Osteonecrosis of the jaw associated with pembrolizumab.

We report a case of osteonecrosis of the jaw (ONJ) with pembrolizumab, a rare yet possibly emerging complication. In this case, a temporal relationship between the development of ONJ and the patient's treatment regimen suggested an association between pembrolizumab/GVD therapy and the development of ONJ. Thrombocytosis and anatomic factors may also have played a role. The number of patients using pembrolizumab will likely continue to increase. We document this instance in order to better inform dental treatment around cancer patients undergoing pembrolizumab therapy.

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.

Dental status and risk of odontogenic complication in patients undergoing hematopoietic stem cell transplant.

PURPOSE: Dental evaluation and management prior to hematopoietic stem cell transplant (HSCT) plays a vital role in identifying and treating infections that may be life-threatening. The purpose of this study is to describe the dental management of patients undergoing pre-HSCT examination with the Dental Service at Memorial Sloan Kettering Cancer Center (MSKCC) and to report on odontogenic complications. METHODS: Patients referred for evaluation as part of the standard preparation for HSCT were included. Following clinical and radiological examination, patients were assigned to one of three groups based on risk of odontogenic infection, and treatment was provided as indicated. Patients were followed, and their medical records were reviewed for odontogenic complications during the transplant admission. RESULTS: Of the 375 patients evaluated, 350 patients underwent HSCT: allogeneic 143 (40.9%) and autologous 207 (59.1%). The distribution of primary cancer diagnosis was as follows: multiple myeloma 104 (29.7%), leukemias 95 (27.1%), Hodgkin's lymphoma 28 (8.0%), non-Hodgkin's Lymphoma 99 (28.3%), and other conditions 24 (6.9%). The median time from dental evaluation to transplant was 29 days. The median Decayed, Missing, Filled Teeth Index was 17. The median Community Periodontal Index was 1. Based on dental status, 145 patients (41.4%) were classified as low risk, 133 (38%) as moderate risk and 72 (20.6%) as high risk of odontogenic infection. One hundred fourteen patients (32.6%) required dental treatment prior to HSCT, and 100 of these (28.6%) completed treatment. Two (0.57%) patients had odontogenic complications. CONCLUSIONS: With conservative pre-HSCT dental treatment based on an infection risk classification system, a low odontogenic complication rate was observed.

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.

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.

A clinicopathologic study on SS18 fusion positive head and neck synovial sarcomas.

OBJECTIVE: To determine clinicopathologic factors on survival in patients with head and neck synovial sarcoma. PATIENTS AND METHODS: We retrospectively identified patients with molecularly confirmed synovial sarcomas of the head and neck (SS-HN), either by the presence of SS18-SSX fusion transcript by RT-PCR or SS18 gene rearrangement by FISH, who were managed at our institution over a 20-year period (1996-2015). Kaplan-Meier survival analysis and log-rank test were performed to evaluate variables related to disease specific survival (DSS). Fisher exact test was performed to evaluate variables related to local recurrence. RESULTS: Thirty-four patients (20 males and 14 females, mean of 31years) with SS18-SSX fusion-positive SS-HN were identified. The parapharyngeal region of the neck was the most common site. The mean tumor size was 4.8cm (0.8-10cm). Two-thirds (n=23) of cases had a monophasic histology. The 2, 5 and 10-year DSS rates were 97%, 79% and 68%. The 5-year DSS rates for the adult/pediatric cohort were 74%/88%. Recurrence showed significant effect on DSS (p=0.021). There was no significant effect on DSS with age, therapy modality, tumor site, surgical margin, tumor size (⩽5cm vs. >5cm) and histopathologic subtype. Tumor site (i.e. skull base/paranasal sinus region) was associated with local recurrence (p=0.003). CONCLUSION: In our cohort DSS rate was associated with recurrence. Tumors located in the skull base/paranasal sinus region were associated with a higher rate of local recurrence. Thus appropriate selection of high risk patients who can benefit from multimodality therapies might improve survival.

The prevalence and risk factors associated with osteoradionecrosis of the jaw in oral and oropharyngeal cancer patients treated with intensity-modulated radiation therapy (IMRT): The Memorial Sloan Kettering Cancer Center experience.

