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Purpose: To assess any correlation between swallowing dysfunction and radiation dose to 5 subregions of the larynx. Methods and Materials: A cohort of 136 patients with head and neck cancer, treated with either photon or proton radiation therapy, was assessed using an endpoint of patient-reported swallowing scores, evaluated with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-H&N35 survey, within 1 month after treatment. Five subregions of the larynx were contoured, and dosimetric metrics were extracted for each subregion as well as the total larynx. Univariate and multivariate logistic regression statistical analyses were used to determine statistical correlation with the dose metrics and clinical variables. Univariate regression models were statistically compared using a non-nested model test. Results: Under univariate analysis, unilateral versus bilateral nodal irradiation (P = .004), concurrent chemotherapy (P = .007), and surgery (P = .015) were statistically significant predictors of poor swallowing score. Unilateral versus bilateral irradiation was statistically significant under multivariate analysis (P = .039). The epiglottis was the most predictive subregion of swallowing score, with a majority (21 of 25) of dosimetric variables being identified as statistically significant. The maximum dose to the epiglottis was the most significant dosimetric variable tested for poor swallowing score in both univariate (P = .003) and multivariate (P = .051) analyses. Comparison of univariate models indicated a general preference for epiglottic variables with the mean dose to the epiglottis being preferred at a statistically significant level in many cases. Conclusions: These results show the relatively increased sensitivity of the epiglottis compared with the rest of the larynx when considering patient-reported decrements in quality-of-life swallowing score and support both the inclusion of the epiglottis in standard larynx contours and the assessment of the epiglottis dose during plan evaluation. Our data suggest that keeping the mean and max doses to the epiglottis

Purpose: This series reports long-term clinical outcomes of patients with salivary duct carcinoma (SDC), which is associated with a poor prognosis. Methods and Materials: Eighty-nine patients with SDC were treated with curative intent from February 5, 1971, through September 15, 2018. Kaplan-Meier and competing risk analyses were used to estimate locoregional control, distant metastasis-free survival (DMFS), progression-free survival, and overall survival (OS). Cox regression analyses of disease and treatment characteristics were performed to discover predictors of locoregional control, DMFS, and OS. Results: Median follow-up was 44.1 months (range, 0.23-356.67). The median age at diagnosis was 66 years (interquartile range, 57-75). Curative surgery followed by adjuvant radiation therapy was performed in 73 patients (82%). Chemotherapy was delivered in 26 patients (29.2%). The 5-year local recurrence and distant metastasis rates were 27% and 44%, respectively, with death as a competing risk. Distant metastasis was associated with lymph node–positive disease (hazard ratio [HR], 3.16; 95% confidence interval [CI], 1.38-7.23; P = .006), stage IV disease (HR, 4.78; 95% CI, 1.14-20.11; P = .033), perineural invasion (HR, 4.56; 95% CI, 1.74-11.97; P = .002), and positive margins (HR, 9.06; 95% CI, 3.88-21.14; P < .001). Median OS was 4.84 years (95% CI, 3.54-7.02). The 5-year OS was 42%. Reduced OS was associated with lymphovascular space invasion (HR, 3.49; 95% CI, 1.2-10.1; P = .022), perineural invasion (HR, 2.05; 95% CI, 1.06-3.97; P = .033), positive margins (HR, 2.7; 95% CI, 1.3-5.6; P = .011), N2 disease (HR, 1.88; 95% CI, 1.03-3.43; P = .04), and N3 disease (HR, 11.76; 95% CI, 3.19-43.3; P < .001). Conclusions: In this single-institution, multicenter retrospective study, the 5-year survival was 42% in patients with SDC. Lymphovascular space invasion, lymph node involvement, and higher staging at diagnosis were associated with lower DMFS and OS.

Purpose: This article presents an in vivo imaging technique based on nuclear fragmentation of carbon ions in irradiated tissues for potential real-time monitoring of carbon-ion radiation therapy (CIRT) treatment delivery and quality assurance purposes in clinical settings. Materials and Methods: A proof-of-concept imaging and monitoring system (IMS) was devised to implement the technique. Monte Carlo simulations were performed for a prospective pencil-beam scanning CIRT nozzle. The development IMS benchmark considered a 5×5-cm2 pixelated charged-particle detector stack positioned downstream from a target phantom and list-mode data acquisition. The abundance and production origins, that is, vertices, of the detected fragments were studied. Fragment trajectories were approximated by straight lines and a beam back-projection algorithm was built to reconstruct the vertices. The spatial distribution of the vertices was then used to determine plan relevant markers. Results: The IMS technique was applied for a simulated CIRT case, a primary brain tumor. Four treatment plan monitoring markers were conclusively recovered: a depth dose distribution correlated profile, ion beam range, treatment target boundaries, and the beam spot position. Promising millimeter-scale (3-mm, ≤ 10% uncertainty) beam range and submillimeter (≤0.6-mm precision for shifts

Purpose: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods and Materials: Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other. Results: At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival (P = .008), disease-free survival (P = .05), and distant metastasis (DM; P = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant. Conclusions: The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM.

