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Background: Evaluate whether extranodal extension (ENE) extent impacts outcomes in patients with oral cavity squamous cell carcinoma (OCSCC)., Methods: From an institutional database, patients with OCSCC and pathologic ENE who received adjuvant treatment were included. Surgical slides were reviewed to confirm ENE extent. Multivariable Cox regression was used to relate patient/treatment characteristics with disease-free survival (DFS) and overall survival (OS). ENE was analyzed as both a dichotomous and continuous variable., Results: A total of 113 patients were identified. Between major (>2 mm) versus minor ENE (≤2 mm), there was no significant difference in DFS (HR 1.18, 95%CI 0.72-1.92, p = 0.51) or OS (HR 1.17, 95%CI 0.70-1.96, p = 0.55). There was no significant association between ENE as a continuous variable and DFS (HR 0.97 per mm, 95%CI 0.87-1.4, p = 0.96) or OS (HR 0.96 per mm, 95%CI 0.83-1.11, p = 0.58)., Conclusion: No significant relationship was seen between ENE extent and DFS or OS in individuals with OCSCC., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS)., Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation., Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023., Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks., Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers., Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed., Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation., Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

Importance: Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence., Objective: To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins., Design, Setting, and Participants: The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023., Main Outcomes and Measures: Main outcomes were risk factors for local recurrence., Results: A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group., Conclusions and Relevance: In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Competing Interests: This study was supported by the Melvin Markey Scholars Program at the Cleveland Clinic.

Background: Metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) can be treated with immunotherapy (IO). Cranial nerve involvement (CNI) is uncommon in cSCC and is a poor prognostic factor. Our aim is to describe how patients with CNI respond to IO monotherapy and/or as an adjunct to RT., Methods: Under an IRB approved protocol, patients with histologically proven cSCC of the head and neck with CNI treated with IO were retrospectively reviewed., Results: Twelve patients were included and received cemiplimab or pembrolizumab. Eight patients had CNI at diagnosis, and 4 at time of recurrence after non-IO therapy. Best responses were complete response (1), partial response (7), stable disease (1), progressive disease (2), and pending response (1). Nine patients are alive, 6 of which remain on IO., Conclusions: In this cohort, IO showed clinical response in 83% of patients, indicating IO can be an effective monotherapy, reserving RT for instances of local failure after IO., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective: Organ preservation (OP) treatment for advanced laryngeal cancer has increased compared to primary total laryngectomy. Our study compares oncologic and functional outcomes between these approaches., Study Design: Retrospective cohort study., Setting: Single tertiary care institution., Methods: Retrospective review of patients receiving primary total laryngectomy or OP for laryngeal cancer between 1/1/2000 and 12/31/2018., Results: A total of 118 patients received primary total laryngectomy and 119 received OP. Overall survival was similar between total laryngectomy and OP. When stratified by T stage, disease-free survival was worse among T3 patients receiving OP versus total laryngectomy. In T3 patients, 28 OP patients experienced local recurrence (28.9%) compared to 3 total laryngectomy patients (7.1%; p < 0.01). In total, 20 OP patients with local recurrence received salvage surgery. These patients had similar overall survival to patients who underwent initial total laryngectomy (TL). About 14 OP patients with local recurrence did not receive salvage surgery. About 89 (75.4%) TL patients achieved normal diet as compared to 64 (53.8%) OP patients (p < 0.001). In TL patients, 106 (89.8%) received primary or secondary tracheoesophageal-prosthesis, 82 (77.4%) of whom achieved completely understandable speech., Conclusions: There was no difference in survival by treatment in T4 patients, possibly because of strict patient selection. However, disease-free survival was worse in T3 patients receiving OP, likely due to a high local recurrence rate. Approximately 40% of patients with local recurrence were not eligible for salvage laryngectomy. TL patients had comparable swallowing and speech outcomes with OP patients., Level of Evidence: 3 Laryngoscope, 133:1122-1131, 2023., (© 2022 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: Evaluate outcomes of patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy (IO)., Methods: Among patients with R/M HNSCC treated with IO in this retrospective single-institution cohort, Cox regression was used to compare overall survival (OS) for those with