Comparing the risk of severe oral mucositis associated with methotrexate as graft-versus host-disease prophylaxis to other immunosuppressive prophylactic agents in hematopoietic cell transplantation: a systematic review and meta-analysis.

PURPOSE: This study examines the risk of severe oral mucositis (SOM) in graft-versus-host disease prophylaxis (GVHD) compared to other agents in hematopoietic cell transplantation patients. METHODS: A comprehensive search of four databases, including PubMed, Embassy, Web of Science, and Scopus, was conducted to identify studies reporting frequency and severity of oral mucositis in association with GVHD prophylactic regimens. RevMan 5.4 was used to perform the meta-analysis. Risk of bias assessment was carried out using the Rob-2 tool for randomized clinical trials (RCTs) and ROBINS-I tool for observational studies. RESULTS: Twenty-five papers, including 11 RCTs and 14 observational studies, met the inclusion criteria. The pooled results from eight RCTs showed a higher risk of SOM in patients receiving MTX or MTX-inclusive GVHD prophylaxis versus non-MTX alternatives (RR = 1.50, 95% CI [1.20, 1.87], I2 = 36%, P = 0.0003). Mycophenolate mofetil (MMF) and post-transplant cyclophosphamide (Pt-Cy) consistently showed lower risk of mucositis than MTX. Folinic acid (FA) rescue and mini-dosing of MTX were associated with reduced oral mucositis severity. CONCLUSION: Patients receiving MTX have a higher SOM risk compared to other approaches to prevent GVHD, which should be considered in patient care. When appropriate, MMF, FA, and a mini-dose of MTX may be an alternative that is associated with less SOM. This work also underlines the scarcity of RCTs on MTX interventions to provide the best evidence-based recommendations.

Self-reported outcomes on oral health and oral health-related quality of life in long-term childhood cancer survivors-A DCCSS-LATER 2 Study.

PURPOSE: The present study aimed to determine the prevalence of self-reported oral problems and the oral health-related quality of life (OHRQoL) in childhood cancer survivors (CCS). METHODS: Patient and treatment characteristics of CCS have been collected in a cross-sectional study, part of the multidisciplinary DCCSS-LATER 2 Study. To assess self-reported oral health problems and dental problems, CCS filled out the 'Toegepast-Natuurwetenschappelijk Onderzoek' (TNO) oral health questionnaire. OHRQoL was assessed by the Dutch version of the Oral Health Impact Profile-14 (OHIP-14). Prevalences were compared with two comparison groups from the literature. Univariable and multivariable analyses were performed. RESULTS: A total of 249 CCS participated in our study. The OHIP-14 total score had a mean value of 1.94 (sd 4.39), with a median score of 0 (range 0-29). The oral problems 'oral blisters/aphthae' (25.9%) and 'bad odor/halitosis' (23.3%) were significantly more often reported in CCS than in comparison groups (12% and 12%, respectively). The OHIP-14 score was significantly correlated with the number of self-reported oral health problems (r = .333, p<0.0005) and dental problems (r = .392, p <0.0005). In multivariable analysis, CCS with a shorter time since diagnosis (10-19 years vs. ≥30 years) had a 1.47-fold higher risk of ≥1 oral health problem. CONCLUSION: Though the perceived oral health is relatively good, oral complications following childhood cancer treatment are prevalent in CCS. This underlines that attention to impaired oral health and awareness on this topic is mandatory and regular visits to the dentist should be a part of long-term follow-up care.

The effect of conditioning regimen and prescribed medications on hyposalivation in haematopoietic cell transplantation (HCT) patients: an 18-month prospective longitudinal study.

