Frederik Spijkervet

Oral Sequelae of Head and Neck Radiotherapy

In addition to anti-tumor effects, ionizing radiation causes damage in normal tissues located in the radiation portals. Oral complications of radiotherapy in the head and neck region are the result of the deleterious effects of radiation on, e.g., salivary glands, oral mucosa, bone, dentition, masticatory musculature, and temporomandibular joints. The clinical consequences of radiotherapy include mucositis, hyposalivation, taste loss, osteoradionecrosis, radiation caries, and trismus. Mucositis and taste loss are reversible consequences that usually subside early post-irradiation, while hyposalivation is normally irreversible. Furthermore, the risk of developing radiation caries and osteoradionecrosis is a life-long threat. All these consequences form a heavy burden for the patients and have a tremendous impact on their quality of life during and after radiotherapy. In this review, the radiation-induced changes in healthy oral tissues and the resulting clinical consequences are discussed.

Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy

An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design, test, and validate a new scoring system for mucositis that can be used easily, is reproducible, and provides an accurate system for research applications.

Prevention and treatment of the consequences of head and neck radiotherapy

The location of the primary tumor or lymph node metastases dictates the inclusion of the oral cavity, salivary glands, and jaws in the radiation treatment portals for patients who have head and neck cancer. The clinical sequelae of the radiation treatment include mucositis, hyposalivation, loss of taste, osteoradionecrosis, radiation caries, and trismus. These sequelae may be dose-limiting and have a tremendous effect on the patients quality of life. Most treatment protocols to prevent these sequelae are still based on clinical experience, but alternatives based on fundamental basic and clinical research are becoming more and more available. Many of these alternatives either need further study before they can be incorporated into the protocols commonly used to prevent and treat the radiation-related oral sequelae or await implementation of these protocols. In this review, the various possibilities for prevention and/or treatment of radiation-induced changes in healthy oral tissues and their consequences are discussed.

Patient-reported Measurements of Oral Mucositis in Head and Neck Cancer Patients Treated With Radiotherapy With or Without Chemotherapy Demonstration of Increased Frequency, Severity, Resistance to Palliation, and Impact on Quality of Life

The risk, severity, and patient‐reported outcomes of radiation‐induced mucositis among head and neck cancer patients were prospectively estimated.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life

PurposeThis systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies.MethodsThe electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article.ResultsThe inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy.ConclusionsSalivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.

Protocol for the Prevention and Treatment of Oral Sequelae Resulting from Head and Neck Radiation Therapy

In addition to the desired antitumor effects, head and neck radiation therapy induces damage in normal tissues that may result in oral sequelae such as mucositis, hypo‐salivation, radiation caries, taste loss, trismus, soft‐tissue necrosis, and osteoradionecrosis. These sequelae may be dose‐limiting and have a tremendous effect on the patients quality of life, Current policies to prevent these sequelae primarily are based on clinical experience and show great diversity. A protocol for the prevention and treatment of oral sequelae resulting from head and neck radiation therapy, based on fundamental research and data derived from the literature, is presented. The protocol is particularly applicable in centers with a dental team. This team should be involved at the time of initial diagnosis so that a successful preventive regimen is an integral part of the overall cancer treatment regimen.

Preventive Intervention Possibilities in Radiotherapy- and Chemotherapy-induced Oral Mucositis: Results of Meta-analyses

The aim of these meta-analyses was to evaluate the effectiveness of interventions for the prevention of oral mucositis in cancer patients treated with head and neck radiotherapy and/or chemotherapy, with a focus on randomized clinical trials. A literature search was performed for reports of randomized controlled clinical studies, published between 1966 and 2004, the aim of which was the prevention of mucositis in cancer patients undergoing head and neck radiation, chemotherapy, or chemoradiation. The control group consisted of a placebo, no intervention, or another intervention group. Mucositis was scored by either the WHO, the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) score, or the absence or presence of ulcerations, or the presence or absence of grades 3 and 4 mucositis. The meta-analyses included 45 studies fulfilling the inclusion criteria, in which 8 different interventions were evaluated: i.e., local application of chlorhexidine; iseganan; PTA (polymyxin E, tobramycine, and amphotericin B); granulocyte macrophage-colony-stimulating factor/granulocyte colony-stimulating factor (GM-CSF/G-CSF); oral cooling; sucralfate and glutamine; and systemic administration of amifostine and GM-CSF/G-CSF. Four interventions showed a significant preventive effect on the development or severity of oral mucositis: PTA with an odds ratio (OR) = 0.61 (95% confidence interval [CI], 0.39–0.96); GM-CSF, OR = 0.53 (CI: 0.33–0.87); oral cooling, OR = 0.3 (CI: 0.16–0.56); and amifostine, OR = 0.37 (CI: 0.15–0.89). To date, no single intervention completely prevents oral mucositis, so combined preventive therapy strategies seem to be required to ensure more successful outcomes.

