Search

Importance: Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors., Objective: To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS)., Design, Setting, and Participants: A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023., Interventions: Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab., Main Outcomes and Measures: The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months., Results: Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable [NE]), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively., Conclusions and Relevance: In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03181100.

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease., Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making., Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

Importance: Extranodal extension (pENE) is a critical prognostic factor in oropharyngeal cancer (OPC) that drives therapeutic disposition. Determination of pENE from radiological imaging has been associated with high inter-observer variability. However, the impact of clinician specialty on human observer performance of imaging-detected extranodal extension (iENE) remains poorly understood., Objective: To characterize the impact of clinician specialty on the accuracy of pre-operative iENE in human papillomavirus-positive (HPV+) OPC using computed tomography (CT) images., Design Setting and Participants: This prospective observational human performance study analyzed pre-therapy CT images from 24 HPV+ OPC patients, with duplication of 6 scans (n=30) of which 21 were pathologically confirmed pENE. Thirty-four expert observers, including 11 radiologists, 12 surgeons, and 11 radiation oncologists, independently assessed these scans for iENE and reported human-detected radiologic criteria and observer confidence., Main Outcomes and Measures: The primary outcomes included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and Brier score for each physician, compared to ground-truth pENE. The significance of radiographic signs for prediction of pENE were determined through logistic regression analysis. Fleiss' kappa measured interobserver agreement, and Hanley-MacNeil AUC discrimination testing., Results: Median accuracy across all specialties was 0.57 (95%CI 0.39 to 0.73), with no specialty showing discriminate performance greater than random estimation (median AUC 0.64, 95%CI 0.44 to 0.83). Significant differences between radiologists and surgeons in Brier scores (0.33 vs. 0.26, p < 0.01), radiation oncologists and surgeons in sensitivity (0.48 vs. 0.69, p > 0.1), and radiation oncologists and radiologists/surgeons in specificity (0.89 vs. 0.56, p > 0.1). Indistinct capsular contour and nodal necrosis were significant predictors of correct pENE status among all specialties. Interobserver agreement was weak for all the radiographic criteria, regardless of specialty ( κ <0.6)., Conclusions and Relevance: Multiobserver testing shows physician discrimination of HPV+OPC pENE on pre-operative CT remains non-different than blind guessing, with high interrater variability and low diagnostic accuracy, regardless of clinician specialty. While minor differences in diagnostic performance among specialties are noted, they do not significantly affect the overall poor agreement and discrimination rates observed. The findings underscore the need for further research into automated detection systems or enhanced imaging techniques to improve the accuracy and reliability of iENE assessments in clinical practice., Competing Interests: Conflict of Interest Statement: Dr. Fuller has received unrelated direct industry grant/in-kind support, honoraria, and travel funding from Elekta AB; honoraria, and travel funding from Philips Medical Systems; and honoraria, and travel funding from Varian/Siemens Healthineers. Dr. Fuller has unrelated licensing/royalties from Kallisio, Inc. Dr. Sandulache is a consultant for, and equity holder in, Femtovox Inc (unrelated to current work).

Background: Sinonasal NUT carcinoma is an extremely rare, lethal malignancy with limited literature., Methods: A case series was conduction of all patients with sinonasal NUT carcinoma at a single institution between 2010 and 2022. Survival and associated were evaluated. A systematic review of the literature was performed., Results: In 12 patients, followed for a median of 1.5 years, the median overall survival (OS) and disease-specific survival (DSS) were both 14.6 months. Patients with maxillary sinus tumors were 91% more likely to survive (hazard ratio [HR]: 0.094, 95% confidence interval [CI]: 0.011-0.78, p = 0.011). Patients with higher-stage disease stage had worse OS (stage IVb-c vs. III-IVa, p = 0.05). All three patients who were alive with no evidence of disease received induction chemotherapy., Conclusion: For patients with sinonasal NUT carcinoma, the median survival was 15 months but better with lower-stage and maxillary tumors. Induction chemotherapy may be beneficial., (© 2023 Wiley Periodicals LLC.)

Purpose: We developed and tested a novel method of creating intensity modulated proton arc therapy (IMPAT) plans that uses computing resources similar to those for regular intensity-modulated proton therapy (IMPT) plans and may offer a dosimetric benefit for patients with ependymoma or similar tumor geometries., Methods: Our IMPAT planning method consists of a geometry-based energy selection step with major scanning spot contributions as inputs computed using ray-tracing and single-Gaussian approximation of lateral spot profiles. Based on the geometric relation of scanning spots and dose voxels, our energy selection module selects a minimum set of energy layers at each gantry angle such that each target voxel is covered by sufficient scanning spots as specified by the planner, with dose contributions above the specified threshold. Finally, IMPAT plans are generated by robustly optimizing scanning spots of the selected energy layers using a commercial proton treatment planning system (TPS). The IMPAT plan quality was assessed for four ependymoma patients. Reference three-field IMPT plans were created with similar planning objective functions and compared with the IMPAT plans., Results: In all plans, the prescribed dose covered 95% of the clinical target volume (CTV) while maintaining similar maximum doses for the brainstem. While IMPAT and IMPT achieved comparable plan robustness, the IMPAT plans achieved better homogeneity and conformity than the IMPT plans. The IMPAT plans also exhibited higher relative biological effectiveness (RBE) enhancement than did the corresponding reference IMPT plans for the CTV in all four patients and brainstem in three of them., Conclusions: The proposed method demonstrated potential as an efficient technique for IMPAT planning and may offer a dosimetric benefit for patients with ependymoma or tumors in close proximity to critical organs. IMPAT plans created using this method had elevated RBE enhancement associated with increased linear energy transfer (LET) in both targets and abutting critical organs., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: To report long-term outcomes of modern radiotherapy for sinonasal cancers., Methods and Materials: A retrospective analysis of patients with sinonasal tumors treated with intensity-modulated radiotherapy or proton therapy. Multivariate analysis was used to determine predictive variables of progression free survival (PFS) and overall survival (OS)., Results: Three hundred and eleven patients were included, with median follow-up of 75 months. The most common histologies were squamous cell (42%), adenoid cystic (15%), and sinonasal undifferentiated carcinoma (15%). Induction chemotherapy was administered to 47% of patients; 68% had adjuvant radiotherapy. Ten-year local control, regional control, distant metastasis free survival, PFS, and overall survival rates were 73%, 88%, 47%, 32%, and 51%, respectively. Age, non-nasal cavity tumor site, T3-4 stage, neck dissection, and radiation dose were predictive of PFS, while age, non-nasal cavity tumor site, T3-4 stage, positive margins, neck dissection, and use of neoadjuvant chemotherapy were predictive of OS. There was a 13% rate of late grade ≥3 toxicities., Conclusion: This cohort of patients with sinonasal cancer treated with modern radiotherapy demonstrates favorable disease control rate and acceptable toxicity profile., (© 2023 Wiley Periodicals LLC.)

