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OBJECTIVE Stereotactic radiosurgery (SRS) treats severe, medically refractory essential tremor and tremor-dominant Parkinson disease. However, the optimal target for SRS treatment within the thalamic ventral intermediate nucleus (VIM) is not clearly defined. This work evaluates the precision of the physician-selected VIM target, and determines the optimal SRS target within the VIM by correlation between early responders and nonresponders. METHODS Early responders and nonresponders were assessed retrospectively by Elements Basal Ganglia Atlas autocontouring of the VIM on the pre–SRS-treatment 1-mm slice thickness T1-weighted MRI and correlating the center of the post–SRS-treatment lesion. Using pre- and posttreatment diffusion tensor imaging, the fiber tracking package in the Elements software generated tremor-related tracts from autosegmented motor cortex, thalamus, red nucleus, and dentate nucleus. Autocontouring of the VIM was successful for all patients. RESULTS Among 23 patients, physician-directed SRS targets had a medial–lateral target range from +2.5 mm to −2.0 mm from the VIM center. Relative to the VIM center, the SRS isocenter target was 0.7–0.9 mm lateral for 6 early responders and 0.9–1.1 mm medial for 4 nonresponders (p = 0.019), and without differences in the other dimensions: 0.2 mm posterior and 0.6 mm superior. Dose–volume histogram analyses for the VIM had no significant differences between responders and nonresponders between 20 Gy and 140 Gy, mean or maximum dose, and dose to small volumes. Tractography data was obtained for 4 patients. CONCLUSIONS For tremor control in early responders, the Elements Basal Ganglia Atlas autocontour for the VIM provides the optimal SRS target location that is 0.7–0.9 mm lateral to the VIM center.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Demographic and expression data

Supplementary Figure 1 from Gene Expression Differences Associated with Human Papillomavirus Status in Head and Neck Squamous Cell Carcinoma

Human papillomavirus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC). Between 15% and 35% of HNSCCs harbor HPV DNA. Demographic and exposure differences between HPV-positive (HPV+) and negative (HPV−) HNSCCs suggest that HPV+ tumors may constitute a subclass with different biology, whereas clinical differences have also been observed. Gene expression profiles of HPV+ and HPV− tumors were compared with further exploration of the biological effect of HPV in HNSCC. Thirty-six HNSCC tumors were analyzed using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV by PCR and real-time PCR. Eight of 36 (22%) tumors were positive for HPV subtype 16. Statistical analysis using Significance Analysis of Microarrays based on HPV status as a supervising variable resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a subset of these genes were verified by real-time PCR. Genes highly expressed in HPV+ samples included cell cycle regulators (p16INK4A, p18, and CDC7) and transcription factors (TAF7L, RFC4, RPA2, and TFDP2). The microarray data were also investigated by mapping genes by chromosomal location (DIGMAP). A large number of genes on chromosome 3q24-qter had high levels of expression in HPV+ tumors. Further investigation of differentially expressed genes may reveal the unique pathways in HPV+ tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment.

Supplementary Table 2 from Gene Expression Profiles Identify Epithelial-to-Mesenchymal Transition and Activation of Nuclear Factor-κB Signaling as Characteristics of a High-risk Head and Neck Squamous Cell Carcinoma

Supplementary Table 1 from Gene Expression Profiles Identify Epithelial-to-Mesenchymal Transition and Activation of Nuclear Factor-κB Signaling as Characteristics of a High-risk Head and Neck Squamous Cell Carcinoma

Gene expression signatures generated from DNA microarray analyses have shown promise as predictive biomarkers of clinical outcome. In this study, we determined a high-risk signature for disease recurrence using formalin-fixed head and neck squamous cell carcinoma (HNSCC) tumors and compared the results with an independent data set obtained from fresh frozen tumors. We also showed that genes involved in epithelial-to-mesenchymal transition (EMT) and nuclear factor-κB (NF-κB) signaling deregulation are the most prominent molecular characteristics of the high-risk tumors. Gene expression was determined in 40 samples, including 34 formalin-fixed tissues and 6 matched frozen tissues, from 29 HNSCC patients. A 75-gene list predictive of disease recurrence was determined by training on the formalin-fixed tumor data set and tested on data from the independent frozen tumor set from 60 HNSCC patients. The difference in recurrence-free survival (RFS) between the high-risk versus low-risk groups in the training and test sets was statistically significant (P = 0.002 and 0.03, respectively, log-rank test). In addition, the gene expression data was interrogated using Gene Set Enrichment Analysis to determine biological significance. The most significant sets of genes enriched in the high-risk tumors were genes involving EMT, NF-κB activation, and cell adhesion. In conclusion, global gene expression analysis is feasible using formalin-fixed tissue. The 75-gene list can be used as a prognostic biomarker of recurrence, and our data suggest that the molecular determinants of EMT and NF-κB activation can be targeted as the novel therapy in the identified high-risk patients. (Cancer Res 2006; 66(16): 8210-8)

