to use in patients whose salivary flow has diminished. Patients who wear complete or partial dentures, orthodontic retainers, or night guards should disinfect these appliances in accordance with the manufacturers' directions (e.g., soaking in antifungal solutions). The acrylic portions of these appliances have microscopic porosities in which C. albicans organisms thrive and re-infect oral tissues that have been cleared of the infection. Systemic fungal infections in these patients have a high mortality rate and should be treated with intravenous antifungal agents in a hospital setting.

Trismus, a condition in which the muscles that coordinate the functional range of jaw movements become spasmodic and contracted, can affect patients weeks or months after radiotherapy has been initiated [72]. Irradiation causes a thickening and scarring of the blood vessels that supply these muscles. The decreased oxygen and nutrient supply cause scars to form among the muscle fibers. This results in a state of relative contraction and a loss of range of motion. The onset of this problem is more gradual than that of mucositis because the muscle cells have a slower rate of mitosis. The prevalence of trismus increases with greater doses of radiation, and levels in excess of 60 Gy are more likely to cause the condition. 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 [72]. A physical therapist can recommend exercises for the facial musculature that minimize this problem. Preventive exercises should be employed before trismus becomes established, as it is difficult to regain muscle function and elasticity after this problem is firmly developed.

Oral complications secondary to surgery and radiotherapy for the treatment of malignancies may occur in patients with optimal oral health. These problems are exacerbated for those patients who have carious lesions, periodontal disease, problematic wisdom teeth, fractured teeth with sharp exposed edges, and prosthetic appliances that fit poorly and persistently traumatize the tissues.

A complete clinical and radiographic examination of the teeth and soft tissues should be completed as far in advance as possible from the surgical phase of oral cancer therapy. This will allow sufficient healing time for the extractions of teeth with unrestorable decay and advanced periodontal disease. Partially erupted wisdom teeth should be removed if they are in an area to be irradiated. Teeth with dental caries should be restored to optimal clinical condition. Teeth in which the carious process has extended into the pulp and has caused irreversible inflammation or necrosis should undergo root canal therapy or be extracted. Those teeth that cannot have deep periodontal pockets reduced to levels that will facilitate oral hygiene should be extracted. Prosthetic appliances should be adjusted so that their use will not promote tissue trauma. The goal is definitive treatment, avoiding a "watch and wait" approach. Patients should be informed that dental problems may exist without any symptoms and that lack of treatment will contribute to infections and even ORN after the completion of oral cancer therapy.

All patients should receive oral hygiene instruction and nutritional counseling. Manufacturers offer special sponge-like toothbrushes with toothpaste impregnated into the foamy material that may provide for an adequate means of cleansing the teeth without causing soft tissue trauma. The use of dental floss or dentotape for the interproximal areas should only be done if it can be accomplished atraumatically. Patients should demonstrate that proper flossing technique is within their capability.

Mouth rinses that contain alcohol may irritate the mucosal tissues and increase the dryness within the mouth. If an alcohol-based mouth rinse can be tolerated, 0.12% chlorhexidine gluconate is an excellent adjunct to the oral hygiene regimen [73]. This mouth rinse has substantivity, the ability to adhere to the tissues within the oral environment for several hours. This bactericidal formulation diminishes the number of bacteria associated with dental caries and periodontal disease. However, as discussed, chlorhexidine may cause additional discomfort for many patients [48].

All patients who will retain some or all of their natural teeth should have custom fluoride trays made before oral cancer treatment. These trays serve as reservoirs for a neutral formulation of 1.1% sodium fluoride or 0.4% stannous fluoride gels, depending on the composition of the patient's dental restorations [74]. These trays should be worn about 10 minutes daily, and patients should refrain from eating or drinking for 30 minutes after the fluoride treatment. Patients who do not want to use trays may brush the gels onto their teeth. Patients should also brush their teeth twice daily using 1.1% fluoride toothpaste [75]. This regimen should be a lifelong commitment for these patients in an attempt to minimize the risk of dental caries in a postsurgical oral environment that poses a high risk of dental caries.

Before surgery and radiotherapy for oral cancer is begun, patients should have an appointment for an oral assessment. The status of the teeth and the soft tissue should be scrutinized to minimize the chance of any condition that would lead to an infection necessitating oral surgery procedures, especially after radiotherapy. If a dental emergency develops that requires an extraction of a tooth, a 14-to 21-day window of healing should be allowed prior to radiotherapy to minimize the risk of ORN. Recall appointments should be frequent to allow for the examination of the oral tissues, as there is always a chance that an oral malignancy can recur at the original site or a new lesion can arise. These appointments also allow for an opportunity to evaluate oral hygiene status, presence of carious lesions, periodontal condition, and overall condition of the oral mucosa.

