Oral Manifestations and Complications of Cancer Therapy

Jane M. Fall-Dickson

Ann M. Berger

Oral Complications

The effectiveness of standard cancer treatments targeted at improving cure rates, extending survival, or providing palliative treatment, and novel cancer therapies tested in the clinical trial setting, is tempered by patient morbidity manifested as side effects. Nonhematologic side effects have become the primary-dose and treatment-limiting clinical challenges due to the standard use of growth factors. Oral complications are clinically significant side effects and include chemotherapy- and radiation therapy-related stomatitis and chronic graft versus host disease (cGVHD)-related oral manifestations, associated oropharyngeal pain, xerostomia, and oral infection (1). Patient outcomes from these oral complications range from symptoms such as severe oral pain to life-threatening medical emergencies such as sepsis. Pathogenic theories of prevention, assessment, and management strategies for these oral complications are presented.

Stomatitis

Chemotherapy-Related Stomatitis

Stomatitis occurs in approximately 40% of chemotherapy patients (2), with about 50% of these patients experiencing severe painful lesions requiring cancer treatment modification and or parenteral analgesia (3). Patients undergoing bone marrow transplantation (BMT) experience incidence rates of stomatitis >60%, and have higher incidence rates for ulcerative stomatitis of up to 78% (4). Oral infection may not only increase the severity of stomatitis, but also has a four times greater relative risk of septicemia due to pathogen entry through damaged mucosal barriers. In the peripheral blood stem cell transplantation (PBSCT) setting, stomatitis typically develops 5 to 7 days post high-dose chemotherapy administration with severe stomatitis usually preceding the white blood cell (WBC) nadir by 2 to 3 days.

Stomatitis clinically presents with asymptomatic erythema. Solitary, white, elevated, desquamative, slightly painful patches may progress to large, contiguous, pseudomembranous, painful lesions. Nonkeratinized mucosa is most affected, including the labial, buccal, and soft palate mucosa, the floor of the mouth, and the ventral surface of the tongue. Typical oral histology of chemotherapy-related stomatitis includes epithelial hyperplasia, collagen and glandular degeneration, epithelial dysplasia, atrophy, edema of the rete pegs, and vascular changes. The loss of basement membrane epithelial cells exposes the underlying connective tissue stroma and its associated innervation, contributing to increasing oropharyngeal pain levels.

Radiation Therapy–Related Stomatitis

Radiation therapy targeted at the oropharyngeal area almost always causes stomatitis, with severity related to type of ionizing radiation, volume of irradiated tissue, daily and cumulative dose, and duration of radiotherapy. Stomatitis remains a dose- and rate-limiting toxicity in the population receiving irradiation for cancer of the head and neck, and also with hyperfractionated radiotherapy and chemotherapy designed to improve survival time. Radiation therapy interacts directly with DNA leading to chromosomal and cellular mitotic apparatus damage. Total doses of 1600 to 2200 cGy, administered at 200 cGy per day usually leads to atrophic changes in the oral epithelium, and doses >6000 cGy may cause permanent salivary gland changes (5). Pseudomembranes and ulcerations develop in parallel with increase in severity of stomatitis. Although decalcification or hypocalcification of teeth may result from direct dental irradiation, radiation therapy–related dental effects depend mainly on salivary changes that occur from irradiated glands. The addition of total body irradiation to the PBSCT treatment leads to an increased risk of severe stomatitis related to both direct mucosal damage and xerostomia.

Radiation-induced dental effects primarily depend on salivary changes and occur when the glands are included in the field of treatment, rather than on direct irradiation of the teeth themselves. Direct irradiation of teeth may alter the organic or inorganic components in some manner, making them more susceptible to decalcification or hypocalcification. Although there have been no clinical studies to support the possibility that radiation therapy directly affects the pupal chamber, many teeth in the direct irradiated field could be desensitized and therefore, early caries involving the nerve might be asymptomatic. Therefore, meticulous mouth or oral care includes daily fluoride application.

