Dose-effect relationships for the submandibular salivary glands and implications for their sparing by intensity modulated radiotherapy.

PURPOSE: Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head-and-neck (HN) cancer. We assessed SMG dose-response relationships and their implications for sparing these glands by intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton's duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT replanning in 8 patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs. RESULTS: Stimulated SMG flow rates decreased exponentially by (1.2%)(Gy) as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses < or =39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%)(Gy) as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT replanning reduced mean contralateral SMG dose by average 12 Gy, achieving < or =39 Gy in 5 of 8 patients, without target underdosing, increasing the mean doses to the parotid glands and swallowing structures by average 2-3 Gy. CONCLUSIONS: SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target underdosing is feasible in some patients, at the expense of modestly higher doses to some other organs.

Open-label, long-term safety study of cevimeline in the treatment of postirradiation xerostomia.

PURPOSE: To assess the safety of long-term cevimeline treatment of radiation-induced xerostomia in patients with head-and-neck cancer; and to assess the efficacy of cevimeline in these patients. METHODS AND MATERIALS: A total of 255 adults with head-and-neck cancer who had received more than 40 Gy of radiation 4 months or more before entry and had clinically significant salivary gland dysfunction received cevimeline hydrochloride 45 mg t.i.d. orally for 52 weeks. Adverse events (AEs), their severity, and their relationship to the study medication were assessed by each investigator. The efficacy assessment was based on subjects' global evaluation of oral dryness on a scale of 0 (none) to 3 (severe). RESULTS: Overall, 175 subjects (68.6%) experienced expected treatment-related AEs, most mild to moderate. The most frequent was increased sweating (47.5%), followed by dyspepsia (9.4%), nausea (8.2%), and diarrhea (6.3%). Fifteen subjects (5.9%) experienced Grade 3 treatment-related AEs, of which the most frequent was increased sweating. Eighteen subjects (7.1%) reported at least one serious AE, and 45 subjects (17.6%) discontinued study medication because of an AE. The global efficacy evaluation at the last study visit showed that cevimeline improved dry mouth in most subjects (59.2%). Significant improvement was seen at each study visit in the mean change from baseline of the numeric global evaluation score (p < 0.0001). CONCLUSIONS: Cevimeline 45 mg t.i.d. was generally well tolerated over a period of 52 weeks in subjects with xerostomia secondary to radiotherapy for cancer in the head-and-neck region.

Use of prophylactic antifungals in the immunocompromised host.

Oral candidiasis is a significant infection in patients being treated with chemotherapy and radiotherapy for cancer, and in patients who are immunocompromised because of HIV infection and AIDS. Candida albicans is the most common fungal pathogen and has developed an extensive array of putative virulent mechanisms that allows successful colonization and infection of the host under suitable predisposing conditions. The purpose of this review of the literature was to assess the effectiveness of interventions for the prevention of oral candidiasis in immunocompromised patients and in patients treated for cancer with radiotherapy and/or chemotherapy. These patient categories were selected because they have been the topic of published randomized controlled clinical trials. The studies reviewed provide strong evidence that oral candidiasis is associated with greater morbidity and mortality in these populations, which substantiates the aggressive treatment and prophylaxis of this infection. The literature supports the recommendation that systemically applied antifungal drugs have the greatest efficacy for the treatment of oral candidiasis in cancer and immunocompromised patients; however, these therapies must be prescribed with a thorough assessment for the risk for developing drug-induced toxicities. Guidelines on the prevention of drug-resistant oral candidiasis in these patients are not available and require elucidation. Further studies are required to expand the knowledge base of evidence-based antifungal therapies in a wider variety of immunocompromised patients and conditions, such as Sjögren's syndrome, diabetes, and denture wearers. Additional exploration is needed to determine which antifungal drug formulation, dose, and method of delivery is preferable for the type of fungal infection and the underlying etiology.

Management of salivary hypofunction during and after radiotherapy.

