A Phase 1 Study of the DNA-PK Inhibitor Peposertib in Combination With Radiation Therapy With or Without Cisplatin in Patients With Advanced Head and Neck Tumors.

PURPOSE: DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B). METHODS AND MATERIALS: Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B). RESULTS: The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared. CONCLUSIONS: Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.

Nivolumab and ipilimumab in combination with radiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with newly diagnosed, stage IVA-IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the association of baseline programmed death-ligand 1 (PD-L1) expression as well as on-treatment changes in immune bias with treatment outcomes. RESULTS: Twenty-four patients were enrolled. With a median follow-up of 36.1 months, grade 3 or higher treatment-related adverse events were reported in 21 individuals (88%); 5 individuals developed in-field soft tissue ulceration during consolidation immunotherapy, resulting in one fatality. The 3-year PFS and OS rates were 74% (95% CI 58% to 94%) and 96% (95% CI 88% to 100%), respectively. PD-L1 combined positive score (CPS) did not correlate with death or disease progression. Decreases in extracellular vesicle PD-L1 within the concurrent RIT phase were associated with prolonged PFS (p=0.006). Also, interval decreases in circulating interleukin (IL)4, IL9, IL12, and IL17a during concurrent RIT were associated with subsequent ulceration. CONCLUSIONS: Definitive RIT with nivolumab and ipilimumab has sufficient clinical activity to support further development. Early changes in circulating biomarkers appear able to predict treatment outcomes as well as ensuing in-field soft tissue ulceration. TRIAL REGISTRATION NUMBER: NCT03162731.

Long-term Outcomes of Bevacizumab and Chemoradiation for Locoregionally Advanced Nasopharyngeal Carcinoma: A Nonrandomized Controlled Trial.

Importance: The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Objective: To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC. Design, Setting, and Participants: This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement. Interventions: Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m2) and RT (69.96 Gy) followed by 3 cycles of adjuvant bevacizumab (15 mg/kg) given concurrently with cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/d). Main Outcomes and Measures: The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression-free (LRPF) interval, distant metastasis-free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation. Results: Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%). Conclusions and Relevance: In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT00408694.

Remote Activity Monitoring and Electronic Patient-Reported Outcomes Collection During Radiotherapy for Head and Neck Cancer: A Pilot Study.

PURPOSE: Modern wearable devices provide objective and continuous activity data that could be leveraged to enhance cancer care. We prospectively studied the feasibility of monitoring physical activity using a commercial wearable device and collecting electronic patient-reported outcomes (ePROs) during radiotherapy (RT) for head and neck cancer (HNC). METHODS: Patients planned for a course of external beam RT with curative intent for HNC were instructed to use a commercial fitness tracker throughout the RT course. During weekly clinic visits, physician-scored adverse events were recorded during using Common Terminology Criteria for Adverse Events version 4.0, and patients completed ePRO surveys using a clinic tablet or computer. Feasibility of activity monitoring was defined as collection of step data for at least 80% of the RT course for at least 80% of patients. Exploratory analyses described associations between step counts, ePROs, and clinical events. RESULTS: Twenty-nine patients with HNC were enrolled and had analyzable data. Overall, step data were recorded on 70% of the days during patients' RT courses, and there were only 11 patients (38%) for whom step data were collected on at least 80% of days during RT. Mixed effects linear regression models demonstrated declines in daily step counts and worsening of most PROs during RT. Cox proportional hazards models revealed a potential association between high daily step counts and both reduced risk of feeding tube placement (hazard ratio [HR], 0.87 per 1,000 steps, P < .001) and reduced risk of hospitalization (HR, 0.60 per 1,000 steps, P < .001). CONCLUSION: We did not achieve our feasibility end point, suggesting that rigorous workflows are required to achieve continuous activity monitoring during RT. Although limited by a modest sample size, our findings are consistent with previous reports indicating that wearable device data can help identify patients who are at risk for unplanned hospitalization.

Variance in 3D anatomic localization of surgical margins based on conventional margin labeling in head and neck squamous cell carcinoma.