Purpose: Radiation therapy (RT) is the standard treatment for patients with inoperable skin malignancies of the head and neck region (H&N), and as adjuvant treatment post surgery in patients at high risk for local or regional recurrence. This study reports clinical outcomes of intensity-modulated proton therapy (IMPT) for these malignancies. Materials and Methods: We retrospectively reviewed cases involving 47 patients with H&N malignancies of the skin (squamous cell, basal cell, melanoma, Merkel cell, angiosarcoma, other) who underwent IMPT for curative intent between July 2016 and July 2019. Overall survival was estimated via Kaplan-Meier analysis, and oncologic outcomes were reported as cumulative incidence with death as a competing risk. Results: The 2-year estimated local recurrence rate, regional recurrence rate, local regional recurrence rate, distant metastasis rate, and overall survival were 11.1% (95% confidence interval [CI], 4.1%–30.3%), 4.4% (95% CI, 1.1%–17.4%), 15.5% (95% CI, 7%-34.3%), 23.4% (95% CI, 5.8%–95.5%), and 87.2% (95% CI, 75.7%–100%), respectively. No patient was reported to have a grade 3 or higher adverse event during the last week of treatment or at the 3-month follow-up visit. Conclusion: IMPT is safe and effective in the treatment of skin malignancies of the H&N.

Purpose: To successfully plan and treat a patient with diffuse angiosarcoma involving the face and scalp with intensity-modulated proton therapy (IMPT) before surgical resection. Materials and Methods: A patient presented to the radiation oncology department for preoperative treatment of an angiosarcoma diffusely involving the face and scalp. A 4-field IMPT technique was used to create a homogeneous dose distribution to the entire target volume while sparing underlying critical structures from toxicity and low-dose spread. A custom Monte Carlo optimizer was necessary to achieve treatment goals. Biological dose was evaluated with a linear energy transfer–based biological enhancement model. Robustness criteria were evaluated per department standard. The patient was successfully planned and treated according to clinical goals. Results: The patient successfully completed the course of IMPT and was able to undergo surgical resection. Pathology indicated no presence of angiosarcoma. Conclusion: IMPT using a custom Monte Carlo optimizer is a suitable radiation therapy treatment option for patients with diffuse angiosarcoma of the scalp and face.

Purpose: External beam radiotherapy is used in a subset of high-risk patients with differentiated thyroid cancer (DTC). Recurrent, radioactive iodine (RAI)–refractory DTC carries a poor prognosis. We report our initial experience of intensity-modulated proton therapy (IMPT) for recurrent, RAI-refractory DTC. Patients and Methods: Fourteen patients with recurrent, RAI-refractory DTC were consecutively treated with IMPT from November 2016 to March 2020 at our multisite institution. Patient, tumor, and treatment characteristics were recorded. Overall survival and local-regional recurrence-free survival were recorded and estimated using the Kaplan-Meier method. Acute and late treatment-related toxicities were recorded based on the Common Terminology Criteria for Adverse Events version 5.0. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Head and Neck Module at baseline and after IMPT. Eleven patients were included in the final analysis. Results: Median follow-up was 8 months (range, 3-40) for all patients. Median age at treatment with IMPT was 64 years (range, 40-77), and the majority were men (64%). Recurrent histologies included papillary (55%), Hurthle cell (36%), and poorly differentiated (9%) carcinoma; 1 patient had tall cell variant. Concurrent chemotherapy was not administered for any patient in this cohort. At 8 months, all patients were alive without local-regional failure. Acute grade 3 toxicities were limited to 1 patient with dysphagia, requiring feeding tube placement. Two patients experienced late grade 3 esophageal stenosis requiring dilation. There were no grade 4 or 5 toxicities. There were no differences in pretreatment versus posttreatment patient-reported outcomes in terms of dysphagia or hoarseness. Conclusion: In our early experience, IMPT provided promising local-regional control for recurrent, RAI-refractory DTC. Further study is warranted to evaluate the long-term efficacy and safety of IMPT in this patient population.

