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PurposeReducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.Patients and methodsIn this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).ResultsThree hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% (P = .04). For IMRT, 2-year PFS was 87.6% (P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% (P = .56).ConclusionThe IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

ObjectiveBuccal cells are an ideal surrogate tissue for studying biologic effects of carcinogens or drugs, however inherent fragility and salivary RNAses limit RNA yield. We conducted healthy volunteer trials to optimize collection conditions.MethodsWe conducted: (a) a single-arm crossover study evaluating four test conditions on RNA yield by buccal cytobrush; (b) a single-arm prospective study evaluating RNA yield by investigator vs self-collection.ResultsAntecedent toothbrushing, time of day, and number of cytobrush strokes did not significantly impact RNA yield. RNA yield was doubled by using 2 vs 1 cytobrush per buccal surface (P = .0054). Self-collection of buccal cells for RNA was feasible; 36 of 50 (72%) samples passed quality control.ConclusionRNA yield was doubled by using two cytobrushes per buccal surface. Healthy volunteers can self-collect sufficient buccal RNA for gene expression studies. Techniques from these pragmatic trials could enhance availability of a limited tissue for serial biomarker measurements.Level of evidence1b-Prognosis Study (Individual prospective cohort study).

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. [ABSTRACT FROM AUTHOR]

BackgroundPatients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC.MethodsThis single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway.ResultsSeven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue.ConclusionEverolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016.

Proteins of the signal transducer and activator of transcription (STAT) family mediate cellular responses to cytokines and growth factors. Aberrant regulation of the STAT3 oncogene contributes to tumor formation and progression in many cancers, including head and neck squamous cell carcinoma (HNSCC), where hyperactivation of STAT3 is implicated in both treatment resistance and immune escape. There are no oncogenic gain-of-function mutations in HNSCC. Rather, aberrant STAT3 signaling is primarily driven by upstream growth factor receptors, such as Janus kinase (JAK) and epidermal growth factor receptor (EGFR). Moreover, genomic silencing of select protein tyrosine phosphatase receptors (PTPRs), tumor suppressors that dephosphorylate STAT3, may lead to prolonged phosphorylation and activation of STAT3. This review will summarize current knowledge of the STAT3 pathway and its contribution to HNSCC growth, survival, and resistance to standard therapies, and discuss STAT3-targeting agents in various phases of clinical development.

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus–negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53 -mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53- mutant HNSCC that can be conducted within the National Clinical Trials Network. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence‐based statement on the definition of advanced thyroid cancer and its targeted systemic treatment. Methods: An expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel. Results: A review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided. Conclusions: With the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Standard of care for high‐risk cutaneous squamous cell carcinoma (cSCC) is surgical excision of the primary lesion with clear margins when possible, and additional resection of positive margins when feasible. Even with negative margins, certain high‐risk factors warrant consideration of adjuvant therapy. However, which patients might benefit from adjuvant therapy is unclear, and supporting evidence is conflicting and limited to mostly small retrospective cohorts. Here, we review literature from the last decade regarding adjuvant radiation therapy and systemic therapy in high‐risk cSCC, including recent and current trials and the role of immune checkpoint inhibitors. We demonstrate evidence gaps in adjuvant therapy for high‐risk cSCC and the need for prognostic tools, such as gene expression profiling, to guide patient selection. More large‐cohort clinical studies are needed for collecting high‐quality, evidence‐based data for determining which patients with high‐risk cSCC may benefit from adjuvant therapy and which therapy is most appropriate for patient management. [ABSTRACT FROM AUTHOR]