BACKGROUND As gross total resection of jugular paragangliomas (JPs) may result in cranial nerve deficits, JPs are increasingly managed with subtotal resection (STR) with postoperative radiological monitoring. However, the validity of commonly used diameter-based models that calculate postoperative volume to determine residual tumor growth is dubious. The purpose of this study was to assess the accuracy of these models compared to manual volumetric slice-by-slice segmentation. METHODS A senior neuroradiologist measured volumes via slice-by-slice segmentation of JPs pre- and postoperatively from patients who underwent STR from 2007 to 2019. Volumes from three linear-based models were calculated. Models with absolute percent error (APE) > 20% were considered unsatisfactory based on a common volumetric definition for residual growth. Bland-Altman plots were used to evaluate reproducibility, and Wilcoxon matched-pairs signed rank test evaluated model bias. RESULTS Twenty-one patients were included. Median postoperative APE exceeded the established 20% threshold for each of the volumetric models as cuboidal, ellipsoidal, and spherical model APE were 63%, 28%, and 27%, respectively. The postoperative cuboidal model had significant systematic bias overestimating volume (p = 0.002) whereas the postoperative ellipsoidal and spherical models lacked systematic bias (p = 0.11 and p = 0.82). CONCLUSION Cuboidal, ellipsoidal, and spherical models do not provide accurate assessments of postoperative JP tumor volume and may result in salvage therapies that are unnecessary or inappropriately withheld due to inaccurate assessment of residual tumor growth. While more time-consuming, slice-by-slice segmentation by an experienced neuroradiologist provides a substantially more accurate and precise measurement of tumor volume that may optimize clinical management.

OBJECTIVES 1: Describe subacute facial nerve paralysis after salvage stereotactic radiosurgery (SRS). 2: To analyze predictors of facial nerve weakness after dual modality treatment. PATIENTS Adult patients with Vestibular Schwannoma who underwent sub-total resection (STR) followed by salvage radiation. INTERVENTIONS Microsurgical resection of VS, stereotactic radiosurgery, intensity-modulated radiotherapy, proton radiotherapy. MAIN OUTCOME MEASURES Serial facial nerve function (House-Brackmann scale). RESULTS Thirteen patients who underwent dual modality treatment for large VS were included (mean age = 43.6 years, 77% females). The mean pre-operative tumor volume was 11.7 cm3 (SD = 6.5) and the immediate mean post-operative remnant volume was 1.5 cm3 (SD = 1.4) with a mean extent of resection of 86.7% (SD = 9.5). The mean salvage-free interval was 20.8 months (SD = 13.3). All patients had excellent one-year FN outcome (HB grade 1, 2) after resection. Three patients developed subacute facial nerve weakness after salvage SRS (4.2-9.4 months after SRS). This paralysis responded to high dose systemic steroids and no surgical interventions for facial rehabilitation were required. At last follow up (mean 61.6 months, SD = 28.5), facial nerve function was favorable (HB grade 1-2 in 12 patients and HB grade 3 in 1 patient). There were no significant associations between various predictors and subacute deterioration of facial nerve function after SRS. CONCLUSIONS Sub-acute transient facial nerve dysfunction can develop infrequently over a variable time frame after post-operative salvage SRS and usually responds to steroids. Patients should be adequately counseled about potential of transient deterioration of facial nerve function after salvage SRS.

Background Radiation for patients with head and neck cancer (HNC) is associated with painful mucositis that impacts the delivery of treatment and contributes to high symptom burden. Methods This was a prospective, randomized pilot trial. Eligible patients received primary or adjuvant chemoradiation. Patients were randomized to usual care vs usual care plus gabapentin titrated to drug tolerance during radiation. Patients completed a symptom survey at baseline and weekly during therapy. Results Seventy-nine patients were enrolled in the study (38 control, 41 treatment). At interim analysis, gabapentin use resulted in a decrease in pain (P = .004), with the biggest decreases being in the latter weeks of therapy. By week 7, the median pain score in the treatment group was below the 0.25 quantile of the control group. Conclusion Prophylactic use of gabapentin during chemoradiation for HNC patients resulted in a decrease in pain, neurosensory symptoms, and general systemic symptoms.