OBJECTIVE: In head and neck cancer (HNC), positive margins are strongly predictive of treatment failure. We sought to measure the accuracy of localization of margin sampling sites based on conventional anatomic labels using a digital 3D-model. METHODS: Preoperative CT scans for 9 patients with HNC treated operatively at our institution were imported into a multiplanar radiology software, which was used to render a digital 3D model of each tumor intended to represent the resection specimen. Surgical margin labels recorded during the operative case were collected from pathology records. Margin labels (N = 64) were presented to participating physicians.Participants were asked to mark the anatomic location of each surgical margin using the 3D-model and corresponding radiographic planes for reference.For each individual margin, the 3D coordinates of each participant's marker were used to calculate a mean localization point called the geometric centroid. Mean distance from individual markers to the centroid was compared between participantsand margin types. RESULTS: Amongst 7 surgeons, markers were placed a mean distance of 12.6 mm ([SD] = 7.5) from the centroid.Deep margins were marked with a greater mean distance than mucosal/skin margins (19.6 [24.8] mm vs. 15.3 [14.9] mm, p = 0.034). When asked to relocate a margin following re-resection, surgeons marked a point an average of 20.6 [12.4] mm from their first marker with a range of 3.9- 45.1 mm. CONCLUSIONS: Retrospective localization of conventionally labeled margins is an imprecise process with variability across the care team. Future interventions targeting margin documentation and communication may improve sampling precision.

PREVLAR: Phase 2a Randomized Trial to Assess the Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Head and Neck Chemoradiotherapy.

PURPOSE: No Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study. METHODS AND MATERIALS: This study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients' blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria. RESULTS: Fifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient. CONCLUSIONS: Our results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy.

Feasibility of collagen matrix tiles with cesium-131 brachytherapy for use in the treatment of head and neck cancer.

BACKGROUND: Locoregional failure is a unique and challenging problem in head and neck cancer with controversy surrounding the use of re-irradiation in the treatment. We aimed to evaluate the dosimetry and technical parameters in utilizing a collagen matrix with embedded Cesium-131 (Cs-131) radioactive isotope seeds as it relates to dose distribution and dose to carotid artery. METHODS AND MATERIALS: Cadaveric feasibility study randomizing Cs-131 strands alone or Cs-131 with collagen matrix to be placed into neck dissection defects. For the dose computation, physicists employed the TG-43 dosimetry calculation algorithm with a point source assumption to compute the dose. Carotid arteries were contoured in MIM-Symphony software and the carotid artery maximum and mean doses were calculated in accordance with TG-43 specifications. Ease of use of collagen matrix tiles on a 7-point Likert scale and mean radiation dose to the carotid artery. RESULTS: Ease of use score was higher in collagen matrix compared to stranded seeds with a mean score of 6.3 +/- 1.2 compared to 4.5 +/- 0.87. Time of implantation was statistically significantly, p = 0.031, lower in the collagen matrix group (M = 5.17 min, SD = 4.62) compared to stranded seeds (M = 15.83 min, SD = 3.24). Mean radiation dose to the carotid artery was 62.8 Gy +/- 9.46 in the collagen matrix group compared to 108.2 Gy +/- 55.6 in the traditional Cs-131 seeds group. CONCLUSIONS: We present a feasibility and concept cadaveric study using a collagen matrix with Cesium-131 demonstrating preliminary evidence to support its ease of use, decreased time to implantation, and decreased dose delivered to the carotid artery.

Impact of adjuvant radiation therapy after definitive surgery in senior adults >80 years old with advanced head and neck squamous cell carcinoma on overall survival.

Background: Adjuvant radiotherapy (RT) following surgical resection confers a survival benefit for adult patients with locally advanced head and neck squamous cell carcinoma (HNSCC). We aim to investigate if adjuvant RT provides a similar survival advantage to patients ages 80+ through a national curated database. Methods: This retrospective cohort study queried the National Cancer Database (NCDB) for all cases of HNSCC between 2004-2016. Patients treated with surgical resection alone were compared to those treated with surgery plus adjuvant RT. Overall survival (OS) was compared within adult (age <80 years) and senior adult (age ≥80 years) cohorts using Kaplan-Meier analysis. Hazard ratios (HR) were assessed using Cox proportional hazards to account for differences in patient characteristics, primary site, and HNSCC stage. Results: NCDB identified 16,504 locally advanced HNSCC treated with definitive surgery with 9,129 (55.3%) also receiving adjuvant RT. The mean age was 63.8 years (SD = 12.0) with 88.7% of patients ages <80 years and 11.3% ages ≥80 years. In the adult cohort, adjuvant RT was associated with a significant increase in OS compared to surgery alone at 1 year (88.4% vs. 83.8%, p=<0.001), 3 years (64.0% vs. 59.2%, p=<0.001) and 5 years (52.8% vs. 47.2%, p=<0.001). Treatment with surgery alone remained a significant predictor of mortality risk at 1 year (HR 1.48, 95% CI 1.35-1.64, p<0.001), 3 years (HR 1.25, 95% CI 1.18-1.33, p<0.001), and 5 years (HR of 1.23, 95% CI 1.17-1.30, p=<0.001). In the senior adult cohort, there were no significant differences in OS between treatment groups at 1 year (73.4% vs. 74.8%, 0.296), 3 years (45.8% vs. 41.8%, p=0.465), or 5 years (28.2% vs. 27.7% p=0.759). Treatment with surgery alone was not a significant predictor of mortality risk at 1 year (HR 1.11, 95% CI 0.90-1.36, p=0.316), 3 years (HR 0.94, 95% CI 0.81-1.08, p=0.423), or 5 years (HR 0.95, 95% CI 0.83-1.08, p=0.476). Conclusion: The addition of adjuvant RT in senior patients (age ≥80 years) may not provide a similar OS benefit to that observed in younger patients. Further research is needed to best guide shared-decision making in this population.

