Osteonecrosis of the jaw risk factors in bisphosphonate-treated patients with metastatic cancer.

BACKGROUND: A case-control study was performed to define clinical and genetic risk factors associated with osteonecrosis of the jaw in patients with metastatic cancer treated with bisphosphonates. METHODS: Clinical data and tissues were collected from patients treated with bisphosphonates for metastatic bone disease who were diagnosed with osteonecrosis of the jaw (cases) and matched controls. Clinical data included patient, behavioral, disease, and treatment information. Genetic polymorphisms in CYP2C8 (rs1934951) and other candidate genes were genotyped. Odds ratios from conditional logistic regression models were examined to identify clinical and genetic characteristics associated with case or control status. RESULTS: The study population consisted of 76 cases and 126 controls. In the final multivariable clinical model, patients with osteonecrosis of the jaw were less likely to have received pamidronate than zoledronic acid (odds ratio = 0.18, 95% Confidence interval: 0.03-0.97, p = .047) and more likely to have been exposed to bevacizumab (OR = 5.15, 95% CI: 1.67-15.95, p = .005). The exploratory genetic analyses suggested a protective effect for VEGFC rs2333496 and risk effects for VEGFC rs7664413 and PPARG rs1152003. CONCLUSIONS: We observed patients with ONJ were more likely to have been exposed to bevacizumab and zoledronic and identified potential genetic predictors that require validation prior to clinical translation.

Mandibular metastases in neuroblastoma: Outcomes and dental sequelae.

BACKGROUND: Although metastatic involvement of bony sites including cranial bones is common in neuroblastoma (NB), mandibular metastases (MM) are uncommon, and specific outcomes have not been reported upon in the modern therapeutic era. METHODS: In this retrospective study, medical records on patients with MM from NB were reviewed. Statistical analysis was performed using the Kaplan-Meier method. RESULTS: Of 29 patients, nine (31%) had MM at diagnosis, whereas in 20 (69%) MM were first detected at NB relapse at a median time of 26 (6-89) months from diagnosis. Median maximal diameter of lesions was 3 (range 0.8-4.9) cm. MM were unilateral in 83% of patients, with ascending ramus (55%) and mandibular body (38%) being the two most common sites. All patients received systemic chemotherapy, and 26 (93%) patients received radiotherapy to MM. At a median follow-up of 37.3 (24.2-219.5) months, eight of nine patients with MM at diagnosis did not experience mandibular progressive disease. Eighteen of 20 patients with MM at relapse received therapeutic radiotherapy; objective responses were noted in 78%. Seventy-two percent (5/18) had not experienced relapse within the radiation field at a median of 12 (2-276) months postradiotherapy. Dental findings at follow-up after completion of NB therapy included hypodontia, hypocalcification of enamel, and trismus. Median 3-year overall survival in patients with relapsed MM was 51 ± 12% months from relapse. CONCLUSION: MM when detected at diagnosis is associated with a prognosis similar to that for other skeletal metastases of NB. Radiotherapy is effective for control of MM detected both at diagnosis and relapse. Significant dental abnormalities posttherapy warrant regular dental evaluations and appropriate intervention.

Primary Ewing Family of Tumors of the Jaw Has a Better Prognosis Compared to Tumors of Extragnathic Sites.

PURPOSE: Primary Ewing sarcoma of the jaw is rare. The aim of this study was to describe new cases of primary Ewing sarcoma of the jaw and investigate reported prognostic factors of Ewing sarcoma in this series and treatment outcome. MATERIALS AND METHODS: Six patients with primary Ewing sarcoma of the jaw were treated at the Memorial Sloan Kettering Cancer Center (MSKCC) from 1992 through 2013. Clinical data, pathology reports, treatment prescribed, treatment regimens, outcome, and follow-up information were reviewed. RESULTS: Five of 6 patients were female and 5 cases were in the mandible. No patient presented with metastatic disease at diagnosis. All cases were positive for CD99, and 3 patients with genetic confirmation were positive for EWS-FLI1 fusion or EWSR1 gene rearrangement. All patients received induction multiagent chemotherapy and surgical resection and 2 patients received adjuvant radiotherapy. Total (grade IV) or nearly total (grade III) tumor necrosis in 3 of 5 patients (60%) assessed for histologic response to chemotherapy indicated intense sensitivity. All patients were alive and free of disease, with no history of local recurrence, at a median follow-up period of 6.5 years. CONCLUSION: Patients with primary Ewing sarcoma of the jaw have a good prognosis and metastasis is an uncommon occurrence at initial presentation.