Pathogenesis of Stomatitis

Stomatitis is an inflammation of the mucous membranes of the oral cavity and oropharynx characterized by tissue erythema,
edema, and atrophy, often progressing to ulceration (6). The pathogenesis of cancer treatment–related stomatitis remains to be completely elucidated. Mucosal epithelial stem cells that are located in the deep squamous epithelium superior to the basement membrane are subjected to trauma by routine actions such as chewing, swallowing, and digestion. Cancer therapy affects rapidly dividing cells, and therefore the oral basal epithelium cell turnover rate of 7 to 14 days places them at risk for chemotherapy targeting. Sonis (3) proposed a hypothetical model for the pathogenesis of stomatitis and healing that includes four interdependent phases: inflammatory/vascular, epithelial, ulcerative, and healing. Each phase results from cytokine-mediated actions and the direct effect of chemotherapy or radiation therapy on the epithelium which is also influenced by the patient’s bone marrow status and oral bacterial flora. Sonis (7) has expanded upon this model recently and has proposed a five-phase biological model of stomatitis that includes dynamic interactions that promote initiation, message generation, signaling and amplification, ulceration, and healing.

The relatively acute inflammatory/vascular phase occurs shortly after chemotherapy or radiation therapy administration (3). Cytokines released from epithelial tissue include tumor necrosis factor-α (TNF-α) that is related to tissue damage, and interleukin-1 (IL-1) both of which incite the inflammatory response and increase subepithelial vascularity that may lead to increased local chemotherapy levels. The epithelial phase demonstrates reduced epithelial renewal and atrophy, and typically begins 4 to 5 days after chemotherapy administration. The cell cycle S-phase specific agents are the most efficient contributors to this phase and include methotrexate, 5-fluorouracil (FU), and cytarabine.

The ulcerative/bacterial phase, which begins approximately 1 week postchemotherapy administration with maximum neutropenia, is the most biologically complex stage (3). This phase is probably not chemotherapy agent class specific. During this most symptomatic phase, patients often experience acute oropharyngeal pain leading to dysphagia, decreased oral intake, and difficulty in speaking. Bacterial colonization of mucosal ulceration occurs, and gram-negative organisms release endotoxins that induce the release of IL-1 and TNF-α and production of nitric oxide which may increase local mucosal injury. Radiation therapy and chemotherapy are likely to amplify and prolong this cytokine release, thus exacerbating tissue response. Genetic expression of cytokines and enzymes critical in tissue damage may be modified by transcription factors (3). Healing of oral lesions in the nonmyelosuppressed patient occurs within 2 to 3 weeks through renewed epithelial proliferation and differentiation in parallel with WBC recovery, reestablishment of normal local microbial flora, and decrease in oropharyngeal pain.

Risk Factors

Risk factors for chemotherapy-related stomatitis are complex and conflicting study results are seen (Table 19.1). Younger patients are considered to be at increased risk for stomatitis, and women have been reported to have more severe stomatitis with greater frequency than men. However, Driezen (8) reported no age or gender risk for stomatitis development. In general, children are three times more likely than adults to develop stomatitis due to their higher fraction of proliferating basal cells. Although both alcohol and tobacco may impair salivary function, it has been suggested that tobacco is associated with a decreased incidence of chemotherapy-induced stomatitis (3). One recent study involving 332 outpatients receiving chemotherapy revealed no significant differences in stomatitis incidence between patients who wore dental appliances, had a history of oral lesions and a history of smoking and patients who did not, as well as those patients who practiced different oral hygiene regimens (9). Also, drug metabolism affects the incidence and severity of stomatitis in patients who are unable to adequately metabolize or excrete certain chemotherapeutic agents.

Table 19.1 Patient-Related and Treatment Related-Stomatitis Risk Factors

PATIENT-RELATED

Age ≥65 and ≤20years

Gender

Poor oral health and hygiene

Periodontal diseases

Microbial flora

Chronic low-grade mouth infections

Salivary gland secretory dysfunction

Herpes simplex viral infection

Inborn inability to metabolize chemotherapeutic agent effectively

Poor nutritional status

Exposure to oral stressors such as alcohol and smoking

Ill-fitting dental prostheses

TREATMENT-RELATED

Radiation therapy: dose, schedule

Chemotherapy: drug, dose, schedule

Myelosuppression

Neutropenia

Immunosuppression

Reduced secretory protein Immunoglobin A

Oral care during treatment

Infections of bacterial, viral, and fungal origin

Use of antidepressants, opiates, antihypertensives, antihistamines, diuretics, and sedatives

Impairment of renal and/or hepatic function

Protein or calorie malnutrition, and dehydration

Xerostomia

IgA, protein Immunoglobin A.
Reference (9,10)
Adapted from Berger AM, Kilroy TJ. Oral Complications. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2004.