Management of jugular paragangliomas (PGL) has evolved toward subtotal resection (STR). The purpose of this study is to analyze neural preservation and adjuvant treatment for long-term local control.Retrospective chart review.Tertiary neurotology practice.Adults undergoing surgical treatment of jugular PGL between 2006 and 2019. Patients, disease, and treatment variables were collected retrospectively. Single predictor logistic regression was used to ascertain predictors of regrowth or need for salvage radiation.A total of 41 patients (median age, 47 years; 76% female) were identified. Most patients presented with advanced-stage disease (Glasscock-Jackson stage III-IV = 76%). Subtotal resection (STR) was performed in 32 (78%) patients. Extended STR (type 1) was the most commonly performed conservative procedure (n = 19, 59%). Postoperative new low cranial neuropathy (LCN) involving CN X and XII was rare (n = 3 and n = 1, respectively). Seventeen patients (41%) underwent postsurgical therapy for tumor regrowth or recurrence, including 15 patients who underwent adjuvant (n = 4) or salvage (n = 11) radiation. Overall tumor control of 94.7% was achieved at a mean follow-up of 35 months. All patients treated with combined modality treatment had local control at last follow-up. Logistic regression identified no single predictor for postsurgical radiation treatment or salvage-free survival.Management of jugular PGL with a conservative approach is safe and effective with a low rate of new LCN deficit. Active surveillance of residual tumor with salvage radiation for growth results in excellent long-term tumor control.

Objective Local failure of incompletely resected vestibular schwannoma (VS) following salvage stereotactic radiosurgery (SRS) using standard doses of 12 to 13 Gy is common. We hypothesized that dose-escalated SRS, corrected for biologically effective dose, would have superior local control of high-grade VS progressing after subtotal or near-total resection compared with standard-dose SRS.Design Retrospective cohort study.Setting Tertiary academic referral center.Participants Adult patients treated with linear accelerator-based SRS for progressive VS following subtotal or near-total resection.Main Outcome Measures Dose-escalated SRS was defined by a biologically effective dose exceeding a single-fraction 13-Gy regimen. Study outcomes were local control and neurologic sequelae of SRS. Binary logistic regression was used to evaluate predictors of study outcomes.Results A total of 18 patients with progressive disease following subtotal (71%) and near-total (39%) resection of Koos grade IV disease (94%) were enrolled. Of the 18 patients, 7 were treated with dose-escalated SRS and 11 with standard-dose SRS. Over a median follow-up of 32 months after SRS, local control was 100% in the dose-escalated cohort and 91% in the standard-dose cohort (p = 0.95). Neurologic sequelae occurred in 28% of patients, including 60% of dose-escalated cohort and 40% of the standard-dose cohort (p = 0.12), although permanent neurologic sequelae were low at 6%.Conclusions Dose-escalated SRS has similar local control of recurrent VS following progression after subtotal or near-total resection and does not appear to have higher neurologic sequalae. Larger studies are needed.

Refractory functional pituitary adenomas are often treated with single-session stereotactic radiosurgery (SRS) or conventionally fractionated intensity-modulated radiotherapy (IMRT). While single-fraction SRS offers convenience and short time to biochemical remission, large tumors with cranial nerve or chiasmatic involvement often preclude single-fraction SRS, and toxicity may be worse following single-fraction SRS compared with IMRT. The purpose of our study was to explore the long-term outcomes of a unique hypofractionated stereotactic radiotherapy (HSRT) regimen delivered in 2–5 fractions. After approval, we studied 16 consecutive patients treated with HSRT for refractory functional pituitary adenoma. Study endpoints included local control, biochemical control, and toxicity. Descriptive statistics summarized endpoints and clinicopathologic factors. Sixteen patients with adrenocorticotropic hormone secretion (n = 9, 56%), growth hormone secretion (n = 4, 25%), and prolactin secretion (n = 3, 19%) were studied with a median follow-up time after HSRT of 10 years (IQR 2–14 years). Patients were treated with two (n = 8), three (n = 1), or five (n = 7) fractions to median dose of 20.5 Gy (range 16–32 Gy). HSRT was well-tolerated with no acute side effects greater than CTCAE grade 1. Local control was 100%, and biochemical control at last follow-up was 58%. Over 142 years patient-years, no instances of optic neuropathy, secondary malignancy, malignant transformation, radionecrosis, cavernous sinus cranial neuropathy, or cerebrovascular complications were noted. HSRT for refractory pituitary adenoma is well-tolerated with long-term local and biochemical control comparable with single-fraction SRS or IMRT. Prospective studies should evaluate whether HSRT provides non-inferior biochemical control and improved toxicity compared with single-fraction SRS.

Objective To report and discuss the effectiveness of stereotactic radiosurgery (SRS) or fractionated radiotherapy (FRT) for tumor control following surgical resection of endolymphatic sac tumors (ELST). Study design Retrospective case series. Setting Multi-institutional academic referral centers. Patients Patients undergoing surgical resection for ELST followed by SRS or FRT. Intervention(s) Surgical resection followed by radiotherapy. Main outcome measures Local tumor control. Results Two of the five patients experienced tumor recurrence after gross total microsurgical at 78 and 11 months, respectively. The former patient received salvage 3D conformal radiotherapy (3D-CRT) and while the latter patient underwent three courses of salvage SRS for recurrence, two of which were in-field and was disease-free at last follow up. Two additional patients underwent subtotal tumor resection (STR) followed by intensity-modulated radiation therapy (IMRT) and are currently without disease. One patient underwent STR followed by proton-beam therapy (PBT) and was free of disease at most recent follow-up. Conclusion SRS/FRT remains a useful adjuvant for treatment of residual or recurrent ELSTs, where the risk of revision microsurgical resection is high.