Background: The aim of this study was to describe the oncologic outcomes of patients with BRAF V600E -mutated anaplastic thyroid cancer (ATC) who had neoadjuvant BRAF-directed therapy with subsequent surgery. For context, we also reviewed patients who received BRAF-directed therapy after surgery, and those who did not have surgery after BRAF-directed therapy. Methods: This was a single-center retrospective cohort study conducted at a tertiary care cancer center in Texas from 2017 to 2021. Fifty-seven consecutive patients with BRAF V600E -mutated ATC and at least 1 month of BRAF-directed therapy were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Results: All patients had stage IVB (35%) or IVC (65%) ATC. Approximately 70% of patients treated with BRAF-directed therapy ultimately had surgical resection of residual disease. Patients who had neoadjuvant BRAF-directed therapy followed by surgery ( n  = 32) had 12-month OS of 93.6% [confidence interval (CI) 84.9-100] and PFS of 84.4% [CI 71.8-96.7]. Patients who had surgery before BRAF-directed therapy ( n  = 12) had 12-month OS of 74.1% [CI 48.7-99.5] and PFS of 50% [CI 21.7-78.3]. Finally, patients who did not receive surgery after BRAF-directed therapy ( n  = 13) had 12-month OS of 38.5% [CI 12.1-64.9] and PFS of 15.4% [CI 0-35.0]. Neoadjuvant BRAF-directed therapy reduced tumor size, extent of surgery, and surgical morbidity score. Subgroup analysis suggested that any residual ATC in the surgical specimen was associated with significantly worse 12-month OS and PFS (OS = 83.3% [CI 62.6-100], PFS = 61.5% [CI 35.1-88]) compared with patients with pathologic ATC complete response (OS = 100%, PFS = 100%). Conclusions: We observed that neoadjuvant BRAF-directed therapy reduced extent of surgery and surgical morbidity. While acknowledging potential selection bias, the 12-month OS rate appeared higher in patients who had BRAF-directed therapy followed by surgery as compared with BRAF-directed therapy without surgery; yet, it was not significantly different from surgery followed by BRAF-directed therapy. PFS appeared higher in patients treated with neoadjuvant BRAF-directed therapy relative to patients in the other groups. These promising results of neoadjuvant BRAF-directed therapy followed by surgery for BRAF-mutated ATC should be confirmed in prospective clinical trials.

