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.

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.

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.

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.

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.

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.

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.

Image-based Data Mining to Probe Dosimetric Correlates of Radiation-induced Trismus.

PURPOSE: To identify imaged regions in which dose is associated with radiation-induced trismus after head and neck cancer radiation therapy (HNRT) using a novel image-based data mining (IBDM) framework. METHODS AND MATERIALS: A cohort of 86 HNRT patients were analyzed for region identification. Trismus was characterized as a continuous variable by the maximum incisor-to-incisor opening distance (MID) at 6 months after radiation therapy. Patient anatomies and dose distributions were spatially normalized to a common frame of reference using deformable image registration. IBDM was used to identify clusters of voxels associated with MID (P ≤ .05 based on permutation testing). The result was externally tested on a cohort of 35 patients with head and neck cancer. Internally, we also performed a dose-volume histogram-based analysis by comparing the magnitude of the correlation between MID and the mean dose for the IBDM-identified cluster in comparison with 5 delineated masticatory structures. RESULTS: A single cluster was identified with the IBDM approach (P < .01), partially overlapping with the ipsilateral masseter. The dose-volume histogram-based analysis confirmed that the IBDM cluster had the strongest association with MID, followed by the ipsilateral masseter and the ipsilateral medial pterygoid (Spearman's rank correlation coefficients: Rs = -0.36, -0.35, -0.32; P = .001, .001, .002, respectively). External validation confirmed an association between mean dose to the IBDM cluster and MID (Rs = -0.45; P = .007). CONCLUSIONS: IBDM bypasses the common assumption that dose patterns within structures are unimportant. Our novel IBDM approach for continuous outcome variables successfully identified a cluster of voxels that are highly associated with trismus, overlapping partially with the ipsilateral masseter. Tests on an external validation cohort showed an even stronger correlation with trismus. These results support use of the region in HNRT treatment planning to potentially reduce trismus.

Parotid gland fat related Magnetic Resonance image biomarkers improve prediction of late radiation-induced xerostomia.

PURPOSE: This study investigated whether Magnetic Resonance image biomarkers (MR-IBMs) were associated with xerostomia 12 months after radiotherapy (Xer12m) and to test the hypothesis that the ratio of fat-to-functional parotid tissue is related to Xer12m. Additionally, improvement of the reference Xer12m model based on parotid gland dose and baseline xerostomia, with MR-IBMs was explored. METHODS: Parotid gland MR-IBMs of 68 head and neck cancer patients were extracted from pre-treatment T1-weighted MR images, which were normalized to fat tissue, quantifying 21 intensity and 43 texture image characteristics. The performance of the resulting multivariable logistic regression models after bootstrapped forward selection was compared with that of the logistic regression reference model. Validity was tested in a small external cohort of 25 head and neck cancer patients. RESULTS: High intensity MR-IBM P90 (the 90th intensity percentile) values were significantly associated with a higher risk of Xer12m. High P90 values were related to high fat concentration in the parotid glands. The MR-IBM P90 significantly improved model performance in predicting Xer12m (likelihood-ratio-test; p = 0.002), with an increase in internally validated AUC from 0.78 (reference model) to 0.83 (P90). The MR-IBM P90 model also outperformed the reference model (AUC = 0.65) on the external validation cohort (AUC = 0.83). CONCLUSION: Pre-treatment MR-IBMs were associated to radiation-induced xerostomia, which supported the hypothesis that the amount of predisposed fat within the parotid glands is associated with Xer12m. In addition, xerostomia prediction was improved with MR-IBMs compared to the reference model.

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 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.

The role of parotid gland irradiation in the development of severe hyposalivation (xerostomia) after intensity-modulated radiation therapy for head and neck cancer: Temporal patterns, risk factors, and testing the QUANTEC guidelines.

BACKGROUND: The aims of this study were to investigate temporal patterns and potential risk factors for severe hyposalivation (xerostomia) after intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC), and to test the two QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) guidelines. PATIENTS AND METHODS: Sixty-three patients treated at the Memorial Sloan Kettering Cancer Center between 2006 and 2015, who had a minimum of three stimulated whole mouth saliva flow measurements (WMSFM) at a median follow-up time of 11 (range: 3-24) months were included. Xerostomia was defined as WMSFM ≤25% compared to relative pre-radiotherapy. Patients were stratified into three follow-up groups: 1: <6 months; 2: 6-11 months; and 3: 12-24 months. Potential risk factors were investigated (Mann-Whitney U test), and relative risks (RRs) assessed for the two QUANTEC guidelines. RESULTS: The incidence of xerostomia was 27%, 14% and 17% at follow-up time points 1, 2 and 3, respectively. At <6 months, the mean dose to the contralateral and the ipsilateral parotid glands (Dmeancontra, Dmeanipsi) was higher among patients with xerostomia (Dmeancontra: 25 Gy vs. 15 Gy; Dmeanipsi: 44 Gy vs. 25 Gy). Patients with xerostomia had higher pre-RT WMSFM (3.5 g vs. 2.4 g), and had been treated more frequently with additional chemotherapy (93% vs. 63%; all 4 variables: p < 0.05). At 6-11 months, Dmeancontra among patients with xerostomia was higher compared to patients without (26 Gy vs. 20 Gy). The RR as specified by the one- and two-gland QUANTEC guideline was 2.3 and 1.4 for patients with <6 months follow-up time, and 2.0 and 1.2 for patients with longer follow-up (6-11 + 6-24 months). CONCLUSION: Xerostomia following IMRT peaks within six months post-radiotherapy and fades with time. Limiting the mean dose to both parotid glands (ipsilateral <25 Gy, contralateral <25 Gy) and reducing the use of chemotherapy will likely decrease the rate of xerostomia. Both QUANTEC guidelines are effective in preventing xerostomia.

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.