Although the full spectrum of treatment-related risk factors for stomatitis remains to be defined, reported risk factors include continuous infusion therapy for breast and colon cancer (5-FU and leucovorin), administration of selected anthracyclines, alkylating agents, taxanes, vinca alkaloids, antimetabolites, antitumor antibiotics, myeloablative conditioning regimens for PBSCT or BMT, and radiation therapy to the head and neck. Drugs that can result in xerostomia include antidepressants, opiates, antihypertensives, antihistamines, diuretics, and sedatives. In general, there are many complicated risk factors for the development of chemotherapy-induced stomatitis, and a lack of stratification criteria and clear definition of risk factors for patients entering clinical trials may contribute to conflicting study results (10).

Radiation Therapy–Related Complications

Long-term effects of head and neck radiation therapy include soft tissue fibrosis, obliterative endarteritis, trismus, non- or
slow healing mucosal ulcerations, and slow healing of dental extraction sites. These changes become more substantial over time. Radiation-related fibrotic changes in the muscles of mastication and/or the temporal mandibular joint can develop till 1 year posttreatment. Oral candidiasis is a common acute and long-term oral sequela of head and neck radiation therapy. These candida lesions, which frequently present as angular cheilitis, may appear white and movable, chronic hyperplastic (nonremovable), or chronic erythematous (diffuse patchy erythema).

Osteoradionecrosis (ORN) is a relatively uncommon clinical entity related to hypocellularity, hypovascularity, and tissue ischemia. Higher incidences are seen when total doses to the bone exceed 65 Gy (11). Although ORN may be spontaneous, the etiology is usually trauma such as dental extraction, and may lead to serious conditions such as pathologic fracture, infection of surrounding soft tissues, and severe pain. Most studies have reported ORN after tooth extractions that were not allowed adequate extraction site healing time of 10 to 14 days before start of radiation therapy. The risk of ORN does not diminish over time, and it may even increase following radiation therapy. See below.

Chronic Graft versus Host Disease Oral Manifestations

Patients with cancer who have undergone allogeneic PBSCT frequently develop GVHD, which is an alloimmune condition derived from an immune attack mediated by donor T-cells recognizing antigens expressed on normal tissues. This condition occurs following allogeneic PBSCT due to disparities in minor histocompatibility antigens between donor and recipient, inherited independently of HLA genes (12). Acute GVHD occurs within the first 100 days postallogeneic PBSCT, and cGVHD begins as early as 70 days or as late as 15 months postallogeneic transplant. Mitchell (13) presents a comprehensive overview of treatment strategies for GVHD.

Oral involvement occurs in approximately 80% of patients who experience extensive cGVHD and is a major contributing factor to patient morbidity seen in the allogeneic PBSCT setting (14). Patients may also present with limited disease involving only the oral cavity. Oral cGVHD clinically presents with tissue atrophy and erythema, lichenoid changes (hyperkeratotic striae, patches, plaques, and papules) and pseudomembranous ulcerations seen typically on buccal and labial mucosa and the lateral tongue, angular stomatitis, and xerostomia (14). Patients’ decreased oral intake related to oropharyngeal pain may lead to serious problems of weight loss and malnutrition. Oral infections in this population may lead to serious, life-threatening systemic infections (15).

Osteonecrosis

Osteonecrosis of the jaw bone has been associated with the use of bisphosphonate therapy, which is used to treat patients with hypercalcemia related to malignancy, bone metastasis, and metabolic bone diseases (16). Ruggiero, Mehrotra, Rosenberg et al. (17) performed a retrospective chart review of 63 patients with a diagnosis of refractory osteomyelitis and a history of chronic bisphosphonate therapy. A subsample of 56 patients had received intravenous bisphosphonates for at least 1 year and 7 patients were receiving chronic oral bisphosphonate therapy. Lesions were presented with either a nonhealing extraction socket or an exposed jawbone. Both of these conditions were refractory to conservative debridement and antibiotic therapy. Most of these patients required surgical procedures to remove the involved bone. In view of the current trend of increasing and widespread use of chronic bisphosphonate therapy, the authors stated that the associated risk of osteonecrosis of the jaw should alert practitioners to monitor this previously unrecognized potential complication. An early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jaw bone.