Long-term effect of chemotherapy-intensity-modulated radiation therapy (chemo-IMRT) on dentofacial development in head and neck rhabdomyosarcoma patients.

Dentofacial developmental abnormalities have been reported in head and neck rhabdomyosarcoma (HNRMS) patients treated with conventional radiotherapy technique and chemotherapy. This current study investigates dentofacial long-term effects among HNRMS survivors managed with intensity-modulated radiotherapy (IMRT) and chemotherapy. In general, IMRT is a more effective 3D-conformal radiotherapy technique, which delivers high doses of radiation to the tumor target while minimizing doses received by the surrounding normal tissues. The medical records and radiographs of thirteen patients were reviewed to identify the following: 1. Facial asymmetry and jaw hypoplasia. 2. Effects on the dental tissue causing tooth agenesis/hypodontia, root agenesis/stunting/malformation, and/or enamel hypoplasia. 3. Trismus, hyposalivation/xerostomia. Seven patients presented with facial asymmetry and jaw hypoplasia, 9 patients presented with effects on the dental tissue [root agenesis/stunting/malformation (9), tooth agenesis/hypodontia (7) and enamel hypoplasia (3)] and 7 patients developed trismus and /or xerostomia. All patients with facial asymmetry and jaw hypoplasia also developed dental abnormalities. Patients with dentofacial developmental abnormalities were ≤7 years of age at treatment. Our study shows that dentofacial developmental abnormalities are still a burden in the era of IMRT and as prognosis of childhood malignancy improves and more patients survive, these late dentofacial sequelae among childhood cancer survivors will become more common. Dental oncologists should be integral members in the management of children with head and neck cancers.

Intraoral angiosarcoma: treatment with a brachytherapy prosthesis.

Angiosarcomas are rare, malignant neoplasms of vascular origin that account for less than 1% of all soft tissue tumors. Angiosarcomas of the oral cavity are especially rare, and brachytherapy may be prescribed as a localized treatment to manage these malignancies. Intraoral brachytherapy requires collaboration between the radiation oncologist and a dental professional for the fabrication of the brachytherapy delivery prosthesis. This clinical report describes an intraoral angiosarcoma and the fabrication of an intraoral brachytherapy prosthesis to manage this malignancy.

Osteoradionecrosis Rates After Head and Neck Radiation Therapy: Beyond the Numbers.

PURPOSE: Osteoradionecrosis (ORN) is a severe late complication of head and neck radiation therapy shown to have profound negative effect on the quality of life of cancer survivors. Over the past few decades, improvements in radiation delivery techniques have resulted in a decrease in the incidence of ORN. However, even with modern radiation therapy techniques, ORN remains an important clinical concern. In recent literature, there is a wide range of reported ORN rates from 0% to as high as 20%. With such a high level of variability in the reported incidence of ORN, oncologists often encounter difficulties estimating the risk of this serious radiation therapy toxicity. METHODS AND MATERIALS: In this review, the authors present a summary of the factors that contribute to the high level of variability in the reported incidence of ORN. RESULTS: Variable definition, variable grading, and heterogeneity of both study inclusion criteria and treatment parameters can each significantly influence the reporting of ORN rates. CONCLUSIONS: Given numerous factors can affect the reported incidence of ORN, a thorough understanding of the clinical context behind the reported ORN rates is needed to comprehend the true risk of this important radiation therapy toxicity.

Association between objective measures of oral health and salivary gland irradiation with patient-reported outcomes following head and neck radiation therapy.

PURPOSE: To determine whether objective measures of oral health and salivary gland irradiation correlates with subjective measures of eating, drinking, and salivation in patients following head and neck radiation therapy (HNRT). METHODS: This cross-sectional study included 112 patients following HNRT with a completed patient-reported outcome (PRO) scale. Objective measures at post-HNRT visit included decayed-missing-filled teeth (DMFT) scores, periodontal disease condition, oral hygiene status, dental prosthesis use, and prescribed radiation dose to salivary glands. Data were collected and statistical analysis was performed. RESULTS: There was no significant association between PRO scales and dental prosthesis use, periodontal disease, and oral hygiene. Although some significant findings were seen with DMFT and prescribed radiation dose to salivary glands, this explained only very small amounts of the variation in eating, drinking, and salivation measures in these patients. CONCLUSION: PRO measures should be integrated in the routine care of patients with head and neck cancer.

Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients.