platinum-refractory disease and those treated in the first-line setting with OS from KEYNOTE-040/048, respectively. Multivariable Cox regression was used to identify predictors of OS., Results: There was no significant OS difference for those treated in the platinum-refractory setting when compared to patients on KEYNOTE-040 (HR = 1.22, p = 0.27), nor for the first-line setting compared to KEYNOTE-048 (HR = 1.23, p = 0.19). ECOG-PS 1 (HR = 2.00, p = 0.02) and ECOG-PS 2 (HR = 3.13, p < 0.01) were associated with worse OS. Higher absolute lymphocyte count (ALC) was associated with improved OS (HR = 0.93 per 100 cells/μL, p = 0.03)., Conclusions: Real-world outcomes of IO in R/M HNSCC are similar to outcomes in randomized control trials, with performance status and ALC correlating with OS., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Introduction/background: For early stage medically inoperable lung cancer treated with fractionated stereotactic body radiotherapy (SBRT), higher local failure is associated with squamous carcinoma (SqC) compared to adenocarcinoma (AC). This study explored whether histology influences single-fraction SBRT local control., Materials and Methods: We surveyed our prospective data registry from 12/2009 to 12/2019 for SF-SBRT cases with biopsy-proven AC or SqC only. Outcomes of interest included local (LF), nodal (NF), distant (DF) failure rates and overall survival (OS), as well as treatment-related toxicity., Results: For the 10-year interval surveyed, 113 patients met study criteria. There was no association between histology and dose received (34 Gy or 30 Gy). Median follow up was 22.9 months. Patient characteristics were balanced between histologic cohorts. Median tumor size was 1.9 cm. Comparing total AC vs. SqC cohorts, 2-year LF rates (%) were 7.3 vs. 9.6, respectively (P = .9805). In %, 2-year LF, NF, DF and OS rates for AC for 30 Gy and 34 Gy, respectively, were 10.8 vs. 6.4; 10.5 vs. 16.2; 15.8 vs. 13.0; 77.9 vs.71.2 (all P = non-significant). In %, 2-year LF, NF, DF, and OS rates for SqC for 30 Gy and 34 Gy, respectively, were 11.8 vs. 8.1; 5.9 vs. 18.0; 23.5 vs. 9.7; 70.6 vs. 77.1 (all P = non-significant). When considering toxicities, there were no grade 4/5 toxicities and no significant differences in any other toxicity rate by histology or dose., Conclusion: SF-SBRT local control was not associated with histology, unlike fractionated schedules. This novel finding adds to the evolving understanding of this treatment schedule., (Copyright © 2022. Published by Elsevier Inc.)

Background: We sought to determine whether detection of cartilage invasion (CI) by computed tomography predicts oncologic outcomes after primary total laryngectomy., Methods: Retrospective cohort study comparing oncologic outcomes between radiologic versus pathologic diagnosis., Results: Assessment of clear CI versus gestalt CI resulted in 84% versus 48% specificity, 90.9% versus 80.3% positive predictive value (PPV), 60.6% versus 80.3% sensitivity, 44.7% versus 48% negative predictive value (NPV), respectively. Disease-free survival (DFS) was similar between cT4a and cT3/cT2 patients (p = 0.87). DFS trended towards superiority among pT3/pT2 versus pT4a patients (p = 0.18). DFS was similar among patients with CI on radiologist gestalt versus no CI (p = 0.94). Histologically confirmed CI was associated with a hazard ratio (HR) of 1.46 (p = 0.27), gestalt CI 1.13 (p = 0.70), and clear CI 1.61 (p = 0.10) for DFS., Conclusion: Gestalt determination of CI results in high sensitivity but low specificity, while clear determination of CI results in moderate sensitivity and high specificity., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background/aim: Definitive treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is often compromised in older adults due to concerns about potential treatment toxicity intolerance. We reviewed our institutional experience with definitive management of older adults with LAHNSCC., Patients and Methods: From our Institutional Review Board-approved registry, we identified patients aged >60 years with stage III-IV, M0 LAHNSCC (seventh/earlier editions of the American Joint Committee on Cancer classification) treated with definitive radiotherapy from 1993-2019. Indications for concurrent chemotherapy included T3-4 or N2-3 disease. Multivariable analysis using Fine and Gray regression was performed to identify risk factors associated with recurrence. The cumulative incidence method was used to calculate recurrence rates., Results: Overall, 350 patients were identified: 223 aged 60-69, 82 aged 70-74, and 45 aged ≥75 years. Median follow-up was 36.3 months. Two-year recurrence rates were 13.7%, 20.2% and 34.8%, respectively; human papillomavirus-positive disease was present in 190 (85%), 44 (54%), and 25 (56%), respectively; and systemic therapy was given to 194 (87%), 64 (88%), and 23 (56%) patients, respectively. Factors significantly associated with increased risk of recurrence included age ≥75 years, Karnofsky performance status 70-80, clinical N2c-N3, and Charlson score 2-3., Conclusion: Patients aged ≥75 years received less aggressive therapy and experienced increased recurrence compared to younger patients. Outcomes for those aged 70-74 years were similar to younger patients treated