OBJECTIVE: To determine the prevalence and correlation of various risk factors [radiation dose, periodontal status, alcohol and smoking] to the development of osteoradionecrosis (ORN). PATIENTS AND METHODS: The records of 1023 patients treated with IMRT for oral cavity cancer (OCC) and oropharyngeal cancer (OPC) between 2004 and 2013 were retrospectively reviewed to identify patients who developed ORN. Fisher exact tests were used to analyze patient characteristics between ORN patients with OCC and OPC. Paired Wilcoxon tests were used to compare the dose volumes to the ORN and contralateral non-ORN sites. To evaluate an association between ORN and risk factors, a case-control comparison was performed. One to 2 ORN-free patients were selected to match each ORN patient by gender, tumor site and size. General estimation equations models were used to compare the risk factors in ORN cases and matched controls. RESULTS: 44 (4.3%) patients developed ORN during a median follow-up time of 52.5months. In 82% of patients, ORN occurred spontaneously. Patients with OPC are prone to develop ORN earlier compared to patients with OCC (P=0.03). OPC patients received a higher Dmax compared to OCC patients (P=0.01). In the matched case-control analysis the significant risk factors on univariate analysis were poor periodontal status, history of alcohol use and radiation dose (P=0.03, 0.002 and 0.009, respectively) and on multivariate analysis were alcohol use and radiation dose (P=0.004 and 0.026, respectively). CONCLUSION: In our study, higher radiation dose, poor periodontal status and alcohol use are significantly related to the risk of developing ORN.

Comparison of mean radiation dose and dosimetric distribution to tooth-bearing regions of the mandible associated with proton beam radiation therapy and intensity-modulated radiation therapy for ipsilateral head and neck tumor.

OBJECTIVE: The purpose of this study was to compare the dosimetric distribution of ipsilateral proton beam radiation therapy (PBRT) with intensity-modulated radiation therapy (IMRT) in the tooth-bearing region of the mandible in patients with head and neck cancer (HNC). STUDY DESIGN: The mandibular dosimetric distribution in patients with head and neck cancer treated with ≥60 Gy relative biologic equivalent PBRT was evaluated. The mean radiation doses were calculated in 5 regions: ipsilateral molar, ipsilateral premolar, anterior, contralateral premolar, and contralateral molar (CM) regions. CM was used as the reference region for comparative analysis. The mandibular dosimetric distribution in patients treated with PBRT was compared with that in IMRT patients with similar tumor sites and planning target volumes. RESULTS: The mean radiation dose to the contralateral regions was lower in patients treated with PBRT compared with those treated with IMRT. The average mean radiation doses to the reference region (CM) in patients treated with PBRT (relative biologic equivalent) versus IMRT were oropharynx (2.2 Gy vs 23.2 Gy; P < .00002), parotid (0 Gy vs 11.8 Gy; P = .01), and oral cavity (0.4 Gy vs 15.6 Gy; P = .006). CONCLUSIONS: This study revealed the effective tissue-sparing capability of PBRT compared with IMRT. Utilization of PBRT could translate to less radiation-related toxicity.

Pentoxifylline and tocopherol in the management of cancer patients with medication-related osteonecrosis of the jaw: an observational retrospective study of initial case series.

OBJECTIVE: Very few studies have evaluated the efficacy of pentoxifylline and tocopherol (PENT-E) in the management of medication-related osteonecrosis of the jaw (MRONJ), although some studies have shown the therapeutic and prophylactic benefit of PENT-E in the management of osteoradionecrosis. We report the outcomes of MRONJ managed with PENT-E in patients with metastatic bone disease or multiple myeloma. STUDY DESIGN: Seven patients diagnosed with established cases of refractory MRONJ caused by antiresorptive medications for the management of metastatic bone tumors or multiple myeloma were administered PENT-E for a mean period of 16.8 months (range 3-48 months). RESULTS: At the latest follow-up visit, all patients demonstrated relief of symptoms. There was radiographic evidence of new bone fill of prior radiolucent defect in all patients. Two patients had resolution of exposed bone, two patients had partial resolution, one patient had no change in exposed bone, and one patient with three sites of exposed bone before starting PENT-E had resolution in one site, partial resolution in another site, and no change in the third site. PENT-E was well tolerated in all patients. CONCLUSIONS: Our case series demonstrated that PENT-E was well tolerated and may be an effective adjunct in the management of MRONJ.

Objective assessment of trismus in oral and oropharyngeal cancer patients treated with intensity-modulated radiation therapy (IMRT).

