Prospective Cohort Study Identifies Medical Predictors of Treatment-Related Oral Toxicities in Oral and Oropharyngeal Cancer Patients.

The dental treatment of patients with oral cavity and oropharyngeal squamous cell carcinoma (OOPSCC) may be challenging for dentists. This study aimed to characterize systemic changes in patients with OOPSCC undergoing dental treatment prior to cancer therapy, with a specific focus on laboratory assessments. The primary objectives included identifying potential adverse events, such as infections or bleeding, resulting from dental procedures. Additionally, the study aimed to correlate baseline patient characteristics with treatment-related toxicities. This was a prospective cohort study that included 110 OOPSCC patients referred to the Dental Oncology Service at São Paulo State Cancer Institute, Brazil, between November/2019 and December/2020. Comorbidities, sociodemographic data, medication in use, cancer treatment-related toxicities, and altered laboratory tests results were correlated. The most common comorbidities and altered laboratory results were hypertension, dyslipidemia, diabetes, as well as elevated levels of C-reactive protein, hemoglobin, and hematocrit. Toxicities exhibited a progressive pattern over time, encompassing oral mucositis (OM), xerostomia, dysphagia, dysgeusia, trismus, and radiodermatitis. No correlation between comorbidities and cancer treatment-related toxicities, a positive correlation between medications in use and OM, and a negative correlation between medications and dysgeusia were found. OM was associated with altered thyroxine (T4) and free thyroxine (FT4), calcium, urea, creatinine, alkaline phosphatase, and syphilis. Family income and housing were OM predictors. Altered T4/FT4/urea/calcium/alkaline phosphatase/creatinine/syphilis may be useful clinical predictors of OM. Despite the elevated prevalence of comorbidities and abnormal laboratory findings, dental treatment prior to cancer treatment yielded no adverse events.

Machine learning for the prediction of toxicities from head and neck cancer treatment: A systematic review with meta-analysis.

INTRODUCTION: The aim of the present systematic review (SR) is to summarize Machine Learning (ML) models currently used to predict head and neck cancer (HNC) treatment-related toxicities, and to understand the impact of image biomarkers (IBMs) in prediction models (PMs). The present SR was conducted following the guidelines of the PRISMA 2022 and registered in PROSPERO database (CRD42020219304). METHODS: The acronym PICOS was used to develop the focused review question (Can PMs accurately predict HNC treatment toxicities?) and the eligibility criteria. The inclusion criteria enrolled Prediction Model Studies (PMSs) with patient cohorts that were treated for HNC and developed toxicities. Electronic database search encompassed PubMed, EMBASE, Scopus, Cochrane Library, Web of Science, LILACS, and Gray Literature (Google Scholar and ProQuest). Risk of Bias (RoB) was assessed through PROBAST and the results were synthesized based on the data format (with and without IBMs) to allow comparison. RESULTS: A total of 28 studies and 4,713 patients were included. Xerostomia was the most frequently investigated toxicity (17; 60.71 %). Sixteen (57.14 %) studies reported using radiomics features in combination with clinical or dosimetrics/dosiomics for modelling. High RoB was identified in 23 studies. Meta-analysis (MA) showed an area under the receiver operating characteristics curve (AUROC) of 0.82 for models with IBMs and 0.81 for models without IBMs (p value < 0.001), demonstrating no difference among IBM- and non-IBM-based models. DISCUSSION: The development of a PM based on sample-specific features represents patient selection bias and may affect a model's performance. Heterogeneity of the studies as well as non-standardized metrics prevent proper comparison of studies, and the absence of an independent/external test does not allow the evaluation of the model's generalization ability. CONCLUSION: IBM-featured PMs are not superior to PMs based on non-IBM predictors. The evidence was appraised as of low certainty.

Can the prophylactic use of pentoxifylline and tocopherol before dental extractions prevent osteoradionecrosis? A systematic review.

PURPOSE: This systematic review aimed to determine whether the pentoxifylline and tocopherol (PENTO) protocol effectively reduce the risk of osteoradionecrosis (ORN) in patients undergoing tooth extraction after head and neck radiotherapy. METHODS: We searched PubMed, SCOPUS, LILACS, EMBASE, Web of Science, and Cochrane databases up to August 2022. We considered only studies that included patients diagnosed with head and neck cancer undergoing tooth extraction with PENTO prophylaxis after radiotherapy. RESULTS: Of the 642 studies identified, 4 were included. Across the included studies, 387 patients had 1871 teeth extracted while on PENTO prophylaxis. The interval of the PENTO protocol differed among the studies included. Overall, a total of 12 (3.1%) patients had ORN, whereas at the individual tooth level analysis the ORN rate was 0.9%. CONCLUSIONS: Insufficient evidence exists to promote using the PENTO protocol before dental extractions to prevent ORN.