Salivary hypofunction, the most common complication of high-dose radiation therapy (RT) to the head and neck, has a significant impact on quality of life, and requires careful planning of long-term dental and oral care. This report documents the results and conclusions of an evidence-based literature review on multidisciplinary team management of salivary hypofunction during and after RT. An update is provided on the pathophysiology of salivary hypofunction during and after RT, and recommendations for clinical management. The paper presents aspects managed by dental professionals (use of cholinergic agonists and other saliva stimulants, prevention of hyposalivation-induced rampant caries, and use of saliva substitutes), as well as the role of the radiation oncologist in minimizing salivary gland damage (parotid-sparing RT; cytoprotectants). This summary includes basic science, translational and clinical research topics with respect to radiation-induced salivary hypofunction, and provides an evidence-based management algorithm.

Mechanisms associated with unusual orofacial pain.

This article presents an overview of possible mechanisms associated with pain perception, with a specific focus on understanding unusual manifestations of orofacial pain associated with nerve insult. It includes recent evidence concerning neurobiological changes that occur in the periphery at tissue and nerve sites, or within the central nervous system, and that may involve chemical and inflammatory responses, sensitization, or alterations of cellular function. Moreover, the contribution of the autonomic nervous system, changes in emotional reactivity and vigilance, the roles of high brain centers such as the basal ganglia (nigro-striatal) system, and the influence of aging and gender, are briefly described.

Radiotherapy-induced salivary dysfunction.

Dry mouth (xerostomia) is one of the most common complaints following radiation therapy (RT) for head and neck cancers. Notably, RT causes irreparable damage to salivary glands that increases the risk for severe and long-term oral and pharyngeal disorders. Several strategies in the treatment of head and neck cancers have been developed to prevent RT-induced salivary dysfunction while providing definitive oncologic therapy. These include salivary-sparing RT; cytoprotectants (such as amifostine); combination therapy of high-dose-rate intraoperative RT, external beam RT, plus a cytoprotectant; salivary gland surgical transfer; and gene therapy. Future research that incorporates biologic, pharmacologic, and technologic advancements that optimize therapeutic ratios and minimizes adverse oral sequelae is warranted.

Management strategies for HIV-associated aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disorder found in men and women of all ages, races, and geographic regions. There are three forms of the lesions (minor, major, and herpetiform), with major aphthous ulcers causing significant pain and potential for scarring. In HIV-infected individuals, these ulcers occur more frequently, last longer, and produce more painful symptoms than in immunocompetent persons. In addition, they may be associated with similar ulcerations involving the esophagus, rectum, anus, and genitals. The diagnosis of HIV-induced RAS requires a careful history of the condition, and a thorough extra- and intra-oral examination. Oral mucosal biopsies are required for non-healing ulcers in order to exclude the possibility of deep fungal infections, viral infections, and neoplasms. The cause of the ulcers in HIV-positive persons has not been elucidated--local diseases, genetic, immunologic, and infectious factors all probably play a role. The goals of current treatments are to promote ulcer healing, to reduce ulcer duration and pain while maintaining nutritional intake, and to prevent or diminish the frequency of recurrence. Initial therapy for infrequent RAS recurrences includes over-the-counter topical protective and analgesic products. Initial therapy for frequent RAS outbreaks requires topical anesthetics, binding agents, and corticosteroids. Major RAS and non-healing minor or herpetiform RAS may require intralesional corticosteroids and systemic prednisone. Second-line immunomodulators for frequent and non-healing ulcers includes thalidomide and other immunomodulators.

Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer.

The goals of this study were to facilitate sparing of the major salivary glands while adequately treating tumor targets in patients requiring comprehensive bilateral neck irradiation (RT), and to assess the potential for improved xerostomia. Since 1994 techniques of target irradiation and locoregional tumor control with conformal and intensity modulated radiation therapy (IMRT) have been developed. In patients treated with these modalities, the salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms (DVHs). In addition, subjective xerostomia questionnaires have been developed and validated. The pattern of locoregional recurrence has been examined from computed tomography (CT) scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans, and regenerating the dose distributions at the recurrence sites. Treatment plans for target coverage and dose homogeneity using static, multisegmental IMRT were found to be significantly better than standard RT plans. In addition, significant parotid gland sparing was achieved in the conformal plans. The relationships among dose, irradiated volume, and the residual saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean radiation dose of 26 Gy was found to be the threshold for preserved stimulated saliva flow. Xerostomia questionnaire scores suggested that xerostomia was significantly reduced in patients irradiated with bilateral neck, parotid-sparing RT, compared to patients with similar tumors treated with standard RT. Examination of locoregional tumor recurrence patterns revealed that the large majority of recurrences occurred inside targets, in areas that had been judged to be at high risk and that had received RT doses according to the perceived risk. Tangible gains in salivary gland sparing and target coverage are being achieved, and an improvement in some measures of quality of life is suggested by our findings. Additional reduction of xerostomia may be achieved by further sparing of the salivary glands and the non-involved oral cavity. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to areas judged to be at highest risk may improve tumor control.