OBJECTIVES: Haematopoietic cell transplantation (HCT) preceded by a conditioning regimen is an established treatment option for (non)malignant haematologic disorders. We aim to describe the development of hyposalivation over time in HCT recipients, and determine risk indicators. MATERIALS AND METHODS: A multi-centre prospective longitudinal observational study was conducted. Unstimulated (UWS) and stimulated (SWS) whole saliva was collected before HCT, early post-HCT, and after 3, 6, 12, and 18 months. The effect of type of transplantation (allogeneic vs autologous) and intensity (full vs reduced) of the conditioning regimen on hyposalivation (UWS < 0.2 mL/min; SWS < 0.7 mL/min) was explored. RESULTS: A total of 125 HCT recipients were included. More than half of the patients had hyposalivation early post-HCT; a quarter still had hyposalivation after 12 months. The conditioning intensity was a risk indicator in the development of hyposalivation of both UWS (OR: 3.9, 95% CI: 1.6-10.6) and SWS (OR: 8.2, 95% CI: 2.9-24.6). After 3 and 12 months, this effect was not statistically significant anymore. CONCLUSIONS: Hyposalivation affects the majority of patients early post-HCT. The conditioning intensity and the type of transplantation were significant risk indicators in the development of hyposalivation. The number of prescribed medications, total body irradiation as part of the conditioning regimen and oral mucosal graft-versus-host disease did not influence hyposalivation significantly. CLINICAL RELEVANCE: Because of the high prevalence of hyposalivation, HCT recipients will have an increased risk of oral complications. It might be reasonable to plan additional check-ups in the dental practice and consider additional preventive strategies.

Caries Progression after Haematopoietic Stem Cell Transplantation and the Role of Hyposalivation.

Haematopoietic stem cell transplantation (HSCT) preceded by a conditioning regimen is an established treatment option for many haematological diseases. Decreased salivary flow rates after HSCT may increase caries risk. We aim to estimate the extent to which caries lesions develop or progress in adult HSCT recipients and assess its association with salivary flow rates. A multi-centre prospective observational study was conducted in which patients receiving HSCT were followed up for 18 months. We included 116 patients (median age 56 years, 43% female) from two medical centres in the Netherlands. Unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) were collected, and full caries charts were made before HSCT and 3, 6, 12, and 18 months post-HSCT. Caries was scored according to the ICDAS criteria by trained dentist-examiners. New dentine lesions or lesion progression into dentine (ICDAS ≥4 or cavitated root lesions) occurred in 32% of patients over 18 months. The median number of affected surfaces was 2 (range: 1-12) per patient with caries progression. The influence of hyposalivation of unstimulated saliva (<0.2 mL/min) and stimulated saliva (<0.7 mL/min) at baseline and after 3 months on caries progression was determined with a negative binomial regression model. Hyposalivation of SWS 3 months after HSCT was a significant risk indicator for caries progression (incidence rate ratio: 5.30, 95% CI: 2.09-13.4, p < 0.001), while hyposalivation of SWS at baseline and hyposalivation of UWS were not. We conclude that caries progression is a common oral complication in patients after HSCT, and stimulated hyposalivation shortly after treatment is a significant risk indicator for caries progression.

Oral health-related quality of life of patients with oral chronic graft-versus-host disease.

PURPOSE: Symptoms of oral chronic graft-versus-host-disease (cGVHD) may significantly affect the oral health-related quality of life (OHRQoL). This study aimed to assess the OHRQoL in patients with oral cGVHD and to examine whether oral cGVHD symptoms, mucosal cGVHD, and salivary gland function correlated with OHRQoL. METHODS: Patients referred to the oral cGVHD outpatient clinic were included. Severity of oral mucosal cGVHD, oral cGVHD symptoms, and OHRQoL was assessed by the NIH OMS, NIH OSS, and OHIP-14, respectively. Unstimulated and stimulated whole salivary flow rates were determined and categorized into "hyposalivation," "normal salivary flow," and "hypersalivation." RESULTS: Of 56 included patients, 80% had mild, moderate, or severe oral mucosal cGVHD. Mean total score of OHRQoL was 16.5 (±11.7), negatively affected by functional problems. Patients reported highest scores regarding oral sensitivity and xerostomia. Significant correlations were found between severity of oral pain and OHRQoL and between oral sensitivity and OHRQoL. No correlation was found between oral mucosal cGVHD and OHRQoL. Patients with hyposalivation, normal salivary flow, and hypersalivation reported equal levels of OHRQoL. CONCLUSION: Results demonstrate that the OHRQoL was mostly negatively affected by complaints of oral pain and oral sensitivity and less by the severity of oral mucosal cGVHD assessed by the NIH OMS score. Special attention of (oral) health care professionals for patients with oral cGVHD is mandatory to alleviate their symptoms and improve OHRQoL.