Strategies for Prevention and Treatment of Oral Complications

Pretherapy Dental Evaluation and Intervention

Oral/dental stabilization before chemotherapy and radiation therapy is critical in avoiding potential serious sequelae. Pretreatment oral/dental stabilization requires close collaboration between an experienced dental team and informed patients to provide adequate cleaning, eliminate sites of oral infection and trauma, and encourage appropriate oral hygiene (18). There exist many private practice or health care institution–specific policies and preventive approaches for oral care for chemotherapy and radiation therapy patients.

Patients scheduled for chemotherapy and/or head and neck radiation therapy should receive dental screening at least 2 weeks before therapy starts. This schedule allows for proper healing of any extraction sites, recovery of soft tissue manipulations, and restoration of teeth necessary to promote optimal mucosal health before, during, and following cancer treatment. Oral hygiene is one of the most important screening areas for all patients regardless of cancer treatment modality. Plaque and gingival hemorrhage on dental pocket probing are clinical signs that necessitate development of the oral/dental treatment plan (e.g., preradiation extractions). These procedures reduce the incidence of oral complications by eliminating bacteria that could lead to local oral infections or sepsis. The dental team must know the patient’s total WBC count, absolute granulocyte count, and platelet count following chemotherapy or in preparation for intense chemotherapy or peripheral blood stem cell transplant, especially if the patient requires dental extractions, oral biopsies, or periodontal surgery.

The initial dental appointment includes examination of the patient’s dentition for carious lesions and defective restorations, which are sources of potential irritation of the oral mucosa and necessitate replacement. The periodontium, as well as pulp vitality must be evaluated. Periodontal status is a major consideration and thorough screening includes measurement of pocket depth and assessment of furcation involvement. Denture fit assessment is important to avoid ill-fitting dentures that may cause irritation of irradiated tissue and potential ulceration to underlying bone (19). Trismus is anticipated if the temporal mandibular joints and other muscles of mastication are included in the radiation field. Therefore, maximum mouth opening should be recorded before radiation therapy at baseline to compare the interarch distance at various time points postradiation therapy to evaluate the degree of trismus. Comprehensive evaluation also includes assessment of the oral mucosa and the alveolar process to prepare for possible future prosthetic intervention, and also to assess ulcerations, fibromas, irritation, hyperplasia, bony spicules, and tori.

A panoramic radiograph combined with intraoral radiographs as needed is necessary to detect periodontal disease, periapical infections, cyst, third molar pathology, unerupted or partially erupted teeth, and residual root tips. Significant oral/dental problems to address before cancer treatment
include poor oral hygiene, periapical pathology, third molar pathology, periodontal disease, defective restorations, dental caries, orthodontic appliances, ill-fitting prostheses, and other potential sources of infection. Also recommended before cancer treatment is root planing, scaling, and prophylaxis, excluding visible tumor located at the site of anticipated dental manipulation, to reduce the bacteria load that could lead to local infection and sepsis. Acyclovir should be considered prophylactically in patients who are seropositive and at high risk for HSV infection reactivation, including BMT patients or those with prolonged myelosuppression. Mucosal lesions with fungal, viral, or bacterial infection require treatment to avoid the risk of systemic infection.

Decisions by the dental team regarding extraction before radiation therapy are based on radiation exposure, type, portal field, fractionation and total dosage, tumor prognosis and expediency of cancer control, and very importantly, the patient’s motivation to adhere to the preventive regimen. Teeth with acute and symptomatic periodontal problems should be extracted with careful follow-up examination of these sites before head and neck radiation therapy. The patient is at risk for ORN following tooth extractions that do not allow 10 to 14 days of healing before radiation therapy. Dental appliances fabricated during the pretreatment time period include fluoride carriers and radiation protective mouthguards. Surgical resection of any anatomic oral or pharyngeal structure including soft palate, tongue, hard palate, mandible, or combination will compromise oral function. Sequelae of many resections can be alleviated by intervention with maxillofacial prosthetics that are designed to restore function and cosmesis, with some limitations.