Background: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population., Methods: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m 2 ) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m 2 ), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete., Findings: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group)., Interpretation: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated., Funding: National Cancer Institute and Novartis., Competing Interests: Declaration of interests KCB declares in the past 36 months an unpaid chair of the Americans Thyroid Association Anaplastic Thyroid Cancer Guidelines Task Force, now published. CHC declares in the past 36 months participation on a Data Safety Monitoring Board or Advisory Board for Bristol-Myers Squibb, Cue Biopharma, Sanofi, Mirati, Merck, Brooklyn ImmunoTherapuetics, and Exelixis. MFD declares in the past 36 months support for attending Radiation Oncologists (PA, USA), American Society for Radiation Oncology (ASTRO) Head and Neck Meeting (Scottsdaye, AZ, USA), 2020 ASTRO Annual Meeting (San Antonio, TX, USA); and reimbursement for travel, registration and food, Health Policy Committee Payer Relations for ASTRO. RLF declares in the past 36 months royalties from Bionix TruGuard oral stent, paid to the Mayo Clinic and to himself, honoria for lecture ITCCIR 2021, Elsevier royalties for providing content for sale textbook as Editor, and Hitachi-unrestricted use of research funds paid to the Mayo Clinic for named professorship (Hitachi Professor of Radiation Oncology Research). RAG declares in the past 36 months receipt of National Institutes of Health grant P30CA008748 to the Memorial Sloan Kettering Cancer Center. SAK declares in the past 36 months research support from Merck, Bristol Myers Squibb, and Castle BioSciences; consulting fees from Regeneron; Merck-paid advisory board; an unpaid advisory board role at Castle BioSciences; author for UpToDate; and a data safety monitoring board role at AlphaTau. NYL declares in the past 36 months advisory board roles at Pfizer, Merck, Merck EMD, Elsie, and Mirati. Q-TL declares in the past 36 months consultant roles for Nanobiotix, Roche, and Coherus; honoraria from Johns Hopkins Lecture and 2021 China International Exchange, and Promotive Association for Medical and Health Care Nasopharyngeal Cancer Branch Inaugural Conference and Minimally Invasive Surgery Training Course of Nasopharyngeal Cancer, paid flights or hotels Radiation Therapy Oncology Group (RTOG) foundation meetings or retreats, RTOG group chair (NRG Oncology), and stock or stock options exceeding US$1000 from Aldea. NR reports since the initial planning of the work research support from Pfizer, Repertoire, REPARE Therapuetics, and BMS, and in the past 36 months consulting fees from Illumina Paige.AI. MHS declares in the past 36 months grants from Merck and Eli-Lilly for clinical trials with payment made to his institution. EJS reports since the initial planning of the work support from GSK/Novartis (no payment) and in the past 36 months consulting fees from Eli Lilly, Roche, Regeneron, Eisai, and Elixis, advisory board roles (no compensation) with Eli Lilly, Novartis, and DSMB, and a Protocol Chair (unpaid) role with Eli Lilly and Novartis. PAT-S reports since the initial planning of the work NRG Oncology Statistics and Data Management Center grant from the National Cancer Institute (NCI). PX declares in past 36 months payment to his institution, research grants from AVO and Philips, and support from Philips to present at a Sun Nuclear QA meeting in 2019. SSY declares in past 36 months research support paid to his institution from Merck, Bristol-Myers Squibb, EMD Serono, Genentech, and BioMimetix; book chapter royalties from Springer and UpToDate; and service positions at ASTRO, Elsevier, and NRG Oncology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: This study investigated the association of hearing loss and tinnitus with overall health-related quality of life (HRQoL) among long-term oropharyngeal cancer (OPC) survivors., Methods: This study included OPC survivors treated between 2000 and 2013 and surveyed from September 2015 to July 2016. Hearing loss and tinnitus were measured by asking survivors to rate their "difficulty with hearing loss and/or ringing in the ears" from 0 (not present) to 10 (as bad as you can imagine). Hearing loss and tinnitus scores were categorized as follows: 0 for none, 1-4 for mild, and 5-10 for moderate to severe. The primary outcome was the mean score of MD nderson Symptom Inventory Head & Neck module interference component as a HRQoL surrogate dichotomized as follows: 0 to 4 for none to mild and 5 to 10 for moderate to severe interference., Results: Among 880 OPC survivors, 35.6% (314), reported none, 39.3% (347) reported mild, and 25.1% (221) reported moderate to severe hearing loss and tinnitus. On multivariable analysis, mild (OR, 5.83; 95% CI; 1.48-22.88; p = 0.012) and moderate (OR, 30.01; 95% CI; 7.96-113.10; p < 0.001) hearing loss and tinnitus were associated with higher odds of reporting moderate to severe symptom interference scores in comparison to no hearing loss and tinnitus. This association of hearing dysfunction was consistent with all domains of HRQoL., Conclusions: Our findings provide preliminary evidence to support the need for continued audiological evaluations and surveillance to detect hearing dysfunction, to allow for early management and to alleviate the long-term impact on QoL., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy. Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman’s correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time. Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that can be assessed on MRI, and 31 patients had nodal disease with 46 nodes assessed. Median primary GTV (GTVp) size was 14.1cc. The rate of GTVp shrinkage was highest between pre-treatment and week 4. Patients with T3-T4 tumours had a 3.8-fold decrease in GTVp compared to T1-T2 tumours. The ADC values correlated with residual GTVp. The median nodal volume (GTVn) was 12.4cc. No clinical features were found to correlate with GTVn reduction. The overall change in ADC for GTVn from pre-treatment was significant for 35th−95th percentiles in weeks 1−4 (p < 0.001). Conclusion: A discrepancy in the trajectory of ADC between primary and nodal sites suggested that they exhibit different treatment responses and should be analysed separately in future studies.

Purpose: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC., Materials and Methods: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models., Results: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAF V600E and RAS , which were mutually exclusive. The BRAF V600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS -mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAF V600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAF V600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21)., Conclusion: Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care.

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1, P = 4.3 × 10 -7 ; 5p13.2-p13.1, rs16903936, MA = G, EGFLAM, P = 5.1 × 10 -6 ; 4q21.1, rs10518156, MA = G, SHROOM3, P = 7.1 × 10 -6 ; 19q13.42, rs11882068, MA = G, NLRP9, P = 1.7 × 10 -5 ; 12q24.33, rs4760542, MA = G, GLT1D1, P = 1.8 × 10 -5 ; and 3q27.3, rs11714564, MA = G, RTP1, P = 2.9 × 10 -5 . Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826, a ncRNA class RNA gene, P = 1.5 × 10 -5 ). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia., (© 2022. The Author(s).)

Background: The study objective is to identify risk factors associated with fatigue among long-term OPC survivors., Methods: This cross-sectional study included disease-free OPC survivors treated curatively between 2000 and 2013 who were surveyed from September 2015 to July 2016. The outcome variable was patient-reported fatigue. Multivariable logistic regression was used to identify factors associated with moderate to severe fatigue., Results: Among 863 OPC survivors, 17.4% reported moderate to severe fatigue. Self-reported thyroid problems (OR: 2.01; p = 0.003), current cigarette smoking at time of survey (OR: 3.85; p = 0.001), late lower cranial neuropathy (OR: 3.44; p = 0.002), and female sex (OR: 1.91; p = 0.010) were concurrent risk factors of reporting moderate to severe fatigue. Ipsilateral intensity-modulated radiotherapy (OR: 0.18; p = 0.014) was associated with lower risk of reporting moderate to severe fatigue., Conclusions: Our study identified thyroid problems, smoking, and late lower cranial neuropathy as associated with moderate to severe fatigue. These findings should be further validated in prospective studies to address fatigue among OPC survivors., (© 2022 Wiley Periodicals LLC.)