OBJECTIVE Accurate volume assessment is essential for the management of vestibular schwannoma after stereotactic radiosurgery (SRS). A cuboidal approximation for volume is the standard surveillance method; however, this may overestimate tumor volume. We sought to evaluate several volumetric models and their suitability for post-SRS surveillance. STUDY DESIGN Retrospective cohort study. SETTING Tertiary referral center. PATIENTS We evaluated 54 patients with vestibular schwannoma before and after SRS. INTERVENTION(S) Gold-standard volumes were obtained by a radiation oncologist using contouring software. Volume was also calculated by cuboidal, ellipsoidal, and spherical formulae using tumor diameters obtained by a neuroradiologist. MAIN OUTCOME MEASURE(S) Percent error (PE) and absolute percent error (APE) were calculated. Paired t test evaluated bias, and the Bland-Altman method evaluated reproducibility. Linear regression evaluated predictors of model error. RESULTS All models overestimated volume compared with the gold standard. The cuboidal model was not reproducible before SRS (p

Effective treatment options for refractory depression are needed. Recent advancements permit both precise ablative radiation and functional neurologic connectome analysis using standard magnetic resonance imaging. We combined these innovations to perform stereotactic radiosurgical capsulotomy for the treatment of medically refractory major depressive disorder and study connectome response using a novel tractography-based approach.Patients with medically refractory depression were enrolled on a prospective pilot single-arm observational trial from 2020 to 2021 at a single academic tertiary referral center. Bilateral ablation of the anterior limb of the internal capsule was accomplished by mask-based linear accelerator stereotactic radiosurgery. Beck's Depression Inventory measured efficacy. Montreal Cognitive Assessment evaluated cognition.Three patients were enrolled. Depression burden was improved by 88% at 12-month follow-up and by 55% at 18-month follow-up for patient 1 and 2, respectively. Patient 1 discontinued ketamine therapy, and patient 2 discontinued electroconvulsive therapy. Patient 3 reported global improvement in symptoms and function at 3 months. All 3 patients had reduction or resolution of suicidal ideation. No patient experienced cognitive decline or neurologic toxicity, and Montreal Cognitive Assessment score, as well as subjective patient-reported evaluations of concentration and attention, were superior after treatment. Tractography confirmed intended disruption of the cortico-striatal-thalamo-cortical loop with structural reorganization in the connectome. Connectome change was consistent between patients. Observed increases in caudate and putamen connectivity and decreases in thalamic connectivity may explain improved concentration, attention, and depression. The diversity and magnitude of connectome change may correlate with degree of clinical response.In 3 patients with refractory depression, radiosurgical capsulotomy significantly reduced the burden of depression. Functional connectome reorganization offers neurobiological evidence to support further investigations of the role of radiosurgery in depression.

Objective To analyze local control (LC) and toxicity rates between stereotactic radiosurgery (SRS) and intensity-modulated radiotherapy (IMRT) in relation to reported surgical rates in the treatment of paragangliomas (PG) in the upfront, adjuvant, and salvage settings, and to explore factors affecting tumor size reduction, toxicity rates, and symptom control. Study design Retrospective cohort analysis. Setting Tertiary referral center. Patients and interventions Thirty patients treated with either linear accelerator-based SRS or IMRT in the definitive, planned adjuvant, or unplanned salvage postsurgery settings. Main outcome measures Local control, toxicities, symptom control, tumor size reduction, and factors affecting each. Results Median follow-up was 4.16 years. LC rates were 100%. Acute grade >3 toxicity rate was 6.7%, 86.7% of tumors had a reduction in volume, and 76.7% of patients had improvement in at least one tumor-induced symptom by last follow-up. Larger tumor size at presentation and longer time to last follow-up were significantly associated with greater tumor size reduction on multivariate analysis. Conclusions SRS and IMRT are safe and effective treatment for PG with high efficacy and low morbidity rates in the upfront, planned adjuvant, and unplanned salvage settings.