Purpose: We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT). Patients and Methods: In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores. Results: Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P < 0.001 for all). Higher magnitudes of recovery from absenteeism (at 1 year, P = 0.05; and at 2 years, P = 0.04) and composite work impairment scores (at 1 year, P = 0.04; and at 2 years, P = 0.04) were seen in patients treated with IMPT versus those treated with IMRT. Conclusion: In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

Purpose: Human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV[+]OPSCC) requires further study to optimize the existing clinical staging system and guide treatment selection. We hypothesize that incorporation of the number of radiographically positive lymph nodes will further stratify patients with clinical N1 (cN1) HPV(+)OPSCC. Methods and Materials: A post hoc analysis from 2 prospective clinical trials at a high-volume referral center was conducted. Patients underwent primary tumor resection and lymphadenectomy, followed by either standard-of-care radiation therapy (60 Gy in 30 fractions) with or without cisplatin (40 mg/m2 weekly) or de-escalated radiation therapy (30 Gy in 20 twice-daily fractions) with concomitant 15 mg/m2 docetaxel once weekly. Imaging studies were independently reviewed by a blinded neuroradiologist classifying radiographic extranodal extension (rENE) and the number and maximal size of involved lymph nodes. Patients without pathologic data available for assessment were excluded. Results: A total of 260 patients were included. Of these, 216 (83%) were cN1. Patients had a median of 2 radiographically positive lymph nodes (range, 0-12), and 107 (41%) had rENE. For cN1 patients, stratifying by radiographically positive lymph nodes (1-2 vs 3-4 vs >4) was predictive of progression-free survival (PFS) (P = .017), with 2-year PFS rates of 96%, 88%, and 81%, respectively. More than 2 radiographically positive lymph nodes was identified as a significant threshold for PFS (P = .0055) and overall survival (P = .029). Radiographic ENE and lymph node size were not predictive of PFS among cN1 patients. Conclusions: The number of radiographically positive lymph nodes is predictive of PFS and overall survival and could be used to meaningfully subcategorize cN1 patients with HPV(+)OPSCC. We recommend further validation of our proposal that cN1 patients with 1 to 2 radiologically positive lymph nodes be categorized as cN1a, patients with 3 to 4 radiologically positive lymph nodes categorized as cN1b, and patients with >4 radiographically positive lymph nodes categorized as cN1c.

Purpose: Carbon ion radiotherapy (CIRT) is an emerging radiotherapy modality with potential advantages over conventional photon-based therapy, including exhibiting a Bragg peak and greater relative biological effectiveness, leading to a higher degree of cell kill. Currently, 13 centers are treating with CIRT, although there are no centers in the United States. We aimed to estimate the number of patients eligible for a CIRT center in the United States. Materials and Methods: Using the National Cancer Database, we analyzed the incidence of cancers frequently treated with CIRT internationally (glioblastoma, hepatocellular carcinoma, cholangiocarcinoma, locally advanced pancreatic cancer, non–small cell lung cancer, localized prostate cancer, soft tissue sarcomas, and specific head and neck cancers) diagnosed in the United States in 2015. The percentage and number of patients likely benefiting from CIRT was estimated with inclusion criteria from clinical trials and retrospective studies, and that ratio was applied to 2019 cancer statistics. An adaption correction rate was applied to estimate the potential number of patients treated with CIRT. Given the high dependency on prostate and lung cancers and the uncertain adoption of CIRT in those diseases, the data were then reanalyzed excluding those diagnoses. Results: Of the 1 127 455 new cases of cancer diagnosed in the United States in 2015, there were 213 073 patients (18.9%) eligible for treatment with CIRT based on inclusion criteria. When applying this rate and the adaption correction rate to the 2019 incidence data, an estimated 89 946 patients (42.2% of those fitting inclusion criteria) are eligible for CIRT. Excluding prostate and lung cancers, there were an estimated 8922 patients (10% of those eligible for CIRT) eligible for CIRT. The number of patients eligible for CIRT is estimated to increase by 25% to 27.7% by 2025. Conclusion: Our analysis suggests a need for CIRT in the United States in 2019, with the number of patients possibly eligible to receive CIRT expected to increase during the coming 5 to 10 years.