Background: To analyze the influence of radiation dose on late radiation-associated taste impairment in oropharyngeal cancer (OPC) patients treated with intensity-modulated radiotherapy (IMRT) using the taste bud bearing tongue mucosa as organ at risk., Material and Methods: This study is part of an ongoing, prospective observational study. Cancer-free OPC survivors with at least 24 months from IMRT were included in this analysis. Scores for taste impairment and dry mouth were extracted from the MD Anderson Symptom Inventory Head and Neck module (MDASI-HN) with scores of ≥5 considered as moderate-to-severe symptoms. The mean dose, minimum and maximum dose to the taste bud bearing tongue mucosa, the ipsi- and contralateral parotid and submandibular glands were extracted and analyzed for correlation with moderate-to-severe taste impairment., Results: One hundred sixteen T1-4 OPC patients were included (81% males, median age: 55). The primary tumor was in the tonsil in 92 cases (79%) and in the base of tongue in 21 cases (18%). Patients were treated with 64.2-72.0 Gy; 37 patients (32%) received concurrent chemotherapy and 22 (19%) concurrent targeted therapy. After a median of 58 months from RT (IQR: 43-68) 38 patients (33%) suffered from moderate-to-severe long-term radiation-associated taste impairment. No dose volume parameter of the taste bud bearing tongue mucosa and the salivary glands was significantly associated with moderate-to-severe taste impairment for the whole patient cohort. For patients without concurrent chemotherapy, the minimum and mean dose to the ipsilateral parotid gland, and the maximum dose to the submandibular gland was significantly associated with late taste impairment (all p  < 0.05). A significant correlation was found between taste impairment and dry mouth ( p  < 0.001)., Conclusion: The dose to the ipsilateral parotid gland seems to play an important role in the development of late taste impairment. The influence of dose to the taste bud bearing tongue mucosa remains unclear and needs further investigation.

Background: Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probability (NTCP) models have been proposed, however variation in relative biological effectiveness (RBE) may challenge the applicability of these dose constraints and models in proton therapy. The purpose of this study was therefore to investigate the influence of RBE variations on risk estimates of TLN after Intensity-Modulated Proton Therapy for HNC., Material and Methods: Seventy-five temporal lobes from 45 previously treated patients were included in the analysis. Sixteen temporal lobes had radiation associated Magnetic Resonance image changes (TLIC) suspected to be early signs of TLN. Fixed (RWD Fix ) and variable RBE-weighed doses (RWD Var ) were calculated using RBE = 1.1 and two RBE models, respectively. RWD Fix and RWD Var for temporal lobes were compared using Friedman's test. Based on RWD Fix , six NTCP models were fitted and internally validated through bootstrapping. Estimated probabilities from RWD Fix and RWD Var were compared using paired Wilcoxon test. Seven dose constraints were evaluated separately for RWD Fix and RWD Var by calculating the observed proportion of TLIC in temporal lobes meeting the specific dose constraints., Results: RWD Var were significantly higher than RWD Fix ( p  < 0.01). NTCP model performance was good (AUC:0.79-0.84). The median difference in estimated probability between RWD Fix and RWD Var ranged between 5.3% and 20.0% points ( p  < 0.01), with V 60GyRBE and D Max at the smallest and largest differences, respectively. The proportion of TLIC was higher for RWD Fix (4.0%-13.1%) versus RWD Var (1.3%-5.3%). For V 65GyRBE ≤ 0.03 cc the proportion of TLIC was less than 5% for both RWD Fix and RWD Var., Conclusion: NTCP estimates were significantly influenced by RBE variations. D max as model predictor resulted in the largest deviations in risk estimates between RWD Fix and RWD Var . V 65GyRBE ≤ 0.03 cc was the most consistent dose constraint for RWD Fix and RWD Var.

Background: This study was conducted to identify clinicodemographic risk factors for xerostomia among long-term oropharyngeal cancer (OPC) survivors., Methods: This cross-sectional study included 906 disease-free, adult OPC survivors with a median survival duration at the time of survey of 6 years (range, 1-16 years); self-reported xerostomia scores were available for 877 participants. Study participants had completed curative treatment between January 2000 and December 2013 and responded to a survey administered from September 2015 to July 2016. The primary outcome variable was cancer patient-reported xerostomia measured with the MD Anderson Symptom Inventory Head and Neck Cancer Module. Clinicodemographic risk factors for moderate to severe xerostomia were identified via multivariable logistic regression., Results: Moderate to severe xerostomia was reported by 343 of the respondents (39.1%). Female sex (odds ratio [OR], 1.82; 95% CI, 1.22-2.71; P = .003; Bayesian false-discovery probability [BFDP] = 0.568), high school or lower education (OR, 1.73; 95% CI, 1.19-2.52; P = .004; BFDP = 0.636), and current cigarette smoking at the time of survey (OR, 2.56; 95% CI, 1.19-5.47; P = .016; BFDP = 0.800) were risk factors for moderate to severe xerostomia, and bilateral intensity-modulated radiotherapy (IMRT) combined with proton therapy and ipsilateral IMRT were protective., Conclusions: In this large xerostomia study, modern radiotherapy was a protective factor, and continued cigarette smoking at the time of survey, female sex, and high school or lower education were identified as other contributing risk factors associated with moderate to severe xerostomia. Importantly, these findings need to be confirmed in prospective studies. These results can inform future research and targeted patient-centered interventions to monitor and manage radiation therapy-associated xerostomia and preserve quality of life among patients with OPC., (© 2021 American Cancer Society.)

Background: Recurrent head and neck cancer has poor prognosis. Stereotactic body radiotherapy (SBRT) may improve outcomes by delivering ablative radiation doses., Methods: We reviewed patients who received definitive-intent SBRT reirradiation at our institution from 2013 to 2020. Patterns of failure, overall survival (OS), and toxicities were analyzed., Results: One hundred and thirty-seven patients were evaluated. The median OS was 44.3 months. The median SBRT dose was 45 Gy and median target volume 16.9 cc. The 1-year local, regional, and distant control was 78%, 66%, and 83%, respectively. Systemic therapy improved regional (p = 0.004) and distant control (p = 0.04) in nonmetastatic patients. Grade 3+ toxicities were more common at mucosal sites (p = 0.001) and with concurrent systemic therapy (p = 0.02)., Conclusions: In a large cohort of SBRT reirradiation for recurrent, small volume head and neck cancers, a median OS of 44.3 months was observed. Systemic therapy improved regional and distant control. Toxicities were modulated by anatomic site and systemic therapy., (© 2021 Wiley Periodicals LLC.)