Objective We sought to determine whether a more widely accessible, non-invasive frameless approach to radiosurgical thalamotomy would improve objective measures of refractory essential or parkinsonian tremor without added toxicity compared to reports of frame-based radiosurgery. Methods We conducted a single-arm pilot observational prospective trial of adult patients with essential or parkinsonian tremor from 2013 to 2019 and report results at one-year follow-up. Patients were treated with frameless unilateral radiosurgical ablation of the thalamic ventral intermediate nucleus to a maximum dose of 160 Gy. Treatment response was measured by the Fahn-Tolosa-Marin (FTM) tremor rating scale and the Quality of Life in Essential Tremor or Parkinson's Disease Questionnaire obtained prior to treatment and at 3, 6, 9, and 12 months. Results Thirty-three patients, including 23 with essential tremor and 10 with Parkinson's disease, were enrolled. Overall treatment response rate per FTM was 83% (n=15/18) at 6 months. There was a marked improvement in tremor, with average total FTM reduction of 21% at 3 months (from 46 to 30 points, p=0.003) and 41% at 6 months (from 46 to 24 points, p=0.001). At 6 months, functional decline had regressed by 54% (from 15 to 7 points, p=0.001). Quality of life improved by 57% (p=0.001) at 6 months in patients with essential tremor, and patients with Parkinson's Disease had unchanged quality of life. At one-year follow-up, grade 2 neurologic adverse events were observed in 6% (n=2/33) of patients without any grade ≥ 3 events. Conclusion Noninvasive, frameless radiosurgical thalamotomy may be a feasible treatment for patients with refractory tremor and demonstrates short-term safety at one-year follow-up. This pilot study provides promising preliminary descriptions of efficacy, and definitive estimates of long-term safety and benefit require further study with longer follow-up.

Electroconvulsive therapy (ECT) is a treatment option for a number of psychiatric disorders, including refractory major depression and obsessive compulsive disorder. There are no known structural sequelae of ECT. Here we present a patient with severe refractory obsessive compulsive disorder and major depression treated over 2 years with ECT every 2 weeks. Planning magnetic resonance imaging intended for a potential procedural intervention for her psychiatric disease incidentally demonstrated a new area of increased enhancement and loss of marrow signal within the right frontal bone. Imaging findings were suggestive of underlying bone marrow or bone changes, although there was no evidence of bone destruction on bone-windowed computed tomography (CT) and there was no uptake on nuclear bone scan. The CT chest/abdomen/pelvis were also reassuring that this did not represent metastatic disease, and findings were unchanged on repeat magnetic resonance imaging 4 months later. Thus, this area corresponded to the site directly underlying the unilateral ECT electrode placement, suggestive of never-before described ECT-induced hyperemia. We report for the first time that frequent, chronic ECT may induce asymptomatic skull bone marrow hyperemia with radiologic findings. This appears to be a direct consequence of electrical current leading to chronic inflammatory and edematous marrow replacement. Electroconvulsive therapy should be added to the neuroradiological differential diagnosis of calvarial enhancement and loss of marrow signal. Psychiatrists should counsel patients on the possibility of this rare radiological finding, which may be confused for other processes.

Purpose Lymphedema and fibrosis (LEF) are common yet overlooked late effects of head and neck cancer and its therapy. Lack of reliable and valid measures of head and neck LEF is a critical barrier to the timely identification and management of head and neck LEF. To fill this gap, we developed and pilot tested a 64-item patient-reported outcome measure ( Lymphedema Symptom Intensity and Distress Survey-Head and Neck, LSIDS-H&N). This article aims to report the process of further validation and refinement of the tool. Methods and Materials A prospective, longitudinal study was conducted, and 120 patients with oral cavity and oropharyngeal cancer were recruited. Participants completed the LSIDS-H&N at pretreatment, end of treatment, and every 3 months up to 12 months after treatment. SAS PROC VARCLUS was used to generate preliminary clusters of item responses. Internal consistency of the item responses within each cluster was assessed using Cronbach’s alpha. Results A total of 117 patients completed the study. The participants reported that the LSIDS-H&N was easy to understand and captured their symptoms and medical conditions. However, >50% of participants indicated that the survey was burdensome due to length. Thus, we proceeded with item reduction, and the shortened tool (33-item) was named Head and Neck Lymphedema and Fibrosis Symptom Inventory (HN-LEF Symptom Inventory). The subsequent exploration of symptom clusters identified 7 symptom domain clusters (eg, soft tissue and neurologic toxicity), all of which demonstrated good internal consistency. Conclusions The HN-LEF Symptom Inventory has been carefully developed and refined to allow clinicians and researchers to capture LEF-associated symptom burden and function impairments. Additional rigorous psychometric testing of the tool is ongoing to further validate the strength and internal validity of this tool.

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

Background We conducted a correlative study for E2399, a function preservation trial for resectable locally advanced oropharynx and larynx cancer, to prospectively assess effects of chemoradiation (CCR) on quality of life (QOL), swallowing and voice. We correlated the results of swallow assessments done via questionnaires and objective assessments by modified barium swallow (MBS). Methods The Functional Assessment of Cancer-HN (FACT-HN), the Performance Status Scale – Head and Neck (PSS-HN), swallow assessments (including modified barium swallow studies), and voice assessments: Voice Handicap Index (VHI), the Voice Disability Assessment (VDA), and American Speech-Language Hearing Association’s Functional Communication Measure (FCM) were conducted at baseline and periodically post-treatment for 2 years. Results Baseline QOL and swallowing function predicted overall survival. Patients experienced a marked decrease in QOL, swallowing, and speech post CCR although the decrease in vocal function was modest. Function and QOL returned towards baseline in the majority of patients by 12 months post treatment. Less than 10% of patients had severe dysphagia and were PEG dependent at 12 months post treatment. There was a high degree of correlation between the FACT-HN and PSS-HN swallow items. Statistically significant correlations were found between subjective and objective measures of swallow function. Conclusions Patients experience marked loss in swallowing function post CCR which returned to baseline in the majority of patients. The correlations between the FCM and self-report swallow items on the PSS and FACT-HN appear to be sufficiently strong to justify their use as a surrogate marker for swallowing disability in large therapeutic trials.