BACKGROUND: The aim of this study was to review the available literature and define clinical practice guidelines for the use of laser and other light therapies for the prevention and treatment of oral mucositis. 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. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. RESULTS: A new recommendation was made for low-level laser (wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the required time to a tissue energy dose of 2 J/cm(2) (2 s/point)) for the prevention of oral mucositis in adult patients receiving hematopoietic stem cell transplantation conditioned with high-dose chemotherapy, with or without total body irradiation. A new suggestion was made for low-level laser (wavelength around 632.8 nm) for the prevention of oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for head and neck cancer. No guideline was possible in other populations and for other light sources due to insufficient evidence. CONCLUSIONS: The increasing evidence in favor of low-level laser therapy allowed for the development of two new guidelines supporting this modality in the populations listed above. Evidence for other populations was also generally encouraging over a range of wavelengths and intensities. However, additional well-designed research is needed to evaluate the efficacy of laser and other light therapies in various cancer treatment settings.

Osteoradionecrosis of the Jaw Following Proton Radiation Therapy for Patients With Head and Neck Cancer.

Importance: Proton radiation therapy (PRT) has reduced radiation-induced toxic effects, such as mucositis and xerostomia, over conventional photon radiation therapy, leading to significantly improved quality of life in patients with head and neck cancers. However, the prevalence of osteoradionecrosis (ORN) of the jaw following PRT in these patients is less clear. Objective: To report the prevalence and clinical characteristics of ORN in patients with oral and oropharyngeal cancer (OOPC) treated with PRT. Design, Setting, and Participants: This case series reports a single-institution experience (Memorial Sloan Kettering Cancer Center, New York, New York) between November 2013 and September 2019 and included 122 radiation therapy-naive patients with OOPC treated with PRT. Data were analyzed from 2013 to 2019. Main Outcomes and Measures: Clinical parameters, including sex, age, comorbidities, tumor histology, concurrent chemotherapy, smoking, comorbidities, and preradiation dental evaluation, were obtained from the medical record. Patients with clinical or radiographic signs of ORN were identified and graded using the adopted modified Glanzmann and Grätz grading system. Characteristics of ORN, such as location, clinical presentation, initial stage at diagnosis, etiology, time to diagnosis, management, and clinical outcome at the last follow-up, were also collected. Results: Of the 122 patients (mean [SD] age, 63 [13] years; 45 [36.9%] women and 77 [63.1%] men) included in this study, 13 (10.6%) developed ORN following PRT during a median (range) follow-up time of 40.6 (<1-101) months. All patients had spontaneous development of ORN. At the time of initial diagnosis, grade 0, grade 1, grade 2, and grade 3 ORN were seen in 2, 1, 9, and 1 patient, respectively. The posterior ipsilateral mandible within the radiation field that received the full planned PRT dose was the most involved ORN site. At a median (range) follow-up of 13.5 (0.2-58.0) months from the time of ORN diagnosis, complete resolution, stable condition, and progression of ORN were seen in 3, 6, and 4 patients, respectively. The 3-year rates of ORN and death in the total cohort were 5.2% and 21.5%, while the 5-year rates of ORN and death were 11.5% and 34.4%, respectively. Conclusions and Relevance: In this case series, the prevalence of ORN following PRT was found to be 10.6%, indicating that ORN remains a clinical challenge even in the era of highly conformal PRT. Clinicians treating patients with OOPC with PRT should be mindful of this complication.

Osteoradionecrosis of the jaw: A mini review.

Osteoradionecrosis (ORN) of the jaw is one of the most dreaded complications of head and neck radiation therapy. Despite the evolution of radiation treatment modalities, ORN continues to remain a therapeutic challenge and its etiopathogenesis still remains unclear. It is clinically characterized by exposed necrotic bone within the head and neck radiation field. Over the past years, several studies have reported on the definition, staging, incidence, etiology, and management of this oral complication. In this review, we summarize the literature on ORN and discuss our institutional experience and management strategies that aim to predict and mitigate risk for ORN.

Comparison of Objective Measures of Trismus and Salivation With Patient-Reported Outcomes Following Treatment for Head and Neck Cancer.