Influence of parotid-sparing radiotherapy on xerostomia in head and neck cancer patients.

Radiotherapy (RT) for head and neck cancers causes permanent salivary gland dysfunction (SGD) and xerostomia. We have previously demonstrated the effectiveness of parotid-sparing RT on salivary function. The aim of this was to characterize the relationship between radiation dosages to parotid glands, SGD, xerostomia, and impaired quality of life (QOL). Ninety-three patients received unilateral (n=38) and bilateral (n=44) neck RT with parotid-sparing techniques, or standard three-field technique RT (n=11). Unstimulated and stimulated parotid saliva was collected pre-RT and 1 year post-RT. Assessment of QOL and xerostomia was conducted with three questionnaires. The results demonstrated that reduced radiation dosages to parotid glands were strongly associated with percentage of baseline parotid flow rates measured at 1 year post-RT. Unilateral and bilateral neck RT with parotid-sparing techniques were successful in preserving salivary output, compared to standard three beam RT techniques. Lower radiation dose to contralateral parotid glands was associated with greater percentage of baseline salivary flow rates at 1 year post-RT, fewer xerostomic complaints, and an enhanced QOL.

Quality of life after parotid-sparing IMRT for head-and-neck cancer: a prospective longitudinal study.

PURPOSE: Parotid-sparing intensity-modulated radiotherapy (IMRT) for head-and-neck cancer reduces xerostomia compared with standard RT. To assess potential improvements in broader aspects of quality of life (QOL), we initiated a study of patient-reported QOL and its predictors after IMRT. MATERIALS AND METHODS: This was a prospective longitudinal study of head-and-neck cancer patients receiving multisegmental static IMRT. Patients were given a validated xerostomia questionnaire (XQ), and a validated head-and-neck cancer-related QOL questionnaire consisting of four multi-item domains: Eating, Communication, Pain, and Emotion. The Eating domain contains one question (total of six) asking directly about xerostomia. In both questionnaires, higher scores denote worse symptoms or QOL. The questionnaires and measurements of salivary output from the major glands were completed before RT started (pre-RT) and at 3, 6, and 12 months after RT. The association between the QOL scores and patient-, tumor-, and therapy-related factors was assessed using the random effects model. RESULTS: Thirty-six patients participating in the study completed the questionnaires through 12 months. The XQ scores worsened significantly at 3 months compared with the pre-RT scores, but later they improved gradually through 12 months (p = 0.003), in parallel with an increase in the salivary output from the spared salivary glands. The QOL summary scores were stable between the baseline (pre-RT) and 3 months after RT scores. Patients receiving postoperative RT (whose pre-RT questionnaires were taken a few weeks after surgery) tended to have improved scores after RT, reflecting the subsidence of acute postoperative sequelae, compared with a tendency toward worsened scores in patients receiving definitive RT. After 3 months, statistically significant improvement was noted in the summary QOL scores for all patients, through 12 months after RT (p = 0.01). The salivary flow rates, tumor doses, mean oral cavity dose, age, gender, sites or stages of tumor, surgery, and use of chemotherapy were not associated with the QOL scores at any point. The mean dose to the parotid glands correlated with the QOL scores at 3 months (p = 0.05) but not at other post-RT periods. The XQ and QOL summary scores did not correlate before RT but were significantly correlated at each post-RT point (p < 0.01), with a linear correlation coefficient (r) of 0.59, 0.72, and 0.67 at 3, 6, and 12 months, respectively. At these points, the XQ scores also correlated significantly with the scores of each of the individual QOL domains (p < or = 0.01), including the domains Pain and Emotion, which did not contain any xerostomia-related question. CONCLUSION: After parotid-sparing IMRT, a statistically significant correlation was noted between patient-reported xerostomia and each of the domains of QOL: Eating, Communication, Pain, and Emotion. Both xerostomia and QOL scores improved significantly over time during the first year after therapy. These results suggest that the efforts to improve xerostomia using IMRT may yield improvements in broad aspects of QOL.