Background: Process‐related measures have been proposed as quality metrics in head and neck cancer care. A recent single‐institution study identified four key metrics associated with increased survival. This study sought to validate the association of these quality metrics with survival in a multi‐institutional cohort. Methods: Multicenter retrospective study of patients with oral cavity squamous cell (1/2005‐1/2015). Baseline patient and disease characteristics and compliance with quality metrics was evaluated. Association between compliance with quality metrics with overall survival (OS), disease‐free survival (DFS), and disease‐specific survival (DSS) was evaluated using Cox proportional hazards models. Results: Failure to comply with two or more of the quality metrics was associated with worse OS, DFS, and DSS. Adherence to all or all but one of the quality metrics was found to be associated with improved survival. Conclusions: Process‐related quality metrics are associated with increased survival in patients with oral cavity squamous cell carcinoma in a multi‐institutional cohort. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between tumor volume and locoregional failure (LRF) after concurrent chemoradiation (CCRT) for locally advanced larynx cancer (LC).Methods: This is a retrospective cohort study from 2009 to 2014 identified from an institutional review board-approved registry. Fifty-nine of 68 patients with locally advanced larynx cancer treated with definitive CCRT who had available imaging for review were identified. The main endpoint to be assessed was the association between gross tumor volumes (GTV; T = total, P = primary, N = nodal) and LRF. Receiver operative characteristic (ROC) curves were used to investigate diagnostic accuracy.Results: Twenty LRFs were observed, resulting in a 2-year LRF rate of 39% (95% CI, 23-52%). On UVA, the GTV-T (P = .01), GTV-P (P = .05), and GTV-N (P = .04) were statistically significant predictors of LRF. Furthermore, age, smoking status, N-stage, larynx subsite, and tracheostomy/feeding tube dependence were potentially associated with LRF (P < .3), whereas T-stage (T3-4 vs. T2) was not (HR 1.05, 95% CI, 0.38-2.91, P = .92). In the multivariable model, GTV-P (HR 1.022, 95% CI, 0.999-1.046, P = .07) and GTV-N (HR 1.053, 95% CI, 1.0004-1.108, P = .05) were the two most impactful covariates on the model's R2 . ROC analysis suggested an optimal cut point of 12 cc in the GTV-T. The 2-year LRF for GTV-T > 12 cc was 64.2% and ≤ 12 cc was 16.4%, P = .006.Conclusion: GTV is associated with LRF after definitive CCRT for LC. Patients with bulky primary and/or nodal tumors may be better served with upfront surgical resection regardless of T-stage. Further investigation into the safety of larynx preservation for low-volume T4 tumors can be considered.Level Of Evidence: 4 Laryngoscope, 130:2372-2377, 2020. [ABSTRACT FROM AUTHOR]

Background: De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved.Methods: From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation).Results: Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%.Conclusions: The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established. [ABSTRACT FROM AUTHOR]

Background: The role of smoking among patients with human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (OPSCC) is unclear. Methods: A retrospective cohort study of patients with HPV(+) OPSCC from 2001 to 2015 at a tertiary‐care institution was conducted. The primary outcome was overall survival (OS). Results: Among 484 included patients, 94 (19.4%) were active smokers, 226 (46.7%) were former smokers, and 164 (33.9%) never smoked. Among active smokers, 82 patients (87.2%) had a ≥10 pack‐year and 69 (73.4%) had a ≥20 pack‐year smoking history. After adjusting for covariates, active smoking was a significant predictor of inferior OS (HR 2.28, P <.001) and PFS (HR 2.26, P <.001). When including pack‐years as the covariate, ≥20 pack‐years predicted a decreased effect‐size for inferior OS and PFS. Conclusions: For patients with HPV(+) OPSCC, active smoking at diagnosis is the most powerful covariate capturing smoking history to predict OS and PFS. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Patients with human papillomavirus (HPV)-induced cancer of unknown primary (CUP) are generally excluded from clinical trials, despite surgical series reporting detection rates of occult oropharynx primaries of >80%. We performed a matched-pair analysis to compare outcomes between T0N1-3M0 HPV+ CUP and T1-2N1-3M0 HPV+ oropharynx known primary (OPX).Study Design: Retrospective cohort study at a single institution.Methods: Patients with early T stage, node positive HPV+ OPX or CUP treated with curative intent between 1998 and 2016 were identified. For a subgroup of CUP patients with an unknown HPV status, we imputed HPV status and included patients with a >80% probability of being HPV+. Cohorts were matched based on patient demographics using a nearest neighbor propensity technique. After matching, patients were grouped according to either a favorable or unfavorable risk stratification designations per current NRG Oncology clinical trial enrollment criteria. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier analysis.Results: Of 298 patients with T1-2N1-3 OPX, 48 were matched to 48 HPV+ CUP patients (32 with confirmed and 16 imputed HPV status). Median follow-up for CUP (34.1 months) and OPX (27.8 months) patients were similar (P = .23).There were no significant differences between the CUP and OPX groups for 3-year DFS (89% vs. 85%, P = .44), and 3-year OS (91% vs. 91%, P = .11), respectively.Conclusions: Patients with T0N+M0 HPV-induced CUP have similar survival outcomes to matched patients with T1-2N+M0 HPV+ OPX. These patients can reasonably be included in clinical trials investigating the role of treatment deintensification and risk stratified similar to patients with early-stage known primary OPX cancer.Level Of Evidence: 4. Laryngoscope, 128:1379-1385, 2018. [ABSTRACT FROM AUTHOR]