Importance: Xerostomia and reduced mouth opening are negatively associated with quality of life after radiation therapy (RT) for head and neck cancer. Studies comparing objective measures of function with patient-reported outcomes (PROs) have not revealed a clear association. Objective: To determine how much of the variation in PROs is explained by objective measures of salivary gland and oral cavity functions (salivary flow and maximal interincisal opening). Design, Setting, and Participants: This cross-sectional study at a single academic cancer center evaluated 112 patients who underwent RT for head and neck cancer between January 2016 and March 2021. Measurements of pre-RT and post-RT saliva and a complete PROs scale within 6 months of the post-RT measurement were analyzed using pairwise associations. Interventions: Three independently scored PRO scales from the validated FACE-Q Head and Neck Cancer Module were evaluated: eating and drinking, eating distress, and salivation. Three objective measures were analyzed: maximal interincisal opening, stimulated salivary flow, and unstimulated salivary flow. Main Outcomes and Measures: Univariable linear regression models were performed for each PRO against each objective measure, and coefficients of determination (R2) and 95% CIs were reported. Results: The patient cohort comprised 86 men (77%). Median age was 61 years (IQR, 53-68 years), 89 patients (80%) were White, and 61 patients (54%) were current or former smokers. Unstimulated saliva accounted for only a small portion of variation on the salivation scale (R2 = 14.0%). The remaining associations were even smaller (R2 = 5.0%-10.0%). No upper 95% CI bound included an R2 of 30%, suggesting that objective measurements do not explain a high level of the variation in PROs. Conclusions and Relevance: In this cross-sectional study, objective measurements of salivary flow and mouth opening explained only a small fraction of variation in PROs. These findings suggest that factors other than objective function, including patient adaptation, are the dominant influence on PROs in this population. Patient-reported outcomes should be integrated into head and neck cancer clinical care and research. Additional research is required to evaluate which clinicopathological factors influence PROs for salivation, eating and drinking, and eating distress.

Intraoral radiation stents-Primer for clinical use in head and neck cancer therapy.

Intraoral radiation stents (IRS) are prosthetic devices that assist in the effective delivery of radiation to tumor tissues and aim to avoid unnecessary radiation to adjacent healthy tissues, thus limiting postradiotherapy toxicities. They are used to protect or displace vital structures, assist in positioning of the treatment beam for effective administration of radiotherapy, carry a radioactive material, shield healthy tissues of the oral cavity, and/or maintain the desired mouth opening during radiotherapy. With close collaboration between radiation oncologist and oral health care provider, several IRS can be fabricated by the latter for appropriate targeting and delivery of planned radiation dose and optimized treatment results. Modification of these IRS based on individual patient need is recommended to maximize prosthesis utility. The purpose of this review is to discuss the various types of IRS and highlight their clinical utility and benefits in patients receiving radiation therapy in the head and neck cancers.

Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis.

BACKGROUND: The present study is aimed at identifying potential candidate genes as prognostic markers in human oral tongue squamous cell carcinoma (SCC) by large scale gene expression profiling. METHODS: The gene expression profile of patients (n=37) with oral tongue SCC were analyzed using Affymetrix HG_U95Av2 high-density oligonucleotide arrays. Patients (n=20) from which there were available tumor and matched normal mucosa were grouped into stage (early vs. late) and nodal disease (node positive vs. node negative) subgroups and genes differentially expressed in tumor vs. normal and between the subgroups were identified. Three genes, GLUT3, HSAL2, and PACE4, were selected for their potential biological significance in a larger cohort of 49 patients via quantitative real-time RT-PCR. RESULTS: Hierarchical clustering analyses failed to show significant segregation of patients. In patients (n=20) with available tumor and matched normal mucosa, 77 genes were found to be differentially expressed (P< 0.05) in the tongue tumor samples compared to their matched normal controls. Among the 45 over-expressed genes, MMP-1 encoding interstitial collagenase showed the highest level of increase (average: 34.18 folds). Using the criterion of two-fold or greater as overexpression, 30.6%, 24.5% and 26.5% of patients showed high levels of GLUT3, HSAL2 and PACE4, respectively. Univariate analyses demonstrated that GLUT3 over-expression correlated with depth of invasion (P<0.0001), tumor size (P=0.024), pathological stage (P=0.009) and recurrence (P=0.038). HSAL2 was positively associated with depth of invasion (P=0.015) and advanced T stage (P=0.047). In survival studies, only GLUT3 showed a prognostic value with disease-free (P=0.049), relapse-free (P=0.002) and overall survival (P=0.003). PACE4 mRNA expression failed to show correlation with any of the relevant parameters. CONCLUSION: The characterization of genes identified to be significant predictors of prognosis by oligonucleotide microarray and further validation by real-time RT-PCR offers a powerful strategy for identification of novel targets for prognostication and treatment of oral tongue carcinoma.

Predicting radiation dosimetric distribution in different regions of the jaw in patients receiving radiotherapy for squamous cell carcinoma of the tonsil.