Dental extractions following radiation therapy require collaborations between dental and radiation oncology team members to minimize the risk of ORN. A low incidence of ORN is seen when preradiation therapy dental consultation and appropriate treatment (e.g., extractions) are rendered (20, 21, 22). Follow-up and recall of the head and neck cancer patient for dental preventive maintenance and treatment are essential to prevent or attenuate negative sequelae in the oral cavity. Generally, any teeth with acute and symptomatic periodontal problems should be extracted before head and neck radiation therapy. The decision to extract asymptomatic teeth before the commencement of radiation therapy is related to several important factors including radiation exposure, type, portal field, fractionization and total dosage, in addition to tumor prognosis, and expediency of control of the cancer (23). Lack of patient motivation regarding appropriate oral hygiene practices should lead to a decision to extract questionable teeth before radiation therapy.

Teeth that are class II or III mobility without use as abutment teeth for prosthetic retention should also be considered for preradiation extraction therapy. Extractions of residual root tips and impacted teeth should be performed atraumatically with regard to tissue handling. Alveolectomy and primary wound closure are considered to eliminate sharp ridges and bone spicules that could project to the overlying soft tissues. This is particularly important for prosthetic consideration because negligible bone remodeling is predicted after radiation therapy.

Nonvital teeth located in the portal fields that do not have periapical radiolucency and are asymptomatic should be treated endodontically. Endodontics with possible retrograde filings are preferred because of increased ORN risk in the portal fields. Teeth with small amounts of periapical granulomas without periodontal involvement but important for oral function or rehabilitation, should be treated with apicoectomies.

Allowing adequate time for healing of extraction sites before radiation therapy is essential. Healing times of 14 to 21 days are generally considered safe and should be the rule. Antibiotics are not routinely recommended because there is no evidence that they influence healing in the absence of infection. Careful examination of extraction sites must be performed before radiation therapy commences. Communication between the dentist, patient, and radiation therapist is pivotal for healthy maintenance of the oral cavity. Patients are susceptible to dental caries (decay) at the cervical areas of all teeth after radiation therapy to the head and neck region and need to be instructed about effective daily plaque removal through use of floss, a soft toothbrush, and fluoridated toothpaste at least three to four times a day. Daily compliancy of fluoride for the patient’s life is more important than the modality of fluoride application.

Patient and family education and counseling within the context of patient motivation are necessary to promote successful preventive strategies. Communication between and among the dentist, dental hygienist, medical oncologist and/or radiation therapist, oncology nurse, and patient is critical for the successful outcome of oral health following cancer treatment. Patients often receive their cancer treatment in the ambulatory setting and are therefore responsible for their oral care at home. Therefore, specific written instructions are needed regarding appropriate use of oral care agents and instruments for effective daily plaque removal, use of prescribed fluoride treatments, and reportable oral observations and symptoms. Numerous educational materials exist including the comprehensive patient education packet “Oral Health, Cancer Care, and You: Fitting the Pieces Together” http://www.nohic.nidcr.nih.gov.easyaccess1.lib.cuhk.edu.hk/campaign/titlepg.htm) that is available through the National Oral Health Information Clearinghouse (24).

Assessment of the Oral Mucosa

Consistent and frequent oral cavity assessment is needed to assess clinical signs before, during, and after the treatment time course, and requires the use of an adequately intense white light to visualize all soft and hard tissues and dentition. Assessment and treatment of oral complications is often performed by medical and nursing staff when the patient is hospitalized, which requires an appropriate knowledge base of clinical signs and symptoms of oral complications and predicted negative sequelae. No standard grading system for severity of oral complications of cancer treatment exists. Numerous available oral complications grading tools are based on two or more clinical parameters combined with functional status, such as eating ability. One commonly used tool is the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 that includes both descriptive terminology and a severity grading scale for each reportable adverse event (25). Other frequently used oral mucosal assessment tools are discussed in the subsequent text.