The article describes a case of primary RET-mutated lung neuroendocrine carcinoma in a patient with multiple endocrine neoplasia (MEN). A chest X-ray and a subsequent computed tomography (CT) scan revealed a neuroendocrine neoplasm of the lung in the patient. Cytotoxic chemotherapy with carboplatin and etoposide was initiated, followed by cabozantinib, which led to an improvement in the patient's performance status and symptoms of cough and skeletal pain.

Opinion Statement: Despite an overall decline in the incidence of tobacco-related cancers, human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) of the oropharynx is on the rise. The prognosis of HPV-related oropharynx cancer (HPV-OPC) is generally favorable even in locoregionally advanced disease, and a variety of treatment options are available. Though the primary treatment modality of choice remains definitive radiation (RT), surgical resection followed by appropriate adjuvant therapy remains an option, especially in those patients who may not be favorable candidates for definitive radiotherapy, particularly when concurrent chemotherapy is warranted. Upfront resection may offer a chance to avoid the well-described acute toxicity and long-term morbidity associated with concurrent chemoradiotherapy (CRT) in select patients. Despite the overall favorable prognosis of HPV-OPC, indications for therapy remain unchanged from the recommendations for treatment in tobacco-related OPC and other anatomic sites of HNSCC. Ongoing studies assessing deintensification strategies in HPV-OPC are focused on maintaining high cure rates while improving treatment-related toxicities. Currently, no clear guidelines exist for the choice of primary therapy, surgical resection, or RT in patients with HPV-OPC, highlighting the need for multidisciplinary discussion and review of the individual patient before selecting the most appropriate curative modality. This review seeks to present the data for postoperative therapy in HPV-related oropharyngeal HNSCC. [ABSTRACT FROM AUTHOR]

mRNA-4157 (V940) is an individualized neoantigen therapy (INT) targeting up to 34 patient-specific tumor neoantigens to induce T cell responses and potentiate anti-tumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T cell responses to neoantigens from the first-in-human phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1mg mRNA-4157 + 200mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event (AE); there were no grade 4/5 AEs or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo, and strengthened pre-existing, T cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA INT approach in oncology.

Despite significant progress and improving outcomes in the management of head and neck squamous cell carcinoma (HNSCC), there are few effective treatment options for patients with recurrent or metastatic head and neck squamous cell carcinoma. The advent of immune checkpoint inhibitors has changed the treatment algorithm of head and neck squamous cell carcinoma and are approved in the frontline setting for recurrent and metastatic (R/M) head and neck squamous cell carcinomas. Although promising for some patients, most patients with R/M HNSCC do not derive clinical benefit from currently approved checkpoint inhibitors. Many studies are underway to identify the patient population that would benefit the most from immunotherapy as well as postimmunotherapy treatment failures, including novel combinations of immunomodulatory therapies. In this review, we summarize the clinical development of all major clinical trials of immunotherapy in HNSCC.