Chronic oral graft-versus-host disease: induction and maintenance therapy with photobiomodulation therapy.

This study presents follow-up of a prior study of patients with chronic symptomatic oral chronic graft-versus-host-disease (cGVHD) managed with photobiomodulation therapy (PBM therapy for 1 month. Here, we report long-term follow-up of a series of patients where PBM therapy in patients with oral cGVHD for maintenance follows the initial period of PBM therapy for continuing management. PATIENTS AND METHODS: We report continuing follow-up of 7 cases of oral cGVHD that were treated with PBM therapy. PBM therapy was continued in these patients with the goal of determining the best management schedule of PBM to maintain or improve control of each patient's symptoms and signs of oral cGVHD. RESULTS: Oral sensitivity and mucosal changes of cGVHD were controlled with a continuing schedule of PBM therapy of up to 6-8-week treatment intervals in patients with continuing GVHD. These findings suggest that PBM therapy represents an additional approach for continuing management of oral cGVHD and that the frequency of treatment should be individualized for each patient to provide best control of oral findings. In one case weekly PBM treatment was continued, while in others, management on a monthly or bimonthly basis was associated with control of the oral condition. PBM may be individualized and provided based upon best control of the symptoms and signs of oral GVHD.

Exploring the role of oral microorganisms in the pathogenesis of mucositis by assessing their impact on metabolic activity and reproductive capacity of epithelial cells in vitro.

PURPOSE: Clinical and in vitro studies showed selected oral microorganisms to be related to delayed wound healing and ulcerative oral mucositis. However, it is not known whether this effect is due to reduced metabolism and/or the reduced reproductive capacity of epithelial cells. Therefore, we studied the influence of the oral microorganisms Porphyromonas gingivalis, Candida glabrata, and Candida kefyr on cell metabolism and reproductive capacity of oral epithelial cells, aimed to further unravel the pathogenesis of oral mucositis. METHODS: Oral epithelial cells were exposed to different concentrations of P. gingivalis, C. glabrata, and C. kefyr as mono-infections or mixed together. An MTT assay was performed to determine the effect on cell metabolism. A clonogenic assay was used to study the effect on the reproductive capacity of oral epithelial cells. RESULTS: The metabolism of oral epithelial cells was reduced when the microorganisms were present in high concentrations: P. gingivalis at a multiplicity of infection (MOI) of 1000 and the Candida spp. at MOI 100. No statistical difference was observed in the ability of a single epithelial cell to grow into a colony of cells between control and P. gingivalis, C. glabrata, and C. kefyr, independent of the concentrations and combinations used. CONCLUSION: P. gingivalis, C. glabrata, and C. kefyr lowered the metabolic activity of oral epithelial cells in high concentrations, yet they did not influence the reproductive capacity of epithelial cells. Their impact on ulcerative oral mucositis is likely due to an effect on the migration, proliferation, and metabolism of epithelial cells.

Systematic review of growth factors and cytokines for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: To update the clinical practice guidelines for the use of growth factors and cytokines for the prevention and/or treatment of oral mucositis (OM). METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: recommendation, suggestion, and no guideline possible. RESULTS: A total of 15 new papers were identified within the scope of this section and were merged with 51 papers that were reviewed in the previous guidelines update. Of these, 14, 5, 13, 2, and 1 were randomized controlled trials about KGF-1, G-CSF, GM-CSF, EGF, and erythropoietin, respectively. For the remaining agents there were no new RCTs. The previous recommendation for intravenous KGF-1 in patients undergoing autologous hematopoietic stem cell transplantation (HSCT) conditioned with high-dose chemotherapy and TBI-based regimens is confirmed. The previous suggestion against the use of topical GM-CSF for the prevention of OM in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation remains unchanged. CONCLUSIONS: Of the growth factors and cytokines studied for the management of OM, the evidence supports a recommendation in favor of KGF-1 and a suggestion against GM-CSF in certain clinical settings.