Purpose: Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT., Methods and Materials: For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LET d ) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve., Results: An overall statistically significant RAIC association with dose and LET d was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30-2.72) for dose and 2.68 (1.93-4.93) for LET d , respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LET d effect demonstrated increased risk of RAIC with increasing LET d for the majority of patients. Estimated probability of RAIC with LET d  = 1 keV/µm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD 15 were estimated to be 63.6 and 50.1 Gy with LET d equal to 2 and 5 keV/µm, respectively., Conclusions: Our results suggest that the LET d effect could be of clinical significance for some patients; LET d assessment in clinical treatment plans should therefore be taken into consideration., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with locoregionally advanced oral cavity squamous cell carcinoma (OCSCC) have a poor survival outcome. Treatment involves extensive surgery, adjuvant radiation, or chemoradiation and results in high morbidity. In this study, the authors' objective was to evaluate their experience with induction chemotherapy (IC) in the treatment of locoregionally advanced OCSCC., Methods: A retrospective review of the medical records of all patients with locoregionally advanced (stage III and IV) OCSCC who received IC followed by definitive local therapy was conducted. Outcomes included response to IC and survival., Results: In total, 120 patients were included in the study. The overall stage was stage IV in 79.2% of patients. After 2 cycles of IC, 76 patients (63.3%) achieved at least a partial response, including 13 who had a complete response. Stable disease was observed in 30 patients (25%), and 14 patients (11.7%) had progressive disease. Among responders, 16 patients received definitive chemoradiation or radiation therapy, and 60 underwent surgical resection, of whom 15 had less extensive surgery than was originally planned. Overall, organ preservation was achieved in 40.8% of patients who had a favorable response to IC. The 5-year overall and disease-specific survival rates were 51.4% and 66.9%, respectively. Patients who had at least a partial response had better 5-year overall survival (60.1%) and disease-specific survival (78.5%) compared with nonresponders (33.8% and 46.4%, respectively)., Conclusions: The results demonstrate a response rate to IC in patients with advanced OCSCC similar to what has been observed in patients with cancer in other head and neck subsites. Patients who achieved at least a partial response to IC had a more favorable outcome, with ensuing organ preservation. Further studies are warranted., (© 2021 American Cancer Society.)

Purpose: Young patients, including pediatric, adolescent, and young adult (YA) patients, are most likely to benefit from the reduced integral dose of proton beam radiation therapy (PBT) resulting in fewer late toxicities and secondary malignancies. This study sought to examine insurance approval and appeal outcomes for PBT among YA patients compared with pediatric patients at a large-volume proton therapy center., Methods and Materials: We performed a cross-sectional cohort study of 284 consecutive patients aged 0 to 39 years for whom PBT was recommended in 2018 through 2019. Pediatric patients were defined as aged 0 to 18 years and YA patients 19 to 39 years. Rates of approval, denials, and decision timelines were calculated. Tumor type and location were also evaluated as factors that may influence insurance decisions., Results: A total of 207 patients (73%) were approved for PBT at initial request. YA patients (n = 68/143, 48%) were significantly less likely to receive initial approval compared with pediatric patients (n = 139/141; 99%) (P < .001). Even after 47% (n = 35 of 75) of the PBT denials for YA patients were overturned, YAs had a significantly lower final PBT approval (72% vs pediatric 99%; P < .001). The median wait time was also significantly longer for YA patients (median, 8 days; interquartile range [IQR] 3-17 vs median, 2 days; IQR, 0-6; P < .001). In those patients requiring an appeal, the median wait time was 16 days (IQR, 9-25)., Conclusion: Given the decades of survivorship of YA patients, PBT is an important tool to reduce late toxicities and secondary malignancies. Compared with pediatric patients, YA patients are significantly less likely to receive insurance approval for PBT. Insurance denials and subsequent appeal requests result in significant delays for YA patients. Insurers need to re-examine their policies to include expedited decisions and appeals and removal of arbitrary age cutoffs so that YA patients can gain easier access to PBT. Furthermore, consensus guidelines encouraging greater PBT access for YA may be warranted from both medical societies and/or AYA experts., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid cancer that requires a rapid diagnosis and treatment to achieve disease control. Gene mutation profiling of circulating cell-free DNA (cfDNA) in peripheral blood may help to facilitate early diagnosis and treatment selection. The relatively rapid turnaround time compared with conventional tumor mutation testing is a major advantage. The objectives of this study were to examine the concordance of ATC-related mutations detected in cfDNA with those detected in the corresponding tumor tissue, and to determine the prognostic significance of cfDNA mutations in ATC patients. Methods: The ATC patients who were diagnosed and treated at The University of Texas MD Anderson Cancer Center between January 2015 and February 2018 and who had cfDNA testing were included in this study. cfDNA was collected by blood draw and was analyzed by next-generation sequencing (NGS) using the Guardant360-73 gene platform. Results: A total of 87 patients were included in the study. The most frequently mutated genes detected in cfDNA were TP53, BRAF , and PIK3CA . In 28 treatment naive ATC patients, the concordance rate of detected mutations in TP53, BRAF V600E , and PIK3CA between cfDNA and matched tissue NGS was 82.1%, 92.9%, and 92.9%, respectively. Patients with a PIK3CA mutation detected on cfDNA had worse overall survival (OS) ( p  = 0.03). This association was observed across various treatment modalities, including surgery, cytotoxic chemotherapy, radiation, and BRAF inhibitor (BRAFi) therapy. With regard to treatment, BRAFi therapy significantly improved ATC OS ( p  = 0.003). Conclusions: cfDNA is a valuable tool to evaluate a tumor's molecular profile in ATC patients. We identified high concordance rates between the gene mutations identified via cfDNA analysis and those identified from the NGS of the corresponding tumor tissue sequencing. Identified mutations in cfDNA can potentially provide timely information to guide treatment selection and evaluate the prognosis in patients with ATC.