Oral Assessment Guide

The Oral Assessment Guide (OAG) (26) is a concise clinical tool to record oral cavity changes related to cancer therapy using eight assessment categories (voice, swallowing, lips, tongue, saliva, mucous membranes, gingiva, and teeth/dentures), each rated on three levels of descriptors: 1 = normal findings; 2 = mild alterations; and 3 = definitely compromised. The overall oral assessment score is the summation of the subscale score with a possible range of 8 to 24. Content-related validity, construct validity, clinical utility, and a high, trained nurse–nurse interrater reliability (r = .912) have been reported (26). The OAG has been used frequently to assess the efficacy of oral care protocols, to compare methods designed to determine the nature and prevalence of stomatitis,
and to describe the incidence and severity of stomatitis in (PBSCT) patients.

Oral Mucositis Rating Scale

The Oral Mucositis Rating Scale (OMRS) was developed as … a research tool for the comprehensive measurement of a broad range of oral tissue changes associated with cancer therapy” (27). The OMRS was originally tested in 60 patients who were 180 to 500 days post PBSCT, to examine the relationship between oral abnormalities and cGVHD (28). Findings demonstrated that oral manifestations and related sequelae most strongly associated with cGVHD included atrophy and erythema, lichenoid lesions located on the buccal and labial mucosa, and oral pain.

The item pool consists of 91 items covering 13 areas of the mouth that are assessed for several types of changes in seven anatomic areas: lips; labial and buccal mucosa; tongue; floor of mouth; palate; and attached gingiva. Each site is divided into upper and lower (lips and labial mucosa), right and left (buccal mucosa), dorsal, ventral, and lateral (tongue), and hard and soft (palate). Descriptive categories are atrophy, pseudomembrane, erythema, hyperkeratosis, lichenoid, ulceration, and edema. Erythema, atrophy, hyperkeratosis, lichenoid, and edema are scored using scales of 0 to 3 (0 = normal/no change, 1 = mild change, 2 = moderate change, and 3 = severe change). Ulceration and pseudomembrane are rated by estimated surface area involved (0 = none, 1 = >0 but ≤1 cm², 2 = >1 cm² but ≤2 cm², and 3 = >2 cm²). The total possible score is the sum of all item scores with a possible range of 0 to 273. The OMRS has shown clinical and research utility (28).

Oral Mucositis Index

The Oral Mucositis Index (OMI) was developed from the finalized OMRS. A downsized 20-item version of the OMI (OMI-20) was developed and validated through a consensus panel of BMT oral complications specialists in the United States (29). The OMI-20 consists of nine items measuring erythema, nine items measuring ulceration, one atrophy item, and one edema item; all scored from 0 = none to 3 = severe, summed for a possible range of 0 to 60. The two sets of nine items measuring erythema and ulceration may be summed to produce subscale scores ranging from 0 to 27. The OMI-20 has demonstrated internal consistency, test–retest, and inter-rater reliability through evaluation in a sample of 133 adult PBSCT/BMT patients (29).

Oral Mucositis Assessment Scale

The Oral Mucositis Assessment Scale (OMAS) was developed as a scoring system for evaluating the anatomic extent and severity of stomatitis in clinical research studies by a team of oral medicine specialists, dentists, dental hygienists, oncologists, and oncology nurses from the United States, Canada, and Europe (30, 31). Oral cavity regions assessed are lip (upper and lower), cheek (right and left), right and lateral tongue, left ventral and lateral tongue, floor of mouth, soft palate/fauces, and hard palate (30). Erythema is rated on a scale 0 to 2 (0 = none, 1 = not severe, and 2 = severe) and ulceration/pseudomembrane is a combined category rated on scores based on estimated surface area involved (0 = no lesion, 1 = ≤1 cm², 2 = 1 to 3 cm², and 3 = > cm²) and summed giving a possible score range of 0 to 45 (30, 31). Validity and reliability have been demonstrated for the OMAS through clinical research studies (31).

World Health Organization Index

The World Health Organization (WHO) Index gives an overall rating of stomatitis and has frequently been used as a general comparison index to other oral assessment scales (6, 32). The WHO Index is scaled as follows: grade 0 = no change; grade 1 = soreness, erythema; grade 2 = erythema, ulcers, can eat solids; and grade 3 = ulcers, requires liquid diet only; and grade 4 = alimentation not possible. Limitations of this instrument are the lack of reliability and validity data, and also the tool’s inability to capture the variety of oral changes that are observed with cancer treatment (6).