Twenty-year analysis of photobiomodulation clinical studies for oral mucositis: a scoping review.

OBJECTIVE: Our objective was to review the first 20 years of photobiomodulation (PBM) clinical studies for oral mucositis (OM) mitigation. STUDY DESIGN: A scoping review screened controlled clinical studies. The PBM devices, protocols, and clinical outcomes were analyzed. RESULTS: Seventy-five studies met the inclusion criteria. The first study dated from 1992, and the term "PBM" was first published in 2017. Public services, placebo-controlled randomized trials, and patients with head and neck chemoradiation were predominant among included studies. Prophylactic red intraoral laser protocols were mostly used. Comparing the outcomes of all protocols was unfeasible due to missing treatment parameters and nonhomogeneous measurements. CONCLUSIONS: The main barrier to optimizing clinical protocols of PBM for OM was the lack of standardization in clinical studies. Although PBM use is now globally present in oncology settings and generally marked by good outcomes reported, additional randomized clinical trials with well-described methods are necessary.

Patient's perceptions of oral and oropharyngeal cancer diagnosis disclosure: communication aspects based on SPIKES protocol.

OBJECTIVE: Breaking bad medical news is a complex task of clinical practice. The manner in which this is done has a significant impact on patients. This study aimed to assess patient's perceptions regarding oral and oropharyngeal cancer diagnosis disclosure according to the "SPIKES" protocol. STUDY DESIGN: This cross-sectional study used a questionnaire with 21 SPIKES-based items. The questionnaire was administered to 100 patients with recently diagnosed oral and oropharyngeal squamous cell carcinoma who evaluated each item according to their preference and experience. RESULTS: Nineteen items showed a significant difference between patient's preference and recalled experience. Eighteen of these items showed lower experience scores primarily related to the amount of information desired by patients, presence of a companion, time to express feelings, and summary of information. Most patients preferred receiving as much information as possible about the diagnosis. However, only 35% reported that they had obtained sufficient information. Patients who were aware of cancer diagnostic suspicion had better communication experiences. CONCLUSIONS: Protocols may be useful to guide health professionals to support patient-centered strategies to disclose oral cancer diagnoses.

Clinical predictors of malignant transformation and recurrence in oral potentially malignant disorders: A systematic review and meta-analysis.

OBJECTIVE: We performed a systematic review dedicated to pooling evidence for the associations of clinical features with malignant transformation (MT) and recurrence of 3 oral potentially malignant disorders (OPMDs) (actinic cheilitis [AC], oral leukoplakia [OL], and proliferative verrucous leukoplakia [PVL]). STUDY DESIGN: We selected studies that included clinical features and risk factors (age, sex, site, size, appearance, alcohol intake, tobacco use, and sun exposure) of OL, PVL, and AC associated with recurrence and/or MT. RESULTS: Based on the meta-analysis results, non-homogeneous OL appears to have a 4.53 times higher chance of recurrence after treatment. We also found 6.52 higher chances of MT of non-homogeneous OL. Another clinical feature related to higher MT chances is the location (floor of the mouth and tongue has 4.48 higher chances) and the size (OL with >200 mm2 in size has 4.10 higher chances of MT). Regarding habits, nonsmoking patients with OL have a 3.20 higher chance of MT. The only clinical feature related to higher chances of MT in patients with PVL was sex (females have a 2.50 higher chance of MT). CONCLUSIONS: Our study showed that some clinical features may indicate greater chances of recurrence after treatment and MT of OPMD.

Over 300 Radiation Caries Papers: Reflections From the Rearview Mirror.

Radiation caries (RC) is an aggressive oral toxicity in head and neck cancer survivors, which develops 6 to 12 months after head and neck radiotherapy. It initially affects the tooth cervical/incisal surfaces, and if not promptly diagnosed/managed, progresses to dental crown amputation and risk of osteoradionecrosis. It results from a multidimensional cluster of treatment-induced oral symptoms, including hyposalivation, dietary changes, and oral hygiene impairment. Although recognized as a frequent complication of radiotherapy and extensively assessed by a myriad of retrospective, in vitro, and in situ studies, RC patients are still orphans of clinically validated methods for risk prediction, prevention, and treatment of early lesions. This review provides a historical overview of science-based concepts regarding RC pathogenesis and treatment, emphasizing the growing demand for interventional clinical studies (randomized trials).