Importance: Voice and speech production are critical physiological functions that affect quality of life and may deteriorate substantially after oropharyngeal cancer (OPC) treatment. There is limited knowledge about risk factors associated with voice and speech outcomes among survivors of OPC., Objective: To identify the risk factors of voice and speech symptoms among long-term survivors of OPC., Design, Setting, and Participants: This retrospective cohort study with cross-sectional survivorship survey administration includes cancer-free survivors of OPC who were treated curatively between January 2000 and December 2013 at MD Anderson Cancer Center (Houston, Texas) who participated in a survey from September 2015 to July 2016. Of 906 survivors of OPC with a median survival duration at time of survey of 6 years (range, 1-16 years), patient-rated voice and speech outcomes for 881 were available and analyzed. The data were analyzed from June 30, 2020, to February 28, 2021., Main Outcomes and Measures: The primary outcome variable was patient-reported voice and speech scores that were measured using the MD Anderson Symptom Inventory-Head and Neck Cancer Module. Voice and speech scores of 0 to 4 were categorized as none to mild symptoms, and scores of 5 to 10 were categorized as moderate to severe symptoms. Risk factors for moderate to severe voice and speech symptoms were identified by multivariable logistic regression., Results: Among 881 survivors of OPC (median [range] age, 56 [32-84] years; 140 women [15.5%]; 837 White [92.4%], 17 Black [1.9%], and 35 Hispanic individuals [3.8%]), 113 (12.8%) reported moderate to severe voice and speech scores. Increasing survival time (odds ratio [OR], 1.17; 95% CI, 1.06-1.30) and increasing total radiation dose (OR, 1.16; 95% CI, 1.00-1.34), Black race (OR, 3.90; 95% CI, 1.02-14.89), Hispanic ethnicity (OR, 3.74; 95% CI, 1.50-9.35), current cigarette smoking at the time of survey (OR, 3.98; 95% CI, 1.56-10.18), treatment with induction and concurrent chemotherapy (OR, 1.94; 95% CI, 1.06-3.57), and late (OR, 7.11; 95% CI, 3.08-16.41) and baseline lower cranial neuropathy (OR, 8.70; 95% CI, 3.01-25.13) were risk factors associated with moderate to severe voice and speech symptoms. Intensity-modulated radiotherapy split-field regimen (OR, 0.31; 95% CI, 0.12-0.80; P = .01) was associated with lower likelihood of moderate to severe voice and speech symptoms., Conclusions and Relevance: This large OPC survivorship cohort study identified many treatment-related factors, including increasing total radiotherapy dose, multimodality induction and concurrent chemotherapy regimens, and continued smoking, as well as clinical and demographic factors, as risk factors that were associated with moderate to severe voice and speech symptoms. The key findings in this study were the protective associations of split-field radiation and that longer-term survivors, and those who continued to smoke, had worse voice and speech symptoms. These findings may inform research and effective targeted clinical voice and speech preservation interventions and smoking cessation interventions to maximize voice and speech function and address quality of life among patients with OPC.

Background and Purpose: To determine rates of xerostomia after intensity-modulated radiotherapy (IMRT) or intensity-modulated proton therapy (IMPT) for oropharyngeal cancer (OPC) and identify dosimetric factors associated with xerostomia risk., Materials and Methods: Patients with OPC who received IMRT (n = 429) or IMPT (n = 103) from January 2011 through June 2015 at a single institution were studied retrospectively. Every 3 months after treatment, each patient completed an eight-item self-reported xerostomia-specific questionnaire (XQ; summary XQ score, 0-100). An XQ score of 50 was selected as the demarcation value for moderate-severe (XQs ≥ 50) and no-mild (XQs < 50) xerostomia. The mean doses and percent volumes of organs at risk receiving various doses (V5-V70) were extracted from the initial treatment plans. The dosimetric variables and xerostomia risk were compared using an independent-sample t-test or chi-square test., Results: The median follow-up time was 36.2 months. The proportions of patients with moderate-severe xerostomia were similar in the two treatment groups up to 18 months after treatment. However, moderate-severe xerostomia was less common in the IMPT group than in the IMRT group at 18-24 months (6% vs. 20%; p = 0.025) and 24-36 months (6% vs. 20%; p = 0.01). During the late xerostomia period (24-36 months), high dose/volume exposures (V25-V70) in the oral cavity were associated with high proportions of patients with moderate-severe xerostomia (all p < 0.05), but dosimetric variables regarding the salivary glands were not associated with late xerostomia., Conclusion: IMPT was associated with less late xerostomia than was IMRT in OPC patients. Oral cavity dosimetric variables were related to the occurrence of late xerostomia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 χ 2 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., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank reports grants and personal fees from Hitachi. Outside the submitted work, Dr Frank is a cofounder of C4 Imaging, LLC, for which he reports grants and personal fees, and he reports grants from Eli Lilly and Elekta, other remuneration from Breakthrough Chronic Care, and personal fees from Varian, Augmenix, and the National Comprehensive Cancer Center (NCCN). The other authors have no conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: In value-based health care delivery, radiation oncologists need to compare empiric costs of care delivery with advanced technologies, such as intensity-modulated proton therapy (IMPT) and intensity-modulated radiation therapy (IMRT). We used time-driven activity-based costing (TDABC) to compare the costs of delivering IMPT and IMRT in a case-matched pilot study of patients with newly diagnosed oropharyngeal (OPC) cancer., Materials and Methods: We used clinicopathologic factors to match 25 patients with OPC who received IMPT in 2011-12 with 25 patients with OPC treated with IMRT in 2000-09. Process maps were created for each multidisciplinary clinical activity (including chemotherapy and ancillary services) from initial consultation through 1 month of follow-up. Resource costs and times were determined for each activity. Each patient-specific activity was linked with a process map and TDABC over the full cycle of care. All calculated costs were normalized to the lowest-cost IMRT patient., Results: TDABC costs for IMRT were 1.00 to 3.33 times that of the lowest-cost IMRT patient (mean ± SD: 1.65 ± 0.56), while costs for IMPT were 1.88 to 4.32 times that of the lowest-cost IMRT patient (2.58 ± 0.39) ( P  < .05). Although single-fraction costs were 2.79 times higher for IMPT than for IMRT (owing to higher equipment costs), average full cycle cost of IMPT was 1.53 times higher than IMRT, suggesting that the initial cost increase is partly mitigated by reductions in costs for other, non-RT supportive health care services., Conclusions: In this matched sample, although IMPT was on average more costly than IMRT primarily owing to higher equipment costs, a subset of IMRT patients had similar costs to IMPT patients, owing to greater use of supportive care resources. Multidimensional patient outcomes and TDABC provide vital methodology for defining the value of radiation therapy modalities., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank reports personal fees from Varian, grants and personal fees from C4 Imaging, grants from Eli Lilly, grants from Elekta, grants and personal fees from Hitachi, other from Breakthrough Chronic Care, personal fees from Augmenix, personal fees from National Comprehensive Cancer Center (NCCN), outside the submitted work. C. David Fuller, MD, PhD, received/receives funding and salary support unrelated to this project during the period of study execution from The National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) Research Education Programs for Residents and Clinical Fellows Grant (R25EB025787-01); the National Institute for Dental and Craniofacial Research Establishing Outcome Measures Award (1R01DE025248/R56DE025248) and Academic Industrial Partnership Grant (R01DE028290); NCI Early Phase Clinical Trials in Imaging and Image-Guided Interventions Program (1R01CA218148); an NIH/NCI Cancer Center Support Grant (CCSG) Pilot Research Program Award from the UT MD Anderson CCSG Radiation Oncology and Cancer Imaging Program (P30CA016672); an NIH/NCI Head and Neck Specialized Programs of Research Excellence (SPORE) Developmental Research Program Award (P50 CA097007); NIH Big Data to Knowledge (BD2K) Program of the National Cancer Institute (NCI) Early Stage Development of Technologies in Biomedical Computing, Informatics, and Big Data Science Award (1R01CA2148250; National Science Foundation (NSF), Division of Mathematical Sciences, Joint NIH/NSF Initiative on Quantitative Approaches to Biomedical Big Data (QuBBD) Grant (NSF 1557679); NSF Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) Grant (NSF 1933369); and the Sabin Family Foundation. Direct infrastructure support is provided to Dr Fuller by the multidisciplinary Stiefel Oropharyngeal Research Fund of the University of Texas MD Anderson Cancer Center Charles and Daneen Stiefel Center for Head and Neck Cancer and the Cancer Center Support Grant (P30CA016672) and the MD Anderson Program in Image-guided Cancer Therapy. Dr Fuller has received direct industry grant support, honoraria, and travel funding from Elekta AB unrelated to this project. Simona F. Shaitelman, MD, reports grants from Varian, during the conduct of the study. Nikhil G. Thaker, MD, reports consulting fees from McKesson Specialty Health, unrelated to this study. Robert S. Kaplan, PhD, serves as a member of the Board of Advisers for Avant-garde Health and reports occasional speaking fees on value-based health care from Medtronic., (©Copyright 2021 The Author(s).)