Two-Year Tumor Outcomes of a Phase 2B, Randomized, Double-Blind Trial of Avasopasem Manganese (GC4419) Versus Placebo to Reduce Severe Oral Mucositis Owing to Concurrent Radiation Therapy and Cisplatin for Head and Neck Cancer.

PURPOSE: Avasopasem manganese (GC4419), an investigational selective dismutase mimetic radioprotector, reduced duration, incidence, and severity of severe oral mucositis (World Health Organization grade 3-4) in a phase 2b, randomized, double-blind trial of patients receiving concurrent cisplatin (cis) and radiation therapy (RT) for head and neck cancer. We report the secondary endpoints of final 1- and 2-year tumor outcomes and exploratory data on trismus and xerostomia. METHODS AND MATERIALS: Patients with locally advanced oral cavity or oropharynx cancer to be treated with definitive or postop cis and RT were randomized to 1 of 3 arms: 30 mg avasopasem, 90 mg avasopasem, or placebo. Pairwise comparisons of Kaplan-Meier estimates (each active arm separately vs placebo) were made for overall survival, progression-free survival, locoregional control, and distant metastasis-free survival. Xerostomia and trismus data were collected at each follow-up visit and analyzed for trends by post-RT timepoint and treatment group. RESULTS: At a median follow-up for the entire cohort of 25.5 months (25th-75th percentile, 24.6-26.2 months; range, 0.2-31.9 months), Kaplan-Meier estimates of 1- and 2-year overall survival, progression-free survival, locoregional control, and distant metastasis-free survival were not statistically different. No trends were apparent in xerostomia or trismus data. CONCLUSIONS: Avasopasem does not lead to statistically different tumor control outcomes when used concurrently with cis and RT for head and neck cancer. There was no detectable effect on trismus or xerostomia.

Scalp-Sparing Radiation With Concurrent Temozolomide and Tumor Treating Fields (SPARE) for Patients With Newly Diagnosed Glioblastoma.

Introduction: Standard-of-care treatment for patients with newly diagnosed glioblastoma (GBM) after surgery or biopsy includes concurrent chemoradiation followed by maintenance temozolomide (TMZ) with tumor treating fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report the results of our trial evaluating the safety of TTFields used concurrently with chemoradiation. Methods: This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a Karnofsky performance score (KPS) of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with TMZ (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included TMZ and continuation of TTFields. Scalp-sparing radiation treatment was used to reduce radiation dermatitis. Radiation treatment was delivered through the TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment. Results: There were 30 patients enrolled, including 20 (66.7%) men and 10 (33.3%) women, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). A total of 12 (40%) patients received a gross total resection and 18 (60%) patients had a subtotal resection. A total of 12 (40%) patients had multifocal disease at presentation. There were 20 (66.7%) patients who had unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promotor status and 10 (33.3%) patients who had methylated MGMT promoter status. Median follow-up was 15.2 months (range 1.7 to 23.6 months). Skin adverse events were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. The primary end point was met; no TTFields discontinuation occurred during the evaluation period due to high grade scalp toxicity. A total of 27 (90%) patients had progression, with a median progression-free survival (PFS) of 9.3 months (95% confidence interval (CI): 8.5-11.6 months). The 1-year progression-free survival was 23% (95% CI: 12%-45%). The median overall survival (OS) was 15.8 months (95% CI: 12.5 months-infinity). The 1-year overall survival was 66% (95% CI: 51%-86%). Conclusions: Concurrent TTFields with scalp-sparing chemoradiation is a feasible and well-tolerated treatment option with limited toxicity. A phase 3, randomized clinical trial (EF-32, clinicaltrials.gov Identifier: NCT04471844) investigating the clinical benefit of concurrent TTFields with chemoradiation treatment is currently enrolling. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT03477110.