State-of-the-science concepts of HPV-related oropharyngeal squamous cell carcinoma: a comprehensive review.

High-risk (HR) human papillomavirus (HPV) infection is recognized as a primary etiologic factor of anogenital cancers and more recently of a subgroup of oropharyngeal squamous cell carcinomas (OPSCC). The incidence of HPV-related OPSCC has increased dramatically in several developed countries in the past 3 decades and is currently the most common cancer caused by HR-HPV in the United States and Germany, surpassing cervical cancer. Consequently, the patient's demographic and clinicopathologic profile has shifted to nonsmoking and nondrinking younger men with higher schooling level and with a history of multiple oral sex partners. Patients with HPV-related OPSCC often show better treatment outcomes and higher survival rates than their HPV-unrelated counterparts, which has led to a change in tumor staging for HPV-related cases. HPV vaccination is emerging as an effective primary prevention strategy, and systematic screening of HPV DNA in blood and salivary oral rinse samples of HR patients is being examined to determine if it may provide a surveillance method and support early diagnosis of HPV-related OPSCC. In this context, a narrative review was conducted to provide an overview of the state-of-the-art of HPV-related OPSCC, including epidemiology, risk factors, clinicopathologic and molecular features, screening, prevention, management, and prognosis.

To extract or not extract teeth prior to head and neck radiotherapy? A systematic review and meta-analysis.

PURPOSE: Teeth with poor prognosis are generally recommended to be extracted prior to head and neck radiotherapy (RT) to reduce the risk of developing osteoradionecrosis (ORN), although controversies have been reported. The present systematic review aimed to determine whether tooth extraction prior to head and neck RT may be associated with a reduced risk of developing ORN compared to dental extraction during or after RT. METHODS: The review protocol was registered in PROSPERO (CRD42021241631). The review was reported according to the PRISMA checklist and involved a comprehensive search of PubMed, Scopus, Embase, Cochrane Library, LILACS, and Web of Science, in addition to the gray literature. The selection of studies was performed in two phases by two reviewers independently. The risk of bias of individual studies was analyzed using the Joanna Briggs Institute checklist for cross-sectional studies, and the certainty of evidence was assessed using the GRADE tool. RESULTS: Twenty-eight observational studies were included in the qualitative synthesis, which showed substantial heterogeneity regarding the association between the timing of tooth extraction and ORN development. Twenty-seven of 28 studies were pooled in a meta-analysis that demonstrated a significant association between an increased risk of ORN and post-RT tooth extraction (odds ratio: 1.98; 95% CI: 1.17-3.35; p = 0.01). CONCLUSION: It was confirmed with moderate certainty that dental extractions should be performed prior to the start of head and neck RT to reduce the risk of ORN.

Oral Complications in Cancer Patients-Medication-Related Osteonecrosis of the Jaw (MRONJ).

Medication-Related Osteonecrosis of the Jaw (MRONJ) was first reported in 2003. Despite the progress in the understanding of this oral complication in cancer patients for the past 18 years, there is still discussion about the best way to define MRONJ, prevent the complication, how to diagnose, and the options of treatment available. The initial reports associated MRONJ to bisphosphonates and denosumab, medications that work as bone-modifying agents. Later, other agents such as the antiangiogenics, have also been reported to cause the oral complication, either alone or in combination with antiresorptives. Initially, these medications were prescribed to patients with osteoporosis and cancers patients with bone metastasis. Today, because of the effect of the medications in the bone remodeling system, patients with several other diseases such as giant cell tumors, rheumatoid arthritis, Paget's disease of bone, fibrous dysplasia, osteogenesis imperfecta, are managed with these medications, significantly increasing the population of individuals at risk for developing MRONJ. This mini review focused on the cancer patient. It updates the dental clinician on the recent scientific literature about MRONJ and provides information on how to diagnose and manage patients being treated with these medications, suggests protocols to prevent the development of MRONJ, and present ways to manage those patients who develop the oral complication.

Oral medicine (stomatology) in Brazil: the first 50 years and counting.