Rehabilitation of the patient with oral cancer is a challenging experience. The extent of necessary rehabilitation is proportionate to lesion size and the presence of metastasis. Larger squamous cell carcinoma lesions can engulf nerves, muscle, and bone. As noted, the removal of larger lesions adversely affects the ability to eat, speak, swallow, and enjoy the previous quality of life. Cosmetic disfigurement may not always be correctable to the patient's satisfaction. The team approach, involving the surgical and radiotherapy team, dentists, oral surgeons, oral and maxillofacial prosthodontists, nurses, nutritionists, occupational therapists, speech therapists, physical therapists, pharmacists, and plastic surgeons, may be needed. Counseling may be necessary to assist these patients as they face life from an entirely new perspective. Because most patients with oral cancer have a history of tobacco use, tobacco cessation education is an important aspect of patient recovery.

When the number of platelets produced or the quality of those in existence are diminished, oral bleeding can occur. The normal range of platelets is 150,000–450,000 per mm³of blood. Spontaneous bleeding occurs when the platelet count decreases to 20,000–50,000 per mm³of blood [78]. When platelets contact a damaged blood vessel, they increase in size and adhesiveness and form a plug upon the damaged vessel. Some chemotherapeutic agents alter the ability of platelets to adhere to each other in the formation of a fibrous plug, which is required for hemostasis. Others may interfere with actual platelet production and decrease the number of platelets available. Regimens that use more than one chemotherapeutic agent may affect both platelet quality and production.

Interference with coagulation causes oral manifestations, including petechiae, ecchymoses, or oozing of blood [79]. The most common areas in which petechiae are found intraorally include the palate, gingiva, lips, and tongue. Petechiae are small areas of bleeding within the tissue that occur because of a decreased platelet count. Similarly, bleeding submucosally or subcutaneously due to platelet deficiencies in quality or quantity may produce ecchymoses. These lesions can occur anywhere within the oral tissues and appear as a dark red or reddish-blue area submucosally. They are exacerbated by accidental trauma or by prostheses that irritate the tissues. The most disconcerting problem for the patient is hemorrhage, which occurs spontaneously or with actions such as eating, brushing, or flossing. This problem is exacerbated in patients who have chronically inflamed gingival tissues characteristic of gingivitis and periodontal disease. Ideal depth of the gingival sulcus in health is 3 mm or less. As gingivitis and periodontal disease progress, destruction of the epithelial attachment causes this sulcus to become deeper. Cleansing the pocket depth becomes increasingly difficult, with a resultant state of chronic inflammation. As alveolar bone is lost during the progression of periodontal disease, the gingival tissues become poorly attached to the tooth and bone.

An environment of continually deepening periodontal pockets causes severe soft tissue inflammation. Despite this, tissues in this pathologic state often do not bleed spontaneously. Patients receiving chemotherapy, however, may have spontaneous gingival bleeding even if the depth of the gingival sulcus is not excessive. The clots usually appear as dark red and are friable, with slight bleeding evident when they are removed. Patients may experience this at any time, but it is most noticeable upon awakening in the morning. Dried blood from nocturnal bleeding can be encrusted on the lips, tongue, or anywhere in the oral mucosa. Sharp edges of fractured teeth or broken fillings, dental restorations that extend below the gingival crest, prostheses that cause tissue irritation, and partially erupted wisdom teeth are all potential sources that compromise tissue integrity and allow easy bleeding during chemotherapy. When bleeding is seen within the oral cavity, the patient should be referred to their physician, as internal bleeding in other areas of the body is possible.

The effect of chemotherapy on hemostasis subsides for most patients after the completion of the regimen. Even basic dental treatment, including prophylaxis, should not be performed until laboratory values ascertain that the platelet levels have returned to a range that is acceptable for hemostasis. Further diagnostic tests, such as a prothrombin time, may need to be done. The oncologist should be consulted before any invasive treatment is planned, as patients can have a wide interval of recovery times after chemotherapy ends. Emergency dental treatment that cannot be postponed, such as oral and maxillofacial trauma or painful exacerbations of dental problems, may need to be performed in a hospital setting.

Oral infections that are usually treated successfully with standard antibiotics can become a life-threatening problem for patients receiving chemotherapy. Oral infections may be bacterial, fungal, or viral in origin. Chemotherapy interferes with the production of the granular and agranular leukocytes, which are important components of the defense mechanism of the immune system. Oral infections in the aftermath of chemotherapy are common and may manifest into systemic conditions [80].