PURPOSE: The aim of this study was to estimate the prevalence of trismus in oral and oropharyngeal cancer patients (OOPC) treated with intensity-modulated radiation therapy (IMRT) and to identify the role of risk factors in patients who developed trismus. MATERIALS AND METHODS: A retrospective cohort study of OOPC treated with IMRT in our institution from 2009 to 2014 was performed. Patients eligible for this study had pre-RT and post-RT maximal inter-incisal opening (MIO) measurements at 6-48 months post-RT, treated with high-dose radiation (≥60 Gy) and pre-RT MIO ≥36 mm. A descriptive analysis to identify the incidence of trismus, with trismus stated as MIO ≤35 mm at or after 6 months post-RT measurement was performed. The role of risk factors such as age, gender, tumor site, tumor size (T), tumor stage, pre-RT MIO measurements and radiation dose to the tumor were assessed using Fisher exact test and the radiation doses to the ipsilateral muscles of mastication in patients who developed trismus were assessed by matching with control (non-trismus) patients using Wilcoxon Signed Rank test. RESULTS: The study consisted of 54 patients with a median age of 55 years and 81% were males. The median follow-up time was 10 months. The prevalence of trismus was 14.8%. Patients with pre-RT MIO measurements ≤40 mm were at risk of developing trismus (P < 0.001). In trismus patients, the average mean radiation dose to the masseter and medial pterygoid muscles was numerically higher but not significantly different (P = 0.08; P = 0.22, respectively) to matched control patients. Age, gender, radiation dose to the tumor, tumor site, size (T) and stage were also found to be not significant. CONCLUSION: Pre-RT MIO measurement was a significant risk factor for the development of trismus. However, this is a non-modifiable factor. Limiting radiation dose to the muscles of mastication could prevent this complication.

Metastatic solid tumors to the jaw and oral soft tissue: A retrospective clinical analysis of 44 patients from a single institution.

PURPOSE: Metastatic solid tumors to the oral cavity are rare, frequently indicative of an end-stage disease process, and associated with poor survival rates. We performed a 20-year retrospective clinical analysis of our institution's cases of solid metastases to the oral cavity, and investigated these patients' clinical outcomes. MATERIAL AND METHODS: A retrospective study of patients with metastatic solid tumors to the oral cavity over a 20-year period (October 1996 to September 2015) was conducted at Memorial Sloan Kettering Cancer Center. Patients were selected if they had a histopathologically confirmed diagnosis. Demographic, pathologic, and clinical information were reviewed to identify patient outcomes. RESULTS: A total of 44 patients with metastatic non-melanocytic non-hematopoietic tumor to the oral cavity were identified: 24 males and 20 females (39 adults and 5 children) with a mean age of 54.3 years. In all, 24 cases involved the jaw and 20 cases involved the oral soft tissue. Eight patients (18.2%) had oral cavity metastases as the first indication of an occult malignancy. In adult patients, the common primary sites were the lungs (n = 9, 20%), kidney (n = 7, 16%), breast (n = 5, 11%), and colon (n = 4, 9%); and in pediatric patients the adrenal gland (3/5) was the most common site. Of the adult patients, 33 (84.6%) died of disease. From the time of metastasis diagnosis, patients with jaw metastases had a median and mean survival of 12 months and 27.7 months, respectively. In comparison, patients with oral soft tissue metastases had a median survival time of 5 months, and mean of 8 months. One pediatric patient (20%) died of disease 8 months after metastasis diagnosis. CONCLUSION: Metastatic solid tumors to the oral cavity can be the first sign of a malignancy. Pediatric patients with oral cavity metastases have a better prognosis compared to adult patients. In this series, adults with oral soft tissue involvement had shorter survival times compared to patients with jaw involvement.

Osteonecrosis of the jaw in patients treated with denosumab for metastatic tumors to the bone: A series of thirteen patients.

This case series describes the course of osteonecrosis of the jaw (ONJ) in thirteen patients with metastatic bone tumors treated solely with denosumab. Patients on denosumab may be more prone to developing ONJ even without a risk/precipitating factor and they may develop ONJ early in their denosumab therapy. The outcomes of ONJ in ten patients following a period of denosumab discontinuation after the onset of ONJ were: 3 had complete resolution of symptoms, 4 patients' ONJ progressed, 2 patients' ONJ was unchanged and in 1 patient there was partial ONJ resolution. The role of drug discontinuation prior to an invasive dental procedure or after the onset of ONJ still remains debatable.

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.