Stereotactic radiosurgery (SRS) is used as a noninvasive treatment option for patients with trigeminal neuralgia (TN), but the effect of obesity on pain relief post SRS, if any, is unknown. The primary goal of our study was to evaluate the association between obesity and response to SRS in patients with TN. We conducted an IRB-approved retrospective review of patients treated with SRS for TN between 2010 and 2017. Barrow Neurologic Institute (BNI) Score was assigned pre-and post-SRS to quantify pain level. Thirty-two patients (65% female) between the ages of 24 and 96 were studied with a median follow-up time of 11 months. Patients with BMI >25 were significantly less likely to have improvement in their symptoms with SRS (p = 0.005). Elevated BMI may be associated with worsened response to SRS in the treatment of TN.

Radiation-associated malignancy and malignant transformation are risks associated with stereotactic radiosurgery (SRS); however, incidence is uncertain. The purpose of our study is to present the rate of radiation-associated malignancy and malignant transformation at our institution. After IRB approval, we undertook a retrospective cohort study evaluating patients treated with Gamma Knife® or linac-based SRS between 1990 and 2014 for benign CNS pathology with at least 5 years of clinical follow-up. Risk of transformation was calculated using the Kaplan-Meier method. A total of 273 patients met selection criteria. Median clinical follow-up after SRS was 11 years (range 5-27). Over 3,216 patient-years following SRS, we found zero cases of radiation-associated malignancy and two cases of radiation-associated malignant transformation for a crude rate of 0.73% or case rate of 0.62 per 1,000 patient-years. The Kaplan-Meier risk of malignant transformation at 5, 10, and 15 years was 0.4% (95% CI 0.05% 2.6%). These data support the continued use of SRS for benign intracranial pathology without significant concern for secondary malignancy.

Radiation dermatitis during radiotherapy is correlated with skin dose and is a common clinical problem for head and neck and thoracic cancer patients. Therefore, accurate prediction of skin dose during treatment planning is clinically important. The objective of this study is to evaluate the accuracy of skin dose calculated by a commercial treatment planning system (TPS). We evaluated the accuracy of skin dose calculations by the anisotropic analytical algorithm (AAA) implemented in Varian Eclipse (V.11) system. Skin dose is calculated as mean dose to a contoured structure of 0.5 cm thickness from the surface. The EGSnrc Monte Carlo (MC) simulations are utilized for the evaluation. The 6, 10 and 15 MV photon beams investigated are from a Varian TrueBeam linear accelerator. The accuracy of the MC dose calculations was validated by phantom measurements with optically stimulated luminescence detectors. The calculation accuracy of patient skin doses is studied by using CT based radiotherapy treatment plans including 3D conformal, static gantry IMRT, and VMAT treatment techniques. Results show the Varian Eclipse system underestimates skin doses by up to 14% of prescription dose for the patients studied when external body contour starts at the patient's skin. The external body contour is used in a treatment planning system to calculate dose distributions. The calculation accuracy of skin dose with Eclipse can be considerably improved to within 4% of target dose by extending the external body contour by 1 to 2 cm from the patient's skin. Dose delivered to deeper target volumes or organs at risk are not affected. Although Eclipse treatment planning system has its limitations in predicting patient skin dose, this study shows the calculation accuracy can be considerably improved to an acceptable level by extending the external body contour without affecting the dose calculation accuracy to the treatment target and internal organs at risk. This is achieved by moving the calculation entry point away from the skin.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1-4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1-4 brain metastases from solid malignancies. Sorafenib was begun 5-7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.