This review outlines the historical perspective, status, and future challenges of oral medicine (stomatology) in Brazil based on the records of the Brazilian Society of Stomatology and Oral Pathology (SOBEP) and the Brazilian Federal Dental Council as well as expert evidence input from academic leaders from 3 different generations of Brazilian oral medicine specialists. The beginning of oral medicine in Brazil dates to 1969, followed by the organization of SOBEP in 1974; however, official recognition as an independent specialty was achieved more recently within the Brazilian Federal Dental Council in 1992. After a 50-year maturation period of oral medicine in Brazil in terms of specialty crystallization across dentistry, medicine, and research, it is now time to follow the historical trends of the specialty internationally and establish a standard curriculum at a post-graduate level that will lead to uniformity of training for oral medicine in Brazil.

Extraoral photobiomodulation for prevention of oral and oropharyngeal mucositis in head and neck cancer patients: interim analysis of a randomized, double-blind, clinical trial.

PURPOSE: To assess the safety and efficacy of prophylactic extraoral photobiomodulation (PBM) for the prevention of oral and oropharyngeal mucositis (OM) on clinical outcomes and survival in patients with oral cavity and oropharyngeal squamous cell carcinoma (OOPSCC). METHODS: OOPSCC patients who received radiotherapy (RT) were prospectively randomized to two groups: prophylactic extraoral PBM and placebo. OM grade (NCI), pain (VAS), analgesia, and anti-inflammatory prescriptions were assessed weekly. Quality of life questionnaires (QoL) were performed at the first and last day of RT. Following RT, participants were evaluated quarterly for oncological outcomes follow-up. RESULTS: Fifty-five patients met the inclusion criteria. The first occurrence of OM was observed at week 1, for the placebo group (p = 0.014). Later, OM onset and severity was observed for the PBM group, with first occurrence at week 2 (p = 0.009). No difference in severe OM incidence was observed (p > 0.05). Lower mean pain score was noted at week 7 for the PBM group (2.1) compared to placebo group (4.5) (p = 0.009). Less analgesics (week 3; p = 0.009/week 7; p = 0.02) and anti-inflammatory prescription (week 5; p = 0.0346) were observed for the PBM group. Better QoL scores were observed for the PBM group at last day of RT (p = 0.0034). No difference in overall survival among groups was observed in 1 year of follow-up (p = 0.889). CONCLUSION: Prophylactic extraoral PBM can delay OM onset, reduce pain, and reduce analgesic and anti-inflammatory prescription requirements. Extraoral PBM was associated with better QoL. There was no evidence of PBM impact on oncological outcomes. TRIAL REGISTRATION: TRN:RBR-4w4swx (date of registration: 01/20/2020).

Oral care and photobiomodulation protocol for the prevention of traumatic injuries and lip necrosis in critically ill patients with COVID-19: an observational study.

It is well reported that severe cases of COVID-19 frequently need critical care in the ICU to manage respiratory complications, often requiring orotracheal intubation (OTI). Due to complex systemic conditions, the patient may remain intubated for a long period of time and be placed in prone position. This positioning and the pressure of the intubation device on the lips may lead to the development of traumatic injuries. Oral care and the use of photobiomodulation (PBM) can be successfully implemented to promote oral mucosa healing and prevent soft tissue necrosis. We describe the outcomes of the management protocol that was routinely used by the ICU oral medicine team, leading to the implementation of a preventive protocol for the OTI-related oral injuries. We retrospectively analyzed the records of 472 patients with COVID-19 in the ICU from May 2020 to February 2021. 60/472 patients developed traumatic injuries and were managed with the oral care protocol and PBM, to prevent the progress to lip necrosis. When appropriated, in addition to oral care and PBM, other measures were taken to prevent further local trauma (lip hydration, changes in tube fixation). The proposed oral care protocol associated with PBM successfully prevented the progress of traumatic lesions, ulceration, necrosis, and loss of tissue associated with IOT. The quality of life of patients in the ICU and after their recovery was preserved.

Awareness of the risk of radiation-related caries in patients with head and neck cancer: A survey of physicians, dentists, and patients.

OBJECTIVES: Radiation-related caries (RRC) is one of the most aggressive complications of radiotherapy (RT) in survivors of head and neck cancer (HNC). Lack of RRC awareness may contribute to the occurrence of this oral cavity complication. RRC may be considered a "forgotten oral complication" by patients with HNC, oncologists, and dentists. The present study aimed to assess the level of awareness of RRC among physicians, dentists, and patients. STUDY DESIGN: Physicians (group 1, G1), dentists (group 2, G2), and patients with HNC undergoing RT (group 3, G3) answered questionnaires concerning their awareness of RRC. Physicians (G1) were divided into group 1A (oncological experience) and group 1B (general physicians/other specialties). Dentists (G2) were divided into group 2A (oncological experience) and group 2B (general dentists/other specialties). Personalized questionnaires were designed for each group. RESULTS: Recruitment was as follows: physicians (n = 124): 1A (n = 64), 1B (n = 60); dentists: (n = 280), 2A (n = 160), 2B (n = 120). In addition, 58 patients answered the questionnaire. In terms of RRC awareness, 46.77% of physicians, 81.78% of dentists, and 24.13% of patients had some knowledge of the problem. CONCLUSION: Patient awareness of RRC was poor. The heterogeneity of answers among physicians and dentists suggests an opportunity to improve patient education and prevention of this serious oral complication of RT.