The impact of hematological malignancies and their treatment on oral health-related quality of life as assessed by the OHIP-14: a systematic review.

Patients with hematologic cancers often develop acute and chronic oral complications from their disease and its treatment. These problems could change patients' oral health-related quality of life (OHRQoL) negatively. Quality of life (QoL) has become an increasingly important outcome measure in oncology. This systematic literature review evaluates the impact of hematological malignancies and their treatment on OHRQoL as assessed by the Oral Health Impact Profile (OHIP-14) questionnaire. Medline through Pubmed and Web of Science were searched through April 2017. Two randomized controlled trials, one cohort study, one cross-sectional study, and one case-control study were included. Heterogeneity across the included studies did not allow for meta-analysis. OHIP-14 domains that were frequently given the highest scores were functional limitation (67%), physical pain (50%), physical disability (50%), and psychological discomfort (33%). The domains that were frequently given the lowest scores were social handicap (100%), social disability (100%), and psychological disability (67%). Insufficient evidence is available to draw any robust conclusions regarding OHRQoL assessed by the OHIP-14 in individuals with hematological malignancies. However, functional limitations because of problems with oral mucosal tissues, the dentition, or dentures, seem to have a larger negative impact on the OHRQoL than social aspects associated with oral health problems. Well-designed larger studies are required to determine effects of hematological malignancies as well as acute and long-term effects of their treatment on patients' OHRQoL.

The impact of the oral cavity in febrile neutropenia and infectious complications in patients treated with myelosuppressive chemotherapy.

Febrile neutropenia (FN) is an inflammatory response causing fever that may develop during cancer therapy-induced neutropenia. FN may herald life-threatening infectious complications and should therefore be considered a medical emergency. Patients presenting with FN are routinely subjected to careful history taking and physical examination including X-rays and microbiological evaluations. Nevertheless, an infection is documented clinically in only 20-30% of cases, whereas a causative microbial pathogen is not identified in over 70% of FN cases. The oral cavity is generally only visually inspected. Although it is recognized that ulcerative oral mucositis may be involved in the development of FN, the contribution of infections of the periodontium, the dentition, and salivary glands may be underestimated. These infections can be easily overlooked, as symptoms and signs of inflammation may be limited or absent during neutropenia. This narrative review is aimed to inform the clinician on the potential role of the oral cavity as a potential source in the development of FN. Areas for future research directed to advancing optimal management strategies are discussed.

Photobiomodulation therapy in the management of chronic oral graft-versus-host disease.

AIM: Patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) may experience oral complications associated with chronic graft-versus-host disease (cGVHD). These complications may significantly affect quality of life, even many years post-HSCT. Current treatment options for oral cGVHD are limited and often include steroid or other immunomodulatory medications, which may not adequately control the oral condition. A non-immunosuppressive intervention for symptomatic relief in oral cGVHD would thus be a welcome addition to the treatment paradigm. MATERIALS AND METHODS: We report seven cases of oral cGVHD that were treated with photobiomodulation therapy (PBM), previously known as low-level laser therapy (LLLT). Patients underwent at least two PBM treatments per week in addition to local treatment with steroids, and if on systemic therapies, these were either unchanged or dosage was reduced during the period of PBM therapy. Follow-up data is presented for 4 weeks of treatment. RESULTS: Oral pain, sensitivity, and dry mouth improved in most patients. These findings suggest PBM therapy may represent an additional approach for management of oral cGVHD, and suggest that controlled studies should be conducted to confirm the efficacy and safety of PBM therapy in oral cGVHD and to determine optimal PBM therapy protocols.

Low level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 1: mechanisms of action, dosimetric, and safety considerations.