with aggressive therapy, despite their inferior performance status/comorbidity, and such patients should not routinely be excluded from standard-of-care therapy. Further study is needed to optimize therapy for a redefined older adult (age ≥75 years) population., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Hypofractionated radiation therapy is not commonly used in head and neck cancers (HNC) due to increased toxicity observed in historical cohorts. This study reviews our institutional experience using hypofractionated intensity modulated radiation therapy (H-IMRT) for HNC., Patients and Methods: A retrospective cohort study of 56 patients with HNC treated with H-IMRT with ≥50 Gy in 20 fractions was conducted. The primary outcomes were acute and late toxicity., Results: Two-year locoregional control was 87% and median overall survival was 46 months. There were no acute or late grade 4 or 5 toxicities. Acute grade 2 and 3 toxicity was seen in 79% (N=44) and 25% (N=14), respectively. Late grade 2 toxicity was seen in 9% (N=5). No patients required the placement of a feeding tube or tracheostomy., Conclusion: H-IMRT for the definitive or post-operative treatment of HNC using ≥50 Gy in 20 fractions appears safe and well tolerated with modest toxicity., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The prognostication of Epstein-Barr virus (EBV) and human papillomavirus (HPV) status in nasopharyngeal cancer (NPC) is unclear., Methods: This retrospective study analyzed NPC from 2000 to 2019., Results: Seventy-eight patients were included: 43 EBV + , 12 HPV + , 23 EBV - /HPV - , and 0 EBV + /HPV + . All p16 + tumors were also positive for HPV-CISH. Baseline characteristics were not different between groups except age, N-classification, and Karnofsky Performance Scale (KPS) (p < 0.05). For EBV + , HPV + , and EBV - /HPV - respectively, 3-year overall survival (OS) was 89.9%, 69.8%, and 52.5% (p = 0.006). EBV - /HPV - status was significantly associated with worse OS but not freedom from progression (FFP) on univariate analysis, and did not remain a significant predictor of OS after adjusting for KPS, age, and group stage., Conclusions: EBV + NPC tumors were seen in younger, healthier patients than HPV + and EBV - tumors, and there were no cases of coinfection. The association of viral status with OS was insignificant after adjusting for KPS and age., (© 2022 Wiley Periodicals LLC.)

Objectives: To explore the influence of treatment package time(TPT) in high-risk oral cavity squamous cell carcinoma(OCSCC) receiving adjuvant radiotherapy with concurrent chemotherapy(CRT)., Materials and Methods: We queried our multi-institutional OCSCC collaborative database for cases diagnosed between 2005 and 2015 who underwent surgery followed by adjuvant CRT. All patients had high-risk features: extranodal extension(ENE) and/or positive surgical margin(PM). TPT was days between surgery to last radiotherapy fraction. Kaplan-Meier curves, log-rank p-values and multivariate analysis(MVA) were used to investigate the impact of TPT on overall(OS), disease-free(DFS), locoregional failure-free(LRFS) and distant metastases-free(DMFS) survival., Results: We identified 187 cases: median age 58 (range, 24-87 years), males 66%, and ever smokers 69%. ENE and PM were detected in 85% and 32%, and oral tongue and floor of the mouth constituted 49% and 18%, respectively. Median radiotherapy and cisplatin doses received were 66 Gy and 200 mg/m2. Overall, median TPT was 98 (range, 63-162 days). OS was worse for TPT > 90-days (n = 134) than TPT ≤ 90 (n = 53) at two-(65% vs. 71%) and five-years (45% vs. 62%); p = 0.05, with similar results for DFS. No influence on LRFS or DMFS was noted. More lymph nodes(LN) dissected(P = 0.039), T3-4 disease(P = 0.017), and unplanned reoperations(P = 0.037) occurred with TPT > 90-days. On MVA, TPT in 10-day increments was independently detrimental for OS (Hazard Ratio: 1.14; 95 %Confidence Interval [1-1.28]; P = 0.043), perineural invasion, age and positive LN (p < 0.05 for all)., Conclusion: In one of the largest multi-institutional cohorts, TPT > 90-days predicted worse OS for high-risk OCSCC receiving adjuvant CRT. All efforts are needed to optimize perioperative care and baseline conditions for favorable outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: To define the location of the initial contralateral lymph node (LN) metastasis in patients with oropharynx cancer., Methods: The location of the LN centroids from patients with oropharynx cancer and a single radiographically positive contralateral LN was defined. A clinical target volume (CTV) inclusive of all LN centroids was created, and its impact on dose to organs at risk was assessed., Results: We identified 55 patients of which 49/55 had a single contralateral LN in level IIA, 4/55 in level III, 1/55 in level IIB, and 1/55 in the retropharynx. Mean radiation dose to the contralateral parotid gland was 15.1 and 21.0 Gy, (p <0.001) using the modeled high-risk elective CTV and a consensus CTV, respectively., Conclusions: We present a systematic approach for identifying the contralateral nodal regions at highest risk of harboring subclinical disease in patients with oropharynx cancer that warrants prospective clinical study., (© 2021 Wiley Periodicals LLC.)