Purpose To report on radiosurgery delivery positioning accuracy in the treatment of tremor patients with frameless image guided radiosurgery using the linear accelerator (LINAC) based ExacTrac system and to describe quality assurance (QA) procedures used. Methods and materials Between 2010 and 2015, 20 patients underwent radiosurgical thalamotomy targeting the ventral intermediate nucleus for the treatment of severe tremor. The median prescription dose was 140 Gy (range, 120-145 Gy) in a single fraction. The median maximum dose was 156 Gy (range, 136-162 Gy). All treatment planning was performed with the iPlan system using a 4-mm circular cone with multiple arcs. Before each treatment, QA procedures were performed, including the imaging system. As a result of the extremely high dose delivered in a single fraction, a well-defined circular mark developed on the posttreatment magnetic resonance imaging (MRI). Eight of these 20 patients were selected to evaluate treatment localization errors because their circular marks were available in posttreatment MRI. In this study, the localization error is defined as the distance between the center of the intended target and the center of the posttreatment mark. Results The mean error of distance was found to be 1.1 mm (range, 0.4-1.5 mm). The mean errors for the left-right, anteroposterior, and superoinferior directions are 0.5 mm, 0.6 mm, and 0.7 mm, respectively. Conclusions The result reported in this study includes all tremor patients treated at our institution when their posttreatment MRI data were available for study. It represents a direct confirmation of target positioning accuracy in radiosurgery with a LINAC-based frameless system and its limitations. This level of accuracy is only achievable with an appropriate QA program in place for a LINAC-based frameless radiosurgery system.

Purpose Human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ≤ 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and ≤ 10 pack-year smoking history who were treated with ≤ 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.

Objectives Hypofractionated stereotactic radiotherapy (HSRT) in two to five fractions may offer patients with large nonfunctioning pituitary adenomas (NFPAs) with chiasm involvement a safe and effective treatment over a single week. However, little has been reported regarding this novel approach. Design We compared the feasibility, outcomes, and toxicity of single-fraction stereotactic radiosurgery and HSRT. Setting This study was conducted at a tertiary academic referral center. Participants After approval by the institutional review board, we performed a retrospective cohort study of patients treated at our institution with stereotactic radiosurgery (SRS) and HSRT for NFPA. Selection for SRS or HSRT was based on clinicopathologic factors including tumor size and cavernous sinus invasion at the discretion of the treating physician. Main Outcome Measures Local control, endocrinopathy, and radiation-associated toxicity were evaluated by binary logistic regression and Cox's proportional hazards regression. Results A total of 45 patients with mean follow-up of 5 years were enrolled including 26 patients treated by HSRT with mean follow-up of 3 years and 19 patients treated by SRS with median follow-up of 6 years. Clinicopathologic characteristics were balanced between cohorts. Local failure at last follow-up was 5% in the SRS cohort and 8% in the HSRT cohort, and rates of post-SRS endocrinopathy were similar between each cohort. Late complications including radionecrosis, visual deficit, and secondary malignancy were minimal in either cohort. Conclusions HSRT is an appropriate treatment strategy for patients with NFPAs, particularly for optic pathway preservation in the setting of large tumors with chiasm involvement. Further studies are needed to optimize fractionated approaches and patient selection.

Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing’s disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS. After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing’s disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes. Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort. HSRT is an appropriate treatment approach for refractory Cushing’s disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.

Background Stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVMs) is well-established. Radiographic advantages exist for 3-dimensional rotational digital subtraction angiography (3DRA) over 2-dimensional digital subtraction angiography (2D DSA) in delineating AVM nidus structure for SRS treatment planning. However, currently there is limited to no data directly comparing 2D DSA versus 3DRA in terms of patient outcomes. Objective To investigate whether the use of 3DRA over 2D DSA in radiosurgical treatment planning for AVMs associates with improved clinical outcomes. Methods All AVM patients treated with SRS at our institution between the years 2000 and 2018 were identified. Primary outcomes were obliteration rates and time to obliteration (TTO); secondary outcomes included rates of post-SRS hemorrhage, salvage therapy, and symptomatic radionecrosis. A minimum of 12 mo of follow-up imaging/angiogram post-SRS was required, or alternatively evidence of obliteration on angiogram prior to 12 mo post-SRS. Single predictor and multivariable Cox regression and logistic regression models were constructed to test for association between radiographic, clinical, and treatment factors with outcomes. Results A total of 75 patients were included. Total 17 patients received 3DRA and 58 patients received 2D DSA, with a median follow-up of 3.29 yr. The 3DRA is significantly associated with improved TTO on single predictor (HR 2.87, 1.29-6.12; P = .0109) and multivariable analysis (HR 2.448, 1.076-5.750; P = .0330) and increased odds of achieving obliteration by 3 yr post-SRS on single predictor analysis (OR 6.044, 1.405-26.009; P = .0157). Conclusion The 3DRA over 2D DSA in SRS treatment planning for AVMs may result in improved TTO and 3-yr obliteration rates. Further investigation and prospective study are warranted.