Assessment of Stomatitis-Related Oral Pain

Oral pain related to cancer treatment is multidimensional. Although this oral pain is often challenging to manage, this is critical to accomplish to avoid suffering and psychological distress (15). Effective oral pain management is promoted through constant communication between and among patient, physician, nurse, and caregiver. Numerous valid and reliable pain intensity assessment tools exist. However, to adequately capture this oral pain experience, it is necessary to use a more comprehensive pain assessment tool such as the painometer (33) whose components include sensory and affective dimensions.

Treatment Strategies

The optimal treatment strategies for oral complications and related sequelae are unknown. Treatment strategies for stomatitis and related oropharyngeal pain are mainly empirical and need testing in the randomized controlled clinical trial setting (Table 19.2). Zlotolow and Berger (34) presented a comprehensive review of clinical research focusing on treatment strategies for oral complications of cancer strategies. Conflicting study results may be attributed to inappropriate design issues, use of limited oral assessment instruments that do not capture variations in oral cavity changes, and incorrect timing and dose of interventions. The only standard forms of care are pretreatment oral/dental stabilization, saline mouthwashes, and oropharyngeal pain management (35). The outcome of any oral care practice standard should be a clean, moist oral cavity that is trauma free, and conducive to healing. Meticulous oral hygiene must be maintained before, during, and following the cancer treatment process.

The need for standardized treatment for stomatitis was appreciated by the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology through their formulation of the “Clinical Practice Guidelines for the Prevention and Treatment of Cancer Therapy-Induced Oral and Gastrointestinal Mucositis” (36). These guidelines are based on a comprehensive review of more than 8000 English language publications (1966–2001). The publications regarding alimentary tract mucositis were scored using criteria that rated the studies for level of evidence and quality of research design (37).

A standardized approach for the prevention and treatment of chemotherapy- and radiotherapy-induced stomatitis is essential, although the efficacy and safety of most of the regimens have not been established through clinical trials. The prophylactic measures usually used for the prevention of stomatitis include chlorhexidine gluconate (Peridex), saline rinses, sodium bicarbonate rinses, acyclovir, amphotericin B, and ice. Regimens commonly used for the treatment of stomatitis and related pain include a local anesthetic such as lidocaine or dyclonine hydrochloride, magnesium-based antacids (Maalox, Mylanta), diphenhydramine hydrochloride (Benadryl), nystatin, or sucralfate. These agents are used either alone or in different combinations in a mouthwash formulation. Other agents used less commonly include kaolin-pectin (Kaopectate),
allopurinol, vitamin E, beta-carotene, chamomile (Kamillosan) liquid, aspirin, antiprostaglandins, prostaglandins, MGI 209 (marketed as Oratect Gel), silver nitrate, and antibiotics. Oral and sometimes parenteral opioids are used to relieve stomatitis-related pain.