Periodontal inflamed surface area: quantifying inflammatory burden

BACKGROUND Currently, a large variety of classifications is used for periodontitis as a risk factor for other diseases. None of these classifications quantifies the amount of inflamed periodontal tissue, while this information is needed to assess the inflammatory burden posed by periodontitis. AIM To develop a classification of periodontitis that quantifies the amount of inflamed periodontal tissue, which can be easily and broadly applied. MATERIAL AND METHODS A literature search was conducted to look for a classification of periodontitis that quantified the amount of inflamed periodontal tissue. A classification that quantified the root surface area affected by attachment loss was found. This classification did not quantify the surface area of inflamed periodontal tissue, however. Therefore, an Excel spreadsheet was developed in which the periodontal inflamed surface area (PISA) is calculated using clinical Attachment Level (CAL), recessions and bleeding on probing (BOP). RESULTS The PISA reflects the surface area of bleeding pocket epithelium in square millimetres. The surface area of bleeding pocket epithelium quantifies the amount of inflamed periodontal tissue. A freely downloadable spreadsheet is available to calculate the PISA. CONCLUSION PISA quantifies the inflammatory burden posed by periodontitis and can be easily and broadly applied.

Clinical and Histologic Evidence of Salivary Gland Restoration Supports the Efficacy of Rituximab Treatment in Sjogren's Syndrome

OBJECTIVE To assess the effect of rituximab (anti-CD20 antibody) therapy on the (immuno)histopathology of parotid tissue in patients with primary Sjögrens syndrome (SS) and the correlation of histologic findings with the flow rate and composition of parotid saliva. METHODS In a phase II study, an incisional parotid biopsy specimen was obtained from 5 patients with primary SS before and 12 weeks after rituximab treatment (4 infusions of 375 mg/m(2)). The relative amount of parotid parenchyma, lymphocytic infiltrate, and fat, and the presence/quantity of germinal centers and lymphoepithelial duct lesions were evaluated. Immunohistochemical characterization was performed to analyze the B:T cell ratio of the lymphocytic infiltrate (CD20, CD79a, CD3) and cellular proliferation in the acinar parenchyma (by double immunohistologic labeling for cytokeratin 14 and Ki-67). Histologic data were assessed for correlations with the parotid flow rate and saliva composition. RESULTS Four patients showed an increased salivary flow rate and normalization of the initially increased salivary sodium concentration. Following rituximab treatment, the lymphocytic infiltrate was reduced, with a decreased B:T cell ratio and (partial) disappearance of germinal centers. The amount and extent of lymphoepithelial lesions decreased in 3 patients and was completely absent in 2 patients. The initially increased proliferation of acinar parenchyma in response to inflammation was reduced in all patients. CONCLUSION Sequential parotid biopsy specimens obtained from patients with primary SS before and after rituximab treatment demonstrated histopathologic evidence of reduced glandular inflammation and redifferentiation of lymphoepithelial duct lesions to regular striated ducts as a putative morphologic correlate of increased parotid flow and normalization of the salivary sodium content. These histopathologic findings in a few patients underline the efficacy of B cell depletion and indicate the potential for glandular restoration in SS.

Progression of salivary gland dysfunction in patients with Sjögren’s syndrome

Background: Salivary gland dysfunction is one of the key manifestations of Sjögren’s syndrome. Objectives: (1) To assess prospectively loss of function of individual salivary glands in patients with primary and secondary Sjögren’s syndrome in relation to disease duration and use of immunomodulatory drugs. (2) To study changes in sialochemical and laboratory values and subjective complaints over time. Methods: 60 patients with Sjögren’s syndrome were included in this study. Whole and gland-specific saliva (parotid and submandibular/sublingual (SM/SL)), samples were collected at baseline and after a mean of 3.6 (SD 2.3) years of follow-up. Disease duration was recorded for all patients. Results: Patients with Sjögren’s syndrome with short disease duration had significantly higher stimulated flow rates at baseline than those with longer disease duration (p<0.05). When compared with healthy controls, the decrease in SM/SL flow rates at baseline was more prominent than that in parotid flow rates (p<0.05). Over time, there was a significant further decrease of stimulated flow rates, especially of the parotid gland, accompanied by increasing problems with swallowing dry food (p<0.05). The decrease was independent of the use of corticosteroids or disease-modifying antirheumatic drugs (DMARDs). Sialochemical variables remained stable. Conclusions: Early Sjögren’s syndrome is characterised by a decreased salivary gland function (parotis>SM/SL), which shows a further decrease over time, regardless of the use of DMARDs or steroids. Patients with Sjögren’s syndrome with longer disease duration are characterised by severely reduced secretions of both the parotid and SM/SL glands. These observations are relevant for identifying patients who would most likely benefit from intervention treatment.