Purpose: To report clinical outcomes in terms of disease control and toxicity in patients with major salivary gland cancers (SGCs) treated with proton beam therapy., Materials and Methods: Clinical and dosimetric characteristics of patients with SGCs treated from August 2011 to February 2020 on an observational, prospective, single-institution protocol were abstracted. Local control and overall survival were calculated by the Kaplan-Meier method. During radiation, weekly assessments of toxicity were obtained, and for patients with ≥ 90 days of follow-up, late toxicity was assessed., Results: Seventy-two patients were identified. Median age was 54 years (range, 23-87 years). Sixty-three patients (88%) received postoperative therapy, and nine patients (12%) were treated definitively. Twenty-six patients (36%) received concurrent chemotherapy. Nine patients (12%) had received prior radiation. All (99%) but one patient received unilateral treatment with a median dose of 64 GyRBE (relative biological effectiveness) (interquartile range [IQR], 60-66), and 53 patients (74%) received intensity-modulated proton therapy with either single-field or multifield optimization. The median follow-up time was 30 months. Two-year local control and overall survival rates were 96% (95% confidence interval [CI] 85%-99%) and 89% (95% CI 76%-95%], respectively. Radiation dermatitis was the predominant grade-3 toxicity (seen in 21% [n = 15] of the patients), and grade ≥ 2 mucositis was rare (14%; n = 10 patients). No late-grade ≥ 3 toxicities were reported., Conclusion: Proton beam therapy for treatment of major SGCs manifests in low rates of acute mucosal toxicity. In addition, the current data suggest a high rate of local control and minimal late toxicity., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank reports grants and personal fees from Hitachi. Outside the submitted work, Dr Frank is a cofounder of C4 Imaging, LLC, for which he reports grants and personal fees, and he reports personal fees from Varian, grants from Eli Lilly, grants from Elekta, other remuneration from Breakthrough Chronic Care, personal fees from Augmenix, and personal fees from the National Comprehensive Cancer Center (NCCN). C. David Fuller, MD, PhD, received funding and salary support from the National Institutes of Health (NIH), National Institute of Biomedical Imaging and Bioengineering (NIBIB), Research Education Programs for residents and clinical fellows grant (R25EB025787-01); the National Institute for Dental and Craniofacial Research Establishing Outcome Measures award (1R01DE025248/R56DE025248), and the Academic Industrial Partnership grant (R01DE028290); the National Cancer Institute (NCI) Early Phase Clinical Trials in Imaging and Image-Guided Interventions program (1R01CA218148); an NIH/NCI Cancer Center Support Grant (CCSG) pilot research program award from the University of Texas MD Anderson CCSG radiation oncology and cancer imaging program (P30CA016672); an NIH/NCI Head and Neck Specialized Programs of Research Excellence (SPORE) developmental research program award (P50 CA097007); an NIH Big Data to Knowledge (BD2K) program of the NCI Early Stage Development of Technologies in Biomedical Computing, Informatics, and Big Data Science award (1R01CA214825); the National Science Foundation (NSF), Division of Mathematical Sciences, Joint NIH/NSF Initiative on Quantitative Approaches to Biomedical Big Data (QuBBD) grant (NSF 1557679); the NSF Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) grant (NSF 1933369); the Stiefel Oropharyngeal Research Fund of The University of Texas MD Anderson Cancer; and the MD Anderson program in image-guided cancer therapy. Dr Fuller has received direct industry grant support, in-kind hardware, honoraria, and travel funding from Elekta AB. The other authors have no conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: To characterize our experience and the disease control and toxicity of proton therapy (PT) for patients with head and neck cancer (HNC)., Patients and Methods: Clinical outcomes for patients with HNC treated with PT at our institution were prospectively collected in 2 institutional review board-approved prospective studies. Descriptive statistics were used to summarize patient characteristics and outcomes. Overall survival, local-regional control, and disease-free survival were estimated by the Kaplan-Meier method. Treatment-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03) scale., Results: The cohort consisted of 573 patients treated from February 2006 to June 2018. Median patient age was 61 years. Oropharynx (33.3%; n = 191), paranasal sinus (11%; n = 63), and periorbital tissues (11%; n = 62) were the most common primary sites. Patients with T3/T4 or recurrent disease comprised 46% (n = 262) of the cohort. The intent of PT was definitive in 53% (n = 303), postoperative in 37% (n = 211), and reirradiation in 10% (n = 59). Median dose was 66 Gy (radiobiological equivalent). Regarding systemic therapy, 43% had received concurrent (n = 244), 3% induction (n = 19), and 15% (n = 86) had both. At a median follow-up of 2.4 years, 88 patients (15%) had died and 127 (22%) developed disease recurrence. The overall survival, local-regional control, and disease-free survival at 2 and 5 years were, respectively, 87% and 75%, 87% and 78%, and 74% and 63%. Maximum toxicity (acute or late) was grade 3 in 293 patients (51%), grade 2 in 234 patients (41%), and grade 1 in 31 patients (5%). There were 381 acute grade 3 and 190 late grade 3 unique toxicities across 212 (37%) and 150 (26%) patients, respectively. There were 3 late-grade 4 events across 2 patients (0.3%), 2 (0.3%) acute-grade 5, and no (0%) late-grade 5 events., Conclusions: The overall results from this prospective study of our initial decade of experience with PT for HNC show favorable disease control and toxicity outcomes in a multidisease-site cohort and provide a reference benchmark for future comparison and study., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank is a scientific advisory board member of Breakthrough Chronic Care; he has received research grants from C4 Imaging, Eli Lilly, Elekta, and Hitachi, and he has reported personal fees from Varian Medical Systems, Inc (consultant/advisory board), C4 Imaging (founder and director), Hitachi (honoraria/advisory board), Augmenix (honoraria), and National Comprehensive Cancer Center (board member). Stephen G. Chun, MD, is a consultant for AstraZeneca, PLC. The authors report no other conflicts of interest., (©Copyright 2021 The Author(s).)