PURPOSE: There is a large body of evidence supporting the efficacy of low level laser therapy (LLLT), more recently termed photobiomodulation (PBM), for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved, may expand the applications for PBM in the management of other complications associated with HNC treatment. This article (part 1) describes PBM mechanisms of action, dosimetry, and safety aspects and, in doing so, provides a basis for a companion paper (part 2) which describes the potential breadth of potential applications of PBM in the management of side-effects of (chemo)radiation therapy in patients being treated for HNC and proposes PBM parameters. METHODS: This study is a narrative non-systematic review. RESULTS: We review PBM mechanisms of action and dosimetric considerations. Virtually, all conditions modulated by PBM (e.g., ulceration, inflammation, lymphedema, pain, fibrosis, neurological and muscular injury) are thought to be involved in the pathogenesis of (chemo)radiation therapy-induced complications in patients treated for HNC. The impact of PBM on tumor behavior and tumor response to treatment has been insufficiently studied. In vitro studies assessing the effect of PBM on tumor cells report conflicting results, perhaps attributable to inconsistencies of PBM power and dose. Nonetheless, the biological bases for the broad clinical activities ascribed to PBM have also been noted to be similar to those activities and pathways associated with negative tumor behaviors and impeded response to treatment. While there are no anecdotal descriptions of poor tumor outcomes in patients treated with PBM, confirming its neutrality with respect to cancer responsiveness is a critical priority. CONCLUSION: Based on its therapeutic effects, PBM may have utility in a broad range of oral, oropharyngeal, facial, and neck complications of HNC treatment. Although evidence suggests that PBM using LLLT is safe in HNC patients, more research is imperative and vigilance remains warranted to detect any potential adverse effects of PBM on cancer treatment outcomes and survival.

Low-level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 2: proposed applications and treatment protocols.

PURPOSE: There is a large body of evidence supporting the efficacy of low-level laser therapy (LLLT), more recently termed photobiomodulation (PBM) for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved and dosimetric parameters may lead to the management of a broader range of complications associated with HNC treatment. This could enhance patient adherence to cancer therapy, and improve quality of life and treatment outcomes. The mechanisms of action, dosimetric, and safety considerations for PBM have been reviewed in part 1. Part 2 discusses the head and neck treatment side effects for which PBM may prove to be effective. In addition, PBM parameters for each of these complications are suggested and future research directions are discussed. METHODS: Narrative review and presentation of PBM parameters are based on current evidence and expert opinion. RESULTS: PBM may have potential applications in the management of a broad range of side effects of (chemo)radiation therapy (CRT) in patients being treated for HNC. For OM management, optimal PBM parameters identified were as follows: wavelength, typically between 633 and 685 nm or 780-830 nm; energy density, laser or light-emitting diode (LED) output between 10 and 150 mW; dose, 2-3 J (J/cm(2)), and no more than 6 J/cm(2) on the tissue surface treated; treatment schedule, two to three times a week up to daily; emission type, pulsed (<100 Hz); and route of delivery, intraorally and/or transcutaneously. To facilitate further studies, we propose potentially effective PBM parameters for prophylactic and therapeutic use in supportive care for dermatitis, dysphagia, dry mouth, dysgeusia, trismus, necrosis, lymphedema, and voice/speech alterations. CONCLUSION: PBM may have a role in supportive care for a broad range of complications associated with the treatment of HNC with CRT. The suggested PBM irradiation and dosimetric parameters, which are potentially effective for these complications, are intended to provide guidance for well-designed future studies. It is imperative that such studies include elucidating the effects of PBM on oncology treatment outcomes.

Clinical approach in the management of oral chronic graft-versus-host disease (cGVHD) in a series of specialized medical centers.