Thermoplastic Mask-Induced Contact Dermatitis: A Case Report.

Thermoplastic masks are commonly used in radiation therapy to immobilize a patient's head and neck during treatment. They are primarily composed of non-toxic polyester compounds that can be manipulated with heat to mold the shape of a patient's head and neck. There is little previously reported evidence of these masks causing allergic contact dermatitis. We present a case of a 44-year-old female with a history of squamous cell carcinoma of the right tonsil with multiple enlarged lymph nodes following surgical excision of the right tonsillar mass and ipsilateral neck dissection elected to undergo adjuvant radiation therapy with volumetric modulated arc therapy (VMAT) technique without concurrent chemotherapy. A thermoplastic mask was issued prior to radiation therapy. Following the mask fitting, the patient developed an allergic contact dermatitis reaction of the head and neck in areas covered by the mask. Her symptoms worsened with continued use of the thermoplastic mask and radiation therapy. As the patient continued and eventually finished the radiation treatment regimen, the dermatologic symptoms failed to respond to topical facial moisturizer and steroid treatment. The contact dermatitis reaction did not completely dissipate until about three months following completion of radiation therapy and contact with the thermoplastic mask. Thermoplastic masks are not known to cause an allergic contact dermatitis reaction. There is only one other reported case documented in the literature. Such reactions can alter the course of radiation therapy if symptoms are severe enough to disrupt treatment or if they cause worsening of the radiation dermatitis. Allergic contact dermatitis to thermoplastic masks should be well documented in the future to better understand the cause and possible risk factors related to the reaction.

Trends in Adjuvant Therapy After Surgery for Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES/HYPOTHESIS: We aim to 1) evaluate trends in adjuvant treatment of human papilloma virus (HPV)-related oropharyngeal cancer; 2) assess change in complications and functional outcomes over time; and 3) assess change in overall and disease-free survival (DFS) over time. STUDY DESIGN: Retrospective analysis. METHODS: Charts of patients who underwent transoral robotic surgery for HPV-related oropharyngeal cancer between 2011 and 2019 were reviewed. Trend analysis was used to compare rate of adjuvant treatment over time. The Kaplan-Meier method was conducted to analyze overall survival (OS) and DFS. RESULTS: Three hundred and forty-two patients met inclusion criteria. One hundred and sixty-three (47.7%) patients underwent adjuvant radiation, and 90 (26.3%) patients underwent adjuvant chemoradiation. Rate of extranodular extension decreased significantly from 38.9% to 24.0% (P = .004). Rate of adjuvant therapy decreased significantly from 90.9% to 62.5% between 2011 and 2019 (P = .001). In patients who received adjuvant treatment, rate of adjuvant chemoradiation therapy decreased significantly from 40.0% to 20.0% (P < .0005). There was a decrease in rate of 1-year gastrostomy tube dependence in patients treated in 2015 to 2019 versus 2011 to 2014 (2.2% vs. 7.1%, P = .025). In 2011 to 2014, 2-year OS and DFS were 96% and 89%, respectively; in 2015 to 2019, 2-year OS and DFS were 96% and 94%, respectively. There was no difference in OS or DFS between the two time periods. CONCLUSIONS: The rate of adjuvant therapy, particularly chemotherapy, has decreased over time. One-year gastrostomy tube dependence rate has decreased significantly from 2011 to 2014 to 2015 to 2019. There was no change in OS and DFS over this time period. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:806-812, 2022.

Functional Swallow-Related Outcomes Following Transoral Robotic Surgery for Base of Tongue Carcinoma.