BACKGROUND: Radiotherapy (RT), the main treatment for patients with head and neck cancer, can lead to dental complications. METHODS: We identified 244 patients with squamous cell carcinoma of the tonsil treated with RT from 2004 to 2013. For each patient, we contoured the 10 tooth-bearing regions and calculated the radiation dose (gray, Gy) to each region. From this data set, we built two predictive models to determine the expected maximum radiation dose, one for the non-molar regions and another for the molar regions. RESULTS: For the non-molars, the final model included location, T-classification, and overall stage, with a median absolute prediction error of 7.0 Gy. For the molars, the final model included location, T-classification, overall stage, and treatment year, with a median absolute error of 6.0 Gy. CONCLUSIONS: Our current model offers a good estimation of the maximum radiation dose delivered to different regions of the jaw; future work will independently validate these models.

Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy.

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.

A Clinicopathologic Study of Head and Neck Malignant Peripheral Nerve Sheath Tumors.

Head and neck high grade malignant peripheral nerve sheath tumors (HN-MPNSTs) are rare highly aggressive soft tissue sarcomas that show overlapping morphologic and immunophenotypic features with melanoma and other high grade sarcomas, resulting in diagnostic challenges, particularly in sporadic settings. Recent discoveries have implicated loss of function mutations in the polycomb repressive complex 2 (PRC2) components, including EED or SUZ12 genes, as one of the leading pathogenetic mechanisms in high grade MPNST. MPNSTs with PRC2 loss are associated with complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3), which emerged as a reliable immunohistochemical marker in the diagnosis of sporadic and radiation induced MPNST. As the diagnosis of MPNST in the HN is particularly challenging to distinguish from melanoma and other sarcoma types, we carried out a clinicopathologic analysis on HN-MPNST patients managed at our institution over a 20-year period (1997-2016), using the latest diagnostic criteria including H3K27me3 staining and other molecular investigations. The overall survival of HN-MPNST was compared with other HN soft tissue sarcomas. The diagnosis of HN-MPNST was confirmed in 13 patients (seven males and six females), with a mean age of 31 years; with 3 (23%) patients being of pediatric age. The most common site was the neck soft tissue (77%). Two-thirds of patients (n = 9) had stigmata of NF1, three had prior radiotherapy and only one developed a de novo MPNST. All except one tumor (86%) tested showed loss of H3K27me3 expression, including all non-NF1 patients. The 2 and 5-year DSS rates were 50 and 30%. The 2-year DFS rate was 21%. Adverse predictors on DSS included adult age (p = 0.011), prior-history of RT (p = 0.003) and recurrence (p = 0.003). Compared to other molecularly confirmed subsets of HN sarcomas (Ewing and Ewing-like sarcoma, rhabdomyosarcoma and synovial sarcoma), HN-MPNST had the worst overall survival (p < 0.0001). We conclude that HN-MPNSTs are highly aggressive sarcomas associated with an unfavorable outcome and the utility of H3K27me3 IHC stains in the evaluation of MPNST is a reliable ancillary diagnostic adjunct.

Medication-related osteonecrosis of the jaw: An update on the memorial sloan kettering cancer center experience and the role of premedication dental evaluation in prevention.

OBJECTIVE: The aim of this study was to investigate the relationship between type of antiresorptive medication and medication-related osteonecrosis of the jaw (MRONJ) onset and the role of premedication dental evaluation (PMDE) in the prevention of MRONJ. STUDY DESIGN: Our database of patients with MRONJ was reviewed. The Kruskal-Wallis test was used to analyze the onset dose of the 3 frequent medication types associated with MRONJ. To evaluate the role of PMDE in the prevention of MRONJ, all patients on antiresorptive and/or antiangiogenic medications seen in the Dental Service of Memorial Sloan Kettering Cancer Center during a 10-year period were subclassified into 2 groups. Group I comprised patients seen for PMDE before the commencement of A/A and group II patients seen after prior exposure to antiresorptive and/or antiangiogenic medications. Fischer's exact test was used to compare the incidence of MRONJ in both groups. RESULTS: Patients on denosumab developed MRONJ earlier compared with zoledronate and pamidronate (P = .003). Group I had a significantly reduced incidence of MRONJ (0.9%) compared with group II (10.5%) (P < .0001). Dentoalveolar trauma as a precipitating factor between groups I and II was not statistically significant. CONCLUSIONS: Denosumab was associated with an earlier occurrence of MRONJ compared with zoledronate and pamidronate. The role of PMDE may be an effective preventive strategy in reducing the incidence of MRONJ.