BACKGROUND: The oral cavity is frequently affected in chronic graft-versus-host disease (cGVHD), with variable clinical presentations. The literature on the effective management of patients suffering from oral cGVHD is limited. OBJECTIVE: The objective of this study was to assess the clinical approaches used in the diagnosis and treatment of cGVHD in a group of health-care providers specialized in the oral care of oncology patients. The secondary objective was to assess the level of implementation of the National Institutes of Health (NIH) guidelines for cGVHD patients. METHODS: One hundred twenty questionnaires were sent to the members of the Oral Care Study Group (OCSG) of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The questionnaire included 50 questions about the responder's demographics, level of exposure to cGVHD patients, diagnostic and evaluation methods in their practice, preferred treatment strategies for mucosal and salivary gland involvement, and preventive measures. RESULTS: Twelve responders, representing 12 sites, stated that they treat oral cGVHD patients on a regular basis. This fraction of responders was confirmed by another online survey. Eleven out of the 12 providers were dentists. Seventy-five percent of the providers did not use biopsy in order to diagnose oral cGVHD. The NIH scale for the clinical assessment was used sporadically. The first-line topical treatment for oral mucosal cGVHD was predominantly steroids (91.7 %), and the second preferred treatment was tacrolimus (41.7 %). The preferred treatment for hyposalivation was pilocarpine (41.7 %). The recommended frequency of oral cancer screening varied; half of the providers suggest a follow-up every 6 months. CONCLUSIONS: The responses described the common practices for oral cGVHD in several specialized centers across the world. The choice of topical treatments was influenced by the availability of medications in the provider's country.

Basic oral care for hematology-oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT).

PURPOSE: Hematology-oncology patients undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT) recipients are at risk for oral complications which may cause significant morbidity and a potential risk of mortality. This emphasizes the importance of basic oral care prior to, during and following chemotherapy/HSCT. While scientific evidence is available to support some of the clinical practices used to manage the oral complications, expert opinion is needed to shape the current optimal protocols. METHODS: This position paper was developed by members of the Oral Care Study Group, Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT) in attempt to provide guidance to the health care providers managing these patient populations. RESULTS: The protocol on basic oral care outlined in this position paper is presented based on the following principles: prevention of infections, pain control, maintaining oral function, the interplay with managing oral complications of cancer treatment and improving quality of life. CONCLUSION: Using these fundamental elements, we developed a protocol to assist the health care provider and present a practical approach for basic oral care. Research is warranted to provide robust scientific evidence and to enhance this clinical protocol.

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.

BACKGROUND: Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis. METHODS: A literature search was conducted to identify eligible published articles, based on predefined inclusion/exclusion criteria. Each article was independently reviewed by 2 reviewers. Studies were rated according to the presence of major and minor flaws as per previously published criteria. The body of evidence for each intervention, in each treatment setting, was assigned a level of evidence, based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The literature search identified 8279 papers, 1032 of which were retrieved for detailed evaluation based on titles and abstracts. Of these, 570 qualified for final inclusion in the systematic reviews. Sixteen new guidelines were developed for or against the use of various interventions in specific treatment settings. In total, the MASCC/ISOO Mucositis Guidelines now include 32 guidelines: 22 for oral mucositis and 10 for gastrointestinal mucositis. This article describes these updated guidelines. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis will help clinicians provide evidence-based management of mucositis secondary to cancer therapy.

Local and systemic pathogenesis and consequences of regimen-induced inflammatory responses in patients with head and neck cancer receiving chemoradiation.

Treatment-related toxicities are common among patients with head and neck cancer, leading to poor clinical outcomes, reduced quality of life, and increased use of healthcare resources. Over the last decade, much has been learned about the pathogenesis of cancer regimen-related toxicities. Historically, toxicities were separated into those associated with tissue injury and those with behavioural or systemic changes. However, it is now clear that tissue-specific damage such as mucositis, dermatitis, or fibrosis is no longer the sole consequence of direct clonogenic cell death, and a relationship between toxicities that results in their presentation as symptom clusters has been documented and attributed to a common underlying pathobiology. In addition, the finding that patients commonly develop toxicities representing tissue injury outside radiation fields and side effects such as fatigue or cognitive dysfunction suggests the generation of systemic as well as local mediators. As a consequence, it might be appropriate to consider toxicity syndromes, rather than the traditional approach, in which each side effect was considered as an autonomous entity. In this paper, we propose a biologically based explanation which forms the basis for the diverse constellation of toxicities seen in response to current regimens used to treat cancers of the head and neck.