Cilostazol and Tocopherol in the Management of Medication-Related Osteonecrosis of the Jaw: New Insights From a Case Report.

Several treatment protocols for medication-related osteonecrosis of the jaw (MRONJ) have been published. Despite the efficacy of surgical therapy of approximately 90% as primary therapy, the role of other agents, such as drug administration, should not be underestimated. Based on previous experience with osteoradionecrosis, the association of pentoxifylline and tocopherol has shown encouraging results in MRONJ patients. Despite the need for long-term use of the combination, compliance has been good. However, studies in breast cancer patients revealed that pentoxifylline can require dose reduction or discontinuation due to nausea and epigastric pain. Cilostazol has been used as a substitute for pentoxifylline in peripheral artery disease. Herein we report a case in which cilostazol replaced pentoxifylline at a dose of 100mg, 2 times/day with tocopherol 500UI, 2 times/day, in a 77-year-old female patient that could not tolerate pentoxifylline for the management of MRONJ. After an uneventful 22 months of follow-up, a cone-beam computed tomography revealed complete bone formation and no signs of recurrence. Cilostazol may be a useful and safe alternative to pentoxifylline as part of MRONJ management protocols.

Long-term safety of photobiomodulation therapy for oral mucositis in hematopoietic cell transplantation patients: a 15-year retrospective study.

Photobiomodulation therapy (PBMT) has demonstrated efficacy in the prevention and treatment of oral mucositis (OM) in hematopoietic cell transplantation (HCT). However, based on the cell stimulation properties, its long-term safety has been questioned, mainly in relation to risk for secondary malignancies in the oral cavity. The aim of this study was to investigate if different PBMT protocols for OM control have association with immediate and late adverse effects in HCT patients. Data on autologous and allogeneic transplantation, conditioning regimen, PBMT protocols, and OM severity were retrospectively collected from medical and dental records. Presence of secondary malignancies in the oral cavity was surveyed during a 15-year follow-up. Impact of OM on overall survival was also analyzed. Different PBMT protocols for prevention and treatment of OM were recorded over the years. Severe OM (grades 3 and 4) was infrequently observed. When present, we observed a significant decrease of the overall survival. No immediate adverse effect and secondary malignancy was associated to PBMT. In conclusion, the PBMT protocols used in the study were considered safe. The low frequency of severe OM observed encourages the implementation of this technique, with a special emphasis on the dosimetry adjustments focused on the HCT context.

Direct costs associated with the management of mucositis: A systematic review.

Mucositis is one of the more frequent and costly adverse events following cancer treatment. To evaluate and report the direct economic outcomes associated with the management of mucositis across several cancer treatments we conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Scopus, MEDLINE/PubMed, and Embase were searched electronically and a total of 37 relevant studies were included. The costs attributable to mucositis in the hematopoietic stem cell transplantation setting ranged from 1124,47 US dollars (USD) to 299 214,14 USD per patient. The radiotherapy/chemoradiotherapy/radiotherapy plus molecular targeted therapy accounted for mucositis costs that ranged from 51,23 USD to 33 560,58 USD per patient. Costs for mucositis in the chemotherapy setting ranged from 4,18 USD to 31 963,64 USD per patient. When the cancer treatment was not specified, costs of mucositis ranged from 565,85 USD to as high as 20 279, 12 USD per patient. Mucositis costs from multimodal therapy ranged from 12,42 USD to 5670,46 USD per patient. The molecular targeted therapy setting included only one study and depending on the healthcare providers' perspective of each country evaluated, mucositis' costs ranged from 45,78 USD to 3484,91 USD per patient. Mucositis is associated with increased resource use, consultations, hospitalizations and extended hospitalizations, leading to a substantial incremental cost that exacerbates the economic burden on the patient, health plan and health system across several cancer treatments and diagnosis. More studies with a prospective evaluation of the economic costs associated with mucositis management are needed.