In an era where the incidence of oropharyngeal cancer is growing steadily, there have been few studies exploring functional outcomes for individuals whose definitive cancer management approach includes transoral robotic surgical (TORS) resection. This study was designed to examine swallow-related outcomes in individuals newly diagnosed with base of tongue cancer whose treatment plan included surgical resection via TORS. The aims of this study were to determine whether TORS resection for early stage BOT SCCA affected: (a) lingual strength, (b) swallow safety and efficiency, (c) oral intake, and (d) swallowing-related quality of life. Nine individuals meeting the inclusion criteria were recruited to participate from March 2017 to April 2018. Each participant was evaluated at four distinct time points: (a) preoperatively, (b) 1 week postoperatively, (c) 1 month postoperatively, and (d) 3 months postoperatively. The following data were collected at each time point: (a) maximum isometric lingual pressure, (b) Penetration-Aspiration Scale score, (c) Yale Pharyngeal Residue Severity Rating Scale scores, (d) Functional Oral Intake Scale score, and (e) EAT-10 score. Data analysis revealed that a significant decline in maximum isometric lingual pressure, EAT-10 scores, and Functional Oral Intake Scale scores occurred between preoperative baseline measurements and 1 week post surgery. All participants in the study demonstrated a return to levels at or near their baseline level of function for maximum isometric lingual pressure, EAT-10 score, and Functional Oral Intake Scale score by 1 or 3 months post surgery. There were no significant changes in swallow safety or efficiency observed at any time point during the study.

Multi-Institutional Study Validates Safety of Intraoperative Cesium-131 Brachytherapy for Treatment of Recurrent Head and Neck Cancer.

INTRODUCTION: Surgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection. METHODS AND MATERIALS: Findings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts-surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)-were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated. RESULTS: Forty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years. CONCLUSIONS: Among patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifiers NCT02794675 and NCT02467738.

Impact of Lymph Node Yield in Patients Undergoing Total Laryngectomy and Neck Dissection.

OBJECTIVES: To determine the impact of lymph node yield (LNY) in patients undergoing neck dissection at the time of total laryngectomy (TL). To determine the impact of radiation therapy (RT) on LNY. METHODS: Retrospective review of LNY and clinical outcomes in 232 patients undergoing primary or salvage total laryngectomy (TL) with ND. RESULTS: Preoperative RT significantly decreased mean LNY from 31.7 to 23.9 nodes (P < .001). In primary TL patients, age (P < .001) and positive margins (P = .044) were associated with decreased OS. In salvage TL patients, only positive margins was associated with poorer OS (P = .009). No LNY cutoff provided significant OS or DFS benefit. CONCLUSIONS: Radiotherapy significantly reduces LNY in patients undergoing TL and ND. Within a single institution cohort, positive margins, but not LNY, is associated with survival in both primary and salvage TL patients.Level of Evidence: 4.

Loss of SMARCB1 Expression Confers Poor Prognosis to Sinonasal Undifferentiated Carcinoma.

Background Due to the diverse histopathologic features and variable survival rates seen in sinonasal undifferentiated carcinoma (SNUC), it is likely that this diagnostic entity is comprised of a heterogonous group of morphologically undifferentiated tumors. As advancements in molecular testing have led to a better understanding of tumor biology, it has become increasingly evident that SNUC may actually encompass several tumor subtypes with different clinical behavior. As a result, it is also likely that all SNUC patients cannot be treated in the same fashion. Recent investigations have identified loss of the tumor suppressor SMARCB1 (INI1) expression in a subset of undifferentiated sinonasal tumors and extrasinonasal tumors and, studies have suggested that this genetic aberration may be a poor prognostic marker. The objective of this study was to identify differential expression of SMARCB1 in SNUC and to analyze and compare the survival outcomes in SNUC patients with and without SMARCB1 expression. Methods All cases of undifferentiated or poorly differentiated neoplasms of the sinonasal tract treated between 2007 and 2018 at a single tertiary care institution were selected. All cases of SNUC were tested for SMARCB1 status by immunohistochemistry (IHC). Clinical parameters were analyzed using Student's t -test and Fischer's test. Kaplan-Meier methods were used to estimate survival durations, while comparison between both the subgroups was done using the log-rank test. Statistical analysis was performed with the use of SPSS software, Version 25 (IBM, New York, NY, United States). Results Fourteen cases of SNUC were identified. Approximately two-thirds (64%; n = 9) of patients were male and the majority (79%; n = 11) were between fifth to seventh decade. Skull base and orbital invasion were seen in 79% ( n = 11) and 93% ( n = 13) of cases, respectively. Fifty-seven percent of tumors ( n = 8) retained SMARCB1 expression by IHC (SR-SNUC), while the remaining 43% ( n = 6) showed loss of SMARCB1 expression and, thus, were considered as SMARCB1 -deficient (SD-SNUC). Although clinicopathological features and treatment modalities were similar, SD-SNUC showed poorer (OS: p = 0.07; disease free survival [DFS]: p = 0.02) overall survival (OS) and DFS on Kaplan-Meier curves. Additionally, SD-SNUC showed higher recurrence (75 vs. 17%) and mortality (67 vs. 14%) (hazard rate = 8.562; p = 0.05) rates. Both OS (28.82 ± 31.15 vs. 53.24 ± 37.50) and DFS durations (10.62 ± 10.26 vs. 43.79 ± 40.97) were consistently worse for SD-SNUC. Five-year survival probabilities were lower for SD-SNUC (0.33 vs. 0.85). Conclusion SNUC represents a heterogeneous group of undifferentiated sinonasal malignancies. Based on the status of SMARCB1 expression, the two subgroups SD-SNUC and SR-SNUC appear to represent distinct clinical entities, with loss of SMARCB1 expression conferring an overall worse prognosis.