Rationale for integrating high-dose rate intraoperative radiation (HDR-IORT) and postoperative external beam radiation with subcutaneous amifostine for the management of stage III/IV head and neck cancer.

Locoregional recurrence remains a major obstacle to achieving cure of locally advanced head and neck cancers despite maximal resection and postoperative external beam radiation therapy (EBRT). Locoregional failure occurs in 30% to 40% of high-risk resected head and neck cancer patients after standard postoperative EBRT. In an effort to overcome this problem, a number of strategies have been designed to enhance the effectiveness of radiation including concurrent postoperative chemoradiation, accelerated radiation schedules, incorporation of targeted biologic therapies, and improved radiation delivery techniques such as intensity modulated radiation and high-dose rate (HDR) intraoperative radiation therapy. Intraoperative radiation therapy (IORT) represents an important approach to improve outcome in head and neck cancer patients treated with definitive surgery. High-dose rate IORT is defined as the delivery of a single, large dose of radiation at the time of surgery when the tumor bed is exposed. In conjunction with EBRT, HDR-IORT offers several advantages including: (1) conformal delivery of a large dose of radiation while the tumor bed is precisely defined, minimizing the risk of a geographic miss; (2) potential for subsequent dose reduction of EBRT; (3) shortening overall treatment time; and (4) dose-escalation. Because mucositis represents the dose-limiting acute toxicity and xerostomia ranks as the most common long-term quality-of-life complaint, a reduction of the EBRT dose may provide an important benefit in reducing toxicity, especially when combined with the radioprotectant amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD). The purpose of this article is to review the rationale for integrating HDR-IORT with a reduced dose of postoperative EBRT combined with amifostine to improve locoregional control and quality of life outcomes in advanced-stage resected head and neck cancer patients.

The role of salivary function in modulating chemotherapy-induced oropharyngeal mucositis: a review of the literature.

Oropharyngeal mucositis is a common and significant complication of cancer chemotherapy and limits the delivery of chemotherapy, affects the quality of life, and increases the cost of care. Oral mucositis caused by cancer chemotherapy is associated with specific agents, but the origin of oral mucositis is poorly understood. These drugs may have direct toxic effects on the rapidly dividing cells of the oral mucosa and on cellular elements of the connective tissue. Microbial flora may play a role in the development of ulcerative mucositis. Chemotherapy may be directly toxic and affect the mucosa by systemic circulation and may be related to secretion of some chemotherapeutic drugs in the saliva, resulting in topical exposure to the oral environment. Other potential mechanisms include reduced saliva volume and change in saliva constituents that may affect epithelial maintenance and repair, the physiology of the oral microflora, and the interaction between the oral flora and the epithelium. Improved understanding of the mechanisms whereby specific chemotherapeutic agents cause mucositis may lead to management approaches that will reduce the incidence and severity of mucositis, improving quality of life and ensuring delivery of the necessary chemotherapy to improve cancer cure rates.

Xerostomia and the geriatric patient.

Saliva is essential for the preservation of oral-pharyngeal health, and disorders of salivary physiology are associated with numerous oral and pharyngeal problems, particularly in older people. Although salivary function is remarkably intact in healthy aging, medical problems, medications, and head and neck radiotherapy can cause salivary dysfunction and complaints of xerostomia among older people. Sjögren's syndrome, an autoimmune exocrinopathy, is the most common medical disease associated with salivary dysfunction. Medications with anticholinergic side effects will impair salivary output, and head and neck radiotherapy for cancer will cause permanent destruction of salivary glands. Treatments for salivary problems are based upon establishing a diagnosis, protecting oral and pharyngeal health, stimulating remaining glands, and replacing lost salivary fluids.