Late Complications in Long-Term Childhood Cancer Survivors: What the Oral Health Professional Needs to Know.

With diagnostic and therapeutic advances, over 80% of children diagnosed with cancer become long-term survivors. As the number of childhood cancer survivors (CCS) continues to increase, dental practitioners become more likely to have CCS among their patients. CCS may develop late complications from damage caused by their cancer treatment to endocrine, cardiovascular, musculoskeletal, and other organ systems. These complications may surface decades after the completion of treatment. Adverse outcomes of childhood cancer treatment frequently involve oral and craniofacial structures including the dentition. Tooth development, salivary gland function, craniofacial growth, and temporomandibular joint function may be disturbed, increasing oral health risks in these individuals. Moreover, CCS are at risk of developing subsequent malignancies, which may manifest in or near the oral cavity. It is important that dental practitioners are aware of the childhood cancer history of their patients and have knowledge of potential late complications. Therefore, this narrative review aims to inform dental practitioners of late oral complications of cancer treatment modalities commonly used in pediatric oncology. Furthermore, selected common non-oral late sequelae of cancer therapy that could have an impact on oral health and on delivering dental care will be discussed.

Subjective Oral Dryness following Hematopoietic Cell Transplantation: A Report from the Orastem Study.

Xerostomia, or subjective oral dryness, is a serious complaint after hematopoietic cell transplantation (HCT). Xerostomia is rated as one of the most bothersome symptoms by HCT recipients, negatively affecting quality of life. This substudy of the Orastem study, a prospective longitudinal, international, observational, multicenter study, aimed to describe the prevalence and severity of xerostomia following HCT. Furthermore, the effect of the conditioning regimen, type of transplantation, and oral mucosal changes related to chronic graft-versus-host disease (cGVHD) in the development of xerostomia were studied. All HCT recipients rated xerostomia on a scale of 0 to 10 before the conditioning regimen, several times early post-HCT, and at 3 months post-HCT, and only allogeneic HCT recipients also rated xerostomia at 6 and 12 months post-HCT. In addition, stimulated whole mouth saliva was collected several times. Linear regression models and longitudinal mixed-effects models were created to investigate the influence of risk indicators on xerostomia. A total of 99 autologous and 163 allogeneic HCT recipients were included from 6 study sites in Sweden, Canada, the Netherlands, and the United States. The prevalence of xerostomia was 40% before the conditioning regimen, 87% early post-HCT, and 64% at 3 months post-HCT. Complaints after autologous HCT were transient in nature, while the severity of xerostomia in allogeneic HCT recipients remained elevated at 12 months post-HCT. Compared to autologous HCT recipients, allogeneic HCT recipients experienced 1.0 point more xerostomia (95% confidence interval [CI], .1 to 2.0) early post-HCT and 1.7 points more (95% CI, .4 to 3.0) at 3 months post-HCT. Allogeneic HCT recipients receiving a high-intensity conditioning regimen experienced more xerostomia compared to those receiving a nonmyeloablative or reduced-intensity conditioning regimen. The difference was 2.0 points (95% CI, 1.1 to 2.9) early post-HCT, 1.8 points (95% CI, .3 to 3.3) after 3 months, and 1.7 points (95% CI, .0 to 3.3) after 12 months. Total body irradiation as part of the conditioning regimen and oral mucosal changes related to cGVHD did not significantly influence the severity of xerostomia. Conditioning regimen intensity was a significant risk indicator in the development of xerostomia, whereas total body irradiation was not. Allogeneic HCT recipients experienced more xerostomia than autologous HCT recipients, a difference that cannot be explained by a reduction in stimulated salivary flow rate or the development of oral mucosal changes related to cGVHD.

Mammalian target of rapamycin inhibitor-associated stomatitis.

With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.