Feasibility of removable balloon implant for simultaneous magnetic nanoparticle heating and HDR brachytherapy of brain tumor resection cavities.

AIM: Hyperthermia (HT) has been shown to improve clinical response to radiation therapy (RT) for cancer. Synergism is dramatically enhanced if HT and RT are combined simultaneously, but appropriate technology to apply treatments together does not exist. This study investigates the feasibility of delivering HT with RT to a 5-10mm annular rim of at-risk tissue around a tumor resection cavity using a temporary thermobrachytherapy (TBT) balloon implant. METHODS: A balloon catheter was designed to deliver radiation from High Dose Rate (HDR) brachytherapy concurrent with HT delivered by filling the balloon with magnetic nanoparticles (MNP) and immersing it in a radiofrequency magnetic field. Temperature distributions in brain around the TBT balloon were simulated with temperature dependent brain blood perfusion using numerical modeling. A magnetic induction system was constructed and used to produce rapid heating (>0.2°C/s) of MNP-filled balloons in brain tissue-equivalent phantoms by absorbing 0.5 W/ml from a 5.7 kA/m field at 133 kHz. RESULTS: Simulated treatment plans demonstrate the ability to heat at-risk tissue around a brain tumor resection cavity between 40-48°C for 2-5cm diameter balloons. Experimental thermal dosimetry verifies the expected rapid and spherically symmetric heating of brain phantom around the MNP-filled balloon at a magnetic field strength that has proven safe in previous clinical studies. CONCLUSIONS: These preclinical results demonstrate the feasibility of using a TBT balloon to deliver heat simultaneously with HDR brachytherapy to tumor bed around a brain tumor resection cavity, with significantly improved uniformity of heating over previous multi-catheter interstitial approaches. Considered along with results of previous clinical thermobrachytherapy trials, this new capability is expected to improve both survival and quality of life in patients with glioblastoma multiforme.

Modeling the Impact of Cardiopulmonary Irradiation on Overall Survival in NRG Oncology Trial RTOG 0617.

PURPOSE: To quantitatively predict the impact of cardiopulmonary dose on overall survival (OS) after radiotherapy for locally advanced non-small cell lung cancer. EXPERIMENTAL DESIGN: We used the NRG Oncology/RTOG 0617 dataset. The model building procedure was preregistered on a public website. Patients were split between a training and a set-aside validation subset (N = 306/131). The 191 candidate variables covered disease, patient, treatment, and dose-volume characteristics from multiple cardiopulmonary substructures (atria, lung, pericardium, and ventricles), including the minimum dose to the hottest x% volume (Dx%[Gy]), mean dose of the hottest x% (MOHx%[Gy]), and minimum, mean (Mean[Gy]), and maximum dose. The model building was based on Cox regression and given 191 candidate variables; a Bonferroni-corrected P value threshold of 0.0003 was used to identify predictors. To reduce overreliance on the most highly correlated variables, stepwise multivariable analysis (MVA) was repeated on 1000 bootstrapped replicates. Multivariate sets selected in ≥10% of replicates were fit to the training subset and then averaged to generate a final model. In the validation subset, discrimination was assessed using Harrell c-index, and calibration was tested using risk group stratification. RESULTS: Four MVA models were identified on bootstrap. The averaged model included atria D45%[Gy], lung Mean[Gy], pericardium MOH55%[Gy], and ventricles MOH5%[Gy]. This model had excellent performance predicting OS in the validation subset (c = 0.89). CONCLUSIONS: The risk of death due to cardiopulmonary irradiation was accurately modeled, as demonstrated by predictions on the validation subset, and provides guidance on the delivery of safe thoracic radiotherapy.

Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma.

INTRODUCTION: Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-sparing radiation with concurrent TTFields. METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m2 daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma. RESULTS: We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70-90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months). CONCLUSIONS: Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.