Purpose: Proton radiation therapy (PRT) may offer dosimetric and clinical benefit in the treatment of head and neck carcinoma of unknown primary (HNCUP). We sought to describe toxicity and quality of life (QOL) in patients with HNCUP treated with PRT., Patients and Methods: Toxicity and QOL were prospectively tracked in patients with HNCUP from 2011 to 2019 after institutional review board approval. Patients received PRT to the mucosa of the nasopharynx, oropharynx, and bilateral cervical lymph nodes with sparing of the larynx and hypopharynx. Patient-reported outcomes were tracked with the MD Anderson Symptom Inventory-Head and Neck Module, the Functional Assessment of Cancer Therapy-Head and Neck, the MD Anderson Dysphagia Inventory, and the Xerostomia-Related QOL Scale. Primary study endpoints were the incidence of grade ≥ 3 (G3) toxicity and QOL patterns., Results: Fourteen patients (median follow-up, 2 years) were evaluated. Most patients presented with human papillomavirus-positive disease (n = 12, 86%). Rates of G3 oral mucositis, xerostomia, and dermatitis were 7% (n = 1), 21% (n = 3), and 36% (n = 5), respectively. None required a gastrostomy. During PRT, QOL was reduced relative to baseline and recovered shortly after PRT. At 2 years after PRT, the local regional control, disease-free survival, and overall survival were 100% (among 7 patients at risk), 79% (among 6 patients at risk), and 90% (among 7 patients at risk), respectively., Conclusion: Therefore, PRT for HNCUP was associated with highly favorable dosimetric and clinical outcomes, including minimal oral mucositis, xerostomia, and dysphagia. Toxicity and QOL may be superior with PRT compared with conventional radiation therapy and PRT maintains equivalent oncologic control. Further prospective studies are needed to evaluate late effects and cost-effectiveness., Competing Interests: Conflicts of Interest: David Fuller, MD, PhD, has received direct industry grant support, honoraria, and travel funding from Elekta AB. Jack Phan, MD, PhD, serves on the scientific advisory board for Cyberknife for Accuray, Inc. David I. Rosenthal, MD, serves on the scientific advisory board for Merck. Erich M. Sturgis, MD, reports research support from Roche. Neil D. Gross, MD, reported receiving personal fees from Intuitive Surgical and nonfinancial support from MedRobotics outside the submitted work. Maura L. Gillison, MD, PhD, reported consulting for Amgen, Aspyrian, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, EMD Serono, Genocea, GlaxoSmithKline, Lilly, NewLink, Merck, Roche, and TRN Oncology; receiving grants from the National Institute of Dental and Craniofacial Research (NIDCR); and receiving personal fees from Roche Diagnostics. Renata Ferrarotto, MD, reported receiving consulting fees from Ayala Pharmaceuticals, Regeneron Sanofi, and Klus. Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank reports personal fees from Varian, grants and personal fees from C4 Imaging, grants from Eli Lilly, grants from Elekta, grants and personal fees from Hitachi, other support from Breakthrough Chronic Care, personal fees from Boston Scientific, and personal fees from the National Comprehensive Cancer Network (NCCN)—all of which are outside the submitted work. The authors have no additional conflicts of interest to report., (©Copyright 2021 The Author(s).)