Table 19.2 Formulary of Common Treatments for Oral Complications

PREVENTION OF STOMATITIS	DIRECTIONS FOR USE
Chlorhexidine gluconate 0.12% oral rinse	Rinse mouth twice daily for 30s. Do not swallow
NaHCO3^a powder: 3 tbsp or 11.6g	Combine all ingredients. Rinse mouth two to four times daily. Do not swallow.
NaCl^b powder: 3 tbsp or 11.6g
Distilled water: 1 gallon
Povidone iodine 0.5% oral rinse	Rinse mouth two to four times daily. Do not swallow.
TREATMENT OF STOMATITIS-ASSOCIATED PAIN
Carafate suspension, 1g	Rinse mouth with suspension four times daily. Do not swallow.
Diphenhydramine (Benadryl) 12.5mg/5mL; kaolin and pectin (Kaopectate)	Combine equal amounts of each. Rinse mouth with 10 to 15mL four to six times daily. Do not swallow.
Diphenhydramine (Benadryl) 12.5mg/5mL: 30mL; Maalox 30mL; Nystatin 100,000 units/mL: 30mL	Combine all ingredients. Rinse mouth with 15mL four to six times per day. Do not swallow.
Diphenhydramine (Benadryl), 12.5mg/5mL: 30mL; Viscous lidocaine (Xylocaine) 2%: 30mL; Maalox: 30mL	Combine all ingredients. Rinse mouth with 15mL four to six times per day. Do not swallow.
Diphenhydramine (Benadryl), 12.5mg/5mL: 30mL; tetracycline 125mg/5mL suspension 60mL; nystatin oral suspension, 100,000 units/mL 45mL; viscous lidocaine (Xylocaine) 2%: 30mL; hydrocortisone suspension, 10mg/5mL: 30mL; sterile water for irrigation 45mL	Combine all ingredients. Rinse mouth with 15mL four to six times per day. Do not swallow.
Gelclair	Follow manufacturer’s (Sinclair Pharma Ltd., Surrey, England, United Kingdom) instructions for mixing contents of a single-dose Gelclair packet with 40mL or 3 tbsp of water. Stir mixture and use at once as a mouth rinse for at least 1min, gargle, and spit out. Use at least three times per day.
Opioids	May use oral or parenteral opioids, such as patient-controlled analgesia. If oral analgesics are selected, use tablets. Do not use elixir, which has alcohol and will exacerbate stomatitis.
Viscous lidocaine (Xylocaine) 2% solution	Rinse mouth with 10 to 15mL q2 to 3h. Do not swallow.
Dyclonine hydrochloride 0.5% or 1% solution	Rinse mouth with 10 to 15mL q2 to 3h. Do not swallow.
XEROSTOMIA
Xerolube, salivary substitute	Rinse mouth four to six times per day.
Salivart synthetic saliva spray	Spray mouth four to six times per day.
Biotene chewing gum	Use as needed.
Pilocarpine	5mg p.o. three times a day.
Amifostine (Ethyol)	Use 200mg/m₂ daily as a 3-min intravenous infusion 15 to 30min before radiation therapy. Hydrate adequately, monitor blood pressure, and administer antiemetics.
Many of the medications listed have been used alone or in combination to treat stomatitis. ^aNaCl =sodium chloride. ^bNaHCO₃ = sodium bicarbonate. Adapted from Berger AM, Kilroy TJ. Oral complications. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2004.

Direct Cytoprotectants

Sucralfate

Sucralfate, which is an aluminum salt of a sulfated disaccharide, has shown efficacy in the treatment of gastrointestinal (GI) ulceration, and has also been tested as a mouthwash for the prevention and treatment of stomatitis. Sucralfate creates a protective barrier at the ulcer site through the formation of an ionic bond to proteins. Additional evidence suggests an increase in the local production of prostaglandin E₂ (PGE₂) leading to an increase in mucosal blood flow, mucus production, mitotic activity, and surface migration of cells.

Study results with sulcrafate are conflicting. In 1984 and 1985, Ferraro and Mattern (38, 39) reported encouraging results for the use of sucralfate for chemotherapy-induced stomatitis. Solomon (40) reported, from a sample of 19 patients receiving chemotherapy, a 55% objective response rate, defined as decrease in one grade on the Cancer and Leukemia Group B (CALGB) oral toxicity rating scale. Pfeiffer et al. (41) found a significant reduction in edema, erythema, erosion, and ulceration in 23 of 40 patients who could be evaluated, who received cisplatin and continuous infusion 5-FU, administered with or without bleomycin. Although not statistically significant, patient preference favored sucralfate. It was noted that 10 patients did not complete the study because swishing the sucralfate or placebo aggravated chemotherapy-induced nausea. The authors suggested that, to help overcome this problem, the solution should have a neutral taste and should not be swallowed. Results from a
similarly designed study in a sample of patients receiving remission–induction chemotherapy for acute nonlymphocytic leukemia did not demonstrate sulcrafate efficacy for stomatitis (42). Additional results from this study showed that chronic administration of the sucralfate suspension had no effect on the incidence of GI bleeding and ulceration. However, some patients did report pain relief (42). A phase III study was conducted by the North Central Cancer Treatment Group (NCCTG) to compare sucralfate suspension versus placebo for 5-FU-related stomatitis. Results demonstrated that in the 50 patients who experienced stomatitis, not only did the sucralfate suspension provide no beneficial reduction in 5-FU-induced stomatitis severity or duration, but also that the sucralfate group had considerable additional GI toxicity (43). Additionally, no efficacy was demonstrated for a sucralfate mouthwash for prevention and treatment of 5-FU induced stomatitis in a randomized controlled clinical trial with 81 patients with colorectal cancer, who received either sucralfate suspension or placebo four times daily during their first cycle of chemotherapy with 5-FU and leucovorin (44).

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