Management of vestibular schwannoma (VS) includes stereotactic radiosurgery (SRS) in single or fractionated treatments. There is a paucity of literature on the three-dimensional (3D) volumetric kinetics and radiological changes following SRS and no consensus on appropriate post-SRS surveillance imaging timeline. This is a retrospective cohort study with institutional review board approval. A total of 55 patients met study criteria. We collected volumetric kinetic data in VS treated with SRS over time using a target volume contouring software. We also tracked radiographic phenomena such as pseudoprogression and necrosis. A secondary objective was to describe our overall treatment success rate and any failures. For all treatments groups, pseudoprogression most typically occurred within 12 months post-SRS, after which tumor volumes on average normalized and then decreased from pretreatment size at the last follow-up. Only two patients required salvage therapy post-SRS and were considered SRS treatment failures. Both patients were in the five-fraction cohort but with a lower biologically equivalent dose. Our study is first to collect 3D volumetric kinetics of VS following single and fractionated SRS in contrast to extrapolations from single and two-dimensional measurements. Our longitudinal data also show initial increases in volume in the first 12 months post-SRS followed by later declines, setting up interesting questions regarding the utility of early posttreatment surveillance imaging in the asymptomatic patient. Finally, we show low rates of treatment failure (3.6%) and show in our cohort that SRS dose de-escalation posed a risk of treatment failure.

The purpose of this study was to determine the prevalence and nature of internal, external, and combined lymphedema and fibrosis in patients with head and neck cancer (HNC).We obtained consent from 100 patients newly diagnosed with having cancer of the head and neck for a 4-year, prospective, longitudinal descriptive study. Recruitment began in August 23, 2010, and the study was completed in April 24, 2014. Eighty-three were evaluated at regular intervals from preradiation therapy to 18 months post-treatment. Percentage developing external, internal, or both types of lymphedema and/or fibrosis and trajectories of the severity of external, internal, or both types of lymphedema and/or fibrosis were determined.Before treatment, lymphedema rates were the following: external: 62.7%, internal: 41.7%, or combined: 29.2%, and/or fibrosis: 42.2%. Ranges of lymphedema late-effect rates were even higher: external: 81.9%-90.1%, internal: 80.4%-89.4%, combined: 70.6%-80.9%, and fibrosis: 66.7%-77.4%. Approximately 75% had a late-effect trajectory characterized by moderate to severe external or internal lymphedema; ∼47% had moderate to severe fibrosis.Lymphatic and soft tissue complications of HNC occur not only post-treatment but also before treatment. They are ubiquitous throughout the first 18 months post-treatment, with greater than 90% of patients in our study experiencing some form of internal, external, or combined lymphedema, and over half of those patients developing fibrosis. Further research regarding these conditions is indicated.

BACKGROUND Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival. METHODS The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group. RESULTS Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status. CONCLUSIONS The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016;122:3464–71. © 2016 American Cancer Society.

Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence in the United States and in many countries worldwide primarily as a result of increasing rates of human papillomavirus (HPV) infection. HPV-positive OPSCC represents a distinct disease entity from head and neck squamous cell carcinoma caused by traditional risk factors such as tobacco and alcohol, with different epidemiology, patterns of failure, and expected outcomes. Because patients with HPV-positive OPSCC have a younger median age and superior prognosis compared with their HPV-negative counterparts, they live longer with the morbidity of treatment, which can be severe. Therefore, efforts are under way to de-escalate therapy in favorable-risk patients while maintaining treatment efficacy. Additional work is being undertaken to discover new therapies that may benefit both HPV-positive and HPV-negative patient subsets. Herein, we will review the available data for the evolving treatment paradigms in OPSCC as well as discuss ongoing clinical trials.

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (HN the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Purpose This paper reports long-term results of RTOG 9903, to determine whether the addition of erythropoietin (EPO) would improve the outcomes of radiation therapy (RT) in mildly to moderately anemic patients with head and neck squamous cell carcinoma (HNSCCa). Methods and Materials The trial included HNSCCa patients treated with definitive RT. Patients with stage III or IV disease received concomitant chemoradiation therapy or accelerated fractionation. Pretreatment hemoglobin levels were required to be between 9.0 and 13.5 g/dL (12.5 g/dL for females). EPO, 40,000 U, was administered weekly starting 7 to 10 days before RT was initiated in the RT + EPO arm. Results A total of 141 of 148 enrolled patients were evaluable. The baseline median hemoglobin level was 12.1 g/dL. In the RT + EPO arm, the mean hemoglobin level at 4 weeks increased by 1.66 g/dL, whereas it decreased by 0.24 g/dL in the RT arm. With a median follow-up of 7.95 years (range: 1.66-10.08 years) for surviving patients and 3.33 years for all patients (range: 0.03-10.08 years), the 5-year estimate of local-regional failure was 46.2% versus 39.4% ( P =.42), local-regional progression-free survival was 31.5% versus 37.6% ( P =.20), and overall survival was 36.9% versus 38.2% ( P =.54) for the RT + EPO and RT arms, respectively. Late toxicity was not different between the 2 arms. Conclusions This long-term analysis confirmed that despite the ability of EPO to raise hemoglobin levels in anemic patients with HNSCCa, it did not improve outcomes when added to RT. The possibility of a detrimental effect of EPO could not be ruled out.