Purpose: To understand how verification computed tomography-quality assurance (CTQA) scans influenced clinical decision-making to replan patients with head and neck cancer and identify predictors for replanning to guide intensity-modulated proton therapy (IMPT) clinical practice. Patients and Methods: We performed a quality-improvement study by prospectively collecting data on 160 consecutive patients with head and neck cancer treated using spot-scanning IMPT who underwent weekly verification CT-QA scans. Kaplan-Meier estimates were used to determine the cumulative probability of a replan by week. Predictors for replanning were determined with univariate (UVA) and multivariate (MVA) Cox model hazard ratios (HRs). Logistic regression was used to determine odds ratios (ORs). P < .05 was considered statistically significant. Results: Of the 160 patients, 79 (49.4%) had verification CT-QA scans, which prompted a replan. The cumulative probability of a replan by week 1 was 13.7% (95% confidence interval [CI], 8.82-18.9), week 2, 25.0% (95% CI, 18.0-31.4), week 3, 33.1% (95% CI, 25.4-40.0), week 4, 45.6% (95% CI, 37.3-52.8), and week 5 and 6, 49.4% (95% CI, 41.0- 56.6). Predictors for replanning were sinonasal disease site (UVA: HR, 1.82, P = .04; MVA: HR, 3.64, P = .03), advanced stage disease (UVA: HR, 4.68, P < .01; MVA: HR, 3.10, P < .05), dose . 60 Gy equivalent (GyE; relative biologic effectiveness, 1.1) (UVA: HR, 1.99, P < .01; MVA: HR, 2.20, P < .01), primary disease (UVA: HR, 2.00 versus recurrent, P = .01; MVA: HR, 2.46, P = .01), concurrent chemotherapy (UVA: HR, 2.05, P < .01; MVA: not statistically significant [NS]), definitive intent treatment (UVA: HR, 1.70 versus adjuvant, P < .02; MVA: NS), bilateral neck treatment (UVA: HR, 2.07, P = .03; MVA: NS), and greater number of beams (5 beam UVA: HR, 5.55 versus 1 or 2 beams, P < .02; MVA: NS). Maximal weight change from baseline was associated with higher odds of a replan (_3 kg: OR, 1.97, P = .04; _ 5 kg: OR, 2.13, P = .02). Conclusions: Weekly verification CT-QA scans frequently influenced clinical decisionmaking to replan. Additional studies that evaluate the practice of monitoring IMPTtreated patients with weekly CT-QA scans and whether that improves clinical outcomes are warranted.

Purpose: This study hypothesized that insurance denial would lead to bias and loss of statistical power when evaluating the results from an intent-to-treat (ITT), per-protocol, and as-treated analyses using a simulated randomized clinical trial comparing proton therapy to intensity modulated radiation therapy where patients incurred increasing rates of insurance denial. Methods and Materials: Simulations used a binary endpoint to assess differences between treatment arms after applying ITT, per-protocol, and as-treated analyses. Two scenarios were developed: 1 with clinical success independent of age and another assuming dependence on age. Insurance denial was assumed possible for patients

Purpose/Objectives: To evaluate the role of external beam radiation therapy (EBRT) for treatment of malignant paraganglioma (PGL) and pheochromocytoma (PCC). Methods and materials: A retrospective review was performed of all patients with malignant PGL/PCC treated with EBRT at our institution between 1973 and 2015. Local control (LC) per treated lesion and overall survival were estimated using the Kaplan-Meier method. Toxicities were scored using the Common Toxicity Criteria for Adverse Events (AE), version 4. Results: The cohort included 41 patients with 107 sites treated. Median (range) age at EBRT was 33 (11-80) years. Treatment intention was curative in 20 patients (30 lesions) and palliative in 21 patients (77 lesions). The primary tumor was PGL (63%) and PCC (37%). Previous local therapies were surgical resection (90%) and percutaneous ablation (19%). Indications for EBRT were local control (66%), pain (22%), or spinal cord compression (12%). Treatment site included bone (69%), soft tissue (30%), and liver (1%). Median (range) EBRT dose was 40 (6.5-70) Gy. Median biologic effective dose using α/β = 10 (BED10) was 53 (9-132). Median follow-up was 3.8 years (0.04-41.5), and mean follow-up was 9.7 years. Overall survival at 5 years was 65%: 79% for curative- and 50% for palliative-intention patients (P = .028). LC at 5 years was 81% for all lesions; 91% for lesions receiving BED10 ≥53, and 62% for lesions receiving BED10