The use of large doses of IV bisphosphonates, as is common among patients with multiple myeloma or metastatic breast cancer, has been linked to the development of jaw osteonecrosis [89]. This phenomenon was previously referred to as bisphosphonate-related osteonecrosis of the jaw. However, the preferred term is now medication-related osteonecrosis of the jaw (MRONJ), which is favored due to the rise in osteonecrosis cases associated with other antiresorptive (denosumab) and antiangiogenic therapies [90,91]. MRONJ is diagnosed by the presence of three characteristics [90]:

The risk of developing MRONJ increases with extended use of the medications. According to one meta-analysis, the majority of cases (60%) were precipitated by tooth extraction or oral surgery, which may involve trauma to the alveolar bone during the procedure as well as complications arising during recovery [89,92,93]. Among patients with jaw osteonecrosis who have not had oral surgery or tooth extraction, the use of dental prostheses or other oral problems are often present [94]. The results of one study suggest that the accurate diagnosis of MRONJ at the time of extraction is critical, and that an additional category of MRONJ that encompasses cases of bony necrosis found in the extraction socket during tooth extraction procedures may be needed. The study results also suggest that the routine discontinuation of bisphosphonates several months prior to the extraction procedure should be considered carefully [95]. All patients who are being treated with bisphosphonates or denosumab should be counseled regarding the possibility of MRONJ developing, including early signs, and the importance of good oral hygiene [90].

When MRONJ does develop, the stage of the disease should be determined, which will in turn guide the treatment plan. MRONJ is categorized as [90]:

Patients with stage 1 MRONJ are usually treated conservatively, with oral antimicrobial rinses (e.g., chlorhexidine 0.12%) and no surgical intervention. Stage 2 MRONJ is treated with the use of antibiotic therapy in addition to oral antimicrobial rinses; certain cases may require surgical intervention to reduce the volume of colonized, necrotic bone. Stage 3 disease often impacts quality of life and requires more intensive intervention. These patients usually require surgical debridement/resection in combination with antibiotic therapy [90].

Systemic chemotherapy can have oral manifestations that are dependent on the agent(s) used, their dosage, and the duration of therapy. As with any medication, there is a considerable variability in the tolerance for a given pharmacotherapeutic regimen as well as any side effects. As noted, one such effect may be xerostomia. This problem is associated with some chemotherapeutic agents more than others. The parotid glands, with their serous secretions, are the glands most frequently affected. Because chemotherapeutic agents are administered as a systemic therapy, these substances course through all salivary glands. With the serous component reduced, the saliva develops a mucus-laden, ropey consistency. The decreased lubrication exacerbates the pain associated with concurrent areas of mucositis and makes it difficult to wear any dental prostheses. Eating, speaking, and swallowing may become difficult, and the taste of foods may be altered.

While radiotherapy-induced xerostomia and all of the problems associated with it are long-term or permanent, those associated with chemotherapy dissipate after the completion of the regimen. Chemotherapy is usually given in an incremental fashion, with several days or weeks separating the appointments. Xerostomia may be a continuous problem until enough time has elapsed after the last session. A 2015 Cochrane Review concluded that cryotherapy (i.e., holding ice chips or ice water in the mouth from 5 minutes prior to 30 minutes after treatment) is effective in reducing mucotoxicity [96]. A simple act to palliate the symptoms associated with this xerostomia and mucositis is to frequently suck on ice chips. Being that the cost and risks of this preventative measure are virtually nonexistent, cryotherapy should always be considered.

Neurologic effects may be seen in some patients on chemotherapy. Vincristine sulfate is the chemotherapeutic agent most commonly associated with this problem [51,97]. Chemotherapeutic agents exert varied effects on any nerve. The most commonly affected nerves that serve the oral and maxillofacial complex are the facial and trigeminal nerves. The facial nerve is the major source of motor innervation for the muscles of facial expression. Transient neural toxicity manifests as weakness of these muscles and decreased facial muscular coordination. The trigeminal nerve is another cranial nerve that provides sensory innervation to many portions of the face and for those structures within the oral cavity. Symptoms of neural toxicity present in a variety of ways. Pain that mimics that of dental origin may affect both the maxillary and the mandibular arches. There may be temporary paresthesia in the soft tissues or in the teeth. Pain in the temporomandibular joint (TMJ) may mimic TMJ problems. Patients should be reassured that these problems will regress after chemotherapy is completed.

The guidelines established for dental pretreatment of patients who will receive radiotherapy should also be followed by those receiving chemotherapy. The major additional caveat is that these patients may have decreased defense mechanisms against oral infections for an extended period of time. Like bone marrow transplant patients, some patients receiving chemotherapy may be so immunocompromised that the cardinal signs of warmth, redness, and swelling may be completely lacking as a warning sign of an infection. It is imperative that within this patient population, any dental pathology related to the teeth, the periodontium, or the soft tissue is eliminated well in advance of chemotherapy [99].

Postchemotherapy dental treatment should include frequent recall appointments to examine the oral cavity and reinforce the need for meticulous oral hygiene. Antimicrobial prophylaxis may be required for any procedure in which bleeding is anticipated due to the increased risk for infection. Laboratory values for the formed elements of human blood may be necessary. The healthcare team, including dentists and oncologists, should be in communication regarding patient dental pretreatment and post-treatment [99,100].