Importance: Survival outcomes for anaplastic thyroid cancer (ATC), the most aggressive subtype of thyroid cancers, have remained poor. However, targeted therapies and immunotherapies present new opportunities for treatment of this disease. Evaluations of survival outcomes over time with new multimodal therapies are needed for optimizing treatment plans., Objective: To evaluate the association of treatment strategies and tumor characteristics with overall survival (OS) among patients with ATC., Design, Setting, and Participants: This retrospective case series study evaluated the survival outcomes stratified by treatment strategies and tumor characteristics among patients with ATC treated at a tertiary level academic institution from January 1, 2000, to December 31, 2021. Demographic, tumor, treatment, and outcome characteristics were analyzed. Kaplan-Meier method and log rank test modeled OS by treatment type and tumor characteristics. Data were analyzed in May 2022., Main Outcomes and Measures: Overall survival (OS)., Results: The study cohort comprised 97 patients with biopsy-proven ATC (median [range] age at diagnosis, 70 [38-93] years; 60 (62%) female and 85 [88%] White individuals; 59 [61%] never smokers). At ATC diagnosis, 18 (19%) patients had stage IVA, 19 (20%) had stage IVB, and 53 (55%) had stage IVC disease. BRAF status was assessed in 38 patients; 18 (47%) had BRAF-V600E variations and 20 (53%), BRAF wild type. Treatment during clinical course included surgery for 44 (45%) patients; chemotherapy, 41 (43%); definitive or adjuvant radiation therapy, 34 (RT; 35%); and targeted therapy, 28 (29%). Median OS for the total cohort was 6.5 (95% CI, 4.3-10.0) months. Inferior OS was found in patients who did not receive surgery (hazard ratio [HR], 2.12; 95% CI, 1.35-3.34; reference, received surgery), chemotherapy (HR, 3.28; 95% CI, 1.99-5.39; reference, received chemotherapy), and definitive or adjuvant RT (HR, 2.47; 95% CI, 1.52-4.02; reference, received definitive/adjuvant RT). On multivariable analysis, age at diagnosis (HR, 1.03; 95% CI, 1.01-1.06), tumor stage IVC (HR, 2.65; 95% CI, 1.35-5.18), and absence of definitive or adjuvant RT (HR, 1.90; 95% CI, 1.01-3.59) were associated with worse OS., Conclusions and Relevance: This retrospective single-institution study found that lower tumor stage, younger age, and the ability to receive definitive or adjuvant RT were associated with improved OS in patients with ATC.

The purpose of this study was to determine the negative predictive value (NPV) of a 12- to 14-wk posttreatment PET/CT for 2-y progression-free survival (PFS) and locoregional control (LRC) in patients with p16-positive locoregionally advanced oropharyngeal cancer (LA-OPC). Study was a secondary endpoint in NRG-HN002, a noncomparative phase II trial in p16-positive LA-OPC, stage T1-T2, N1-N2b or T3, N0-N2b, and ≤10 pack-year smoking. Patients were randomized in a 1:1 ratio to reduced-dose intensity-modulated radiotherapy (IMRT) with or without cisplatin. Methods: PET/CT scans were reviewed centrally. Tumor response evaluations for the primary site, right neck, and left neck were performed using a 5-point ordinal scale (Hopkins criteria). Overall scores were then assigned as negative, positive, or indeterminate. Patients with a negative score for all 3 evaluation sites were given an overall score of negative. The hypotheses were NPV for PFS and LRC at 2-y posttreatment ≤ 90% versus >90% (1-sided P value, 0.10). Results: A total of 316 patients were enrolled, of whom 306 were randomized and eligible. Of these, 131 (42.8%) patients consented to a posttherapy PET/CT, and 117 (89.3%) patients were eligible for PET/CT analysis. The median time from the end of treatment to PET/CT scan was 94 d (range, 52-139 d). Estimated 2-y PFS and LRC rates in the analysis subgroup were 91.3% (95% CI, 84.6, 95.8%) and 93.8% (95% CI, 87.6, 97.5%), respectively. Posttreatment scans were negative for residual tumor for 115 patients (98.3%) and positive for 2 patients (1.7%). NPV for 2-y PFS was 92.0% (90% lower confidence bound [LCB] 87.7%; P = 0.30) and for LRC was 94.5% (90% LCB 90.6%; P = 0.07). Conclusion: In the context of deintensification with reduced-dose radiation, the NPV of a 12- to 14-wk posttherapy PET/CT for 2-y LRC is estimated to be >90%, similar to that reported for patients receiving standard chemoradiation. However, there is insufficient evidence to conclude that the NPV is >90% for PFS., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Importance: Tall cell morphology (TCM) is a rare and aggressive variant of papillary thyroid carcinoma (PTC) that has been associated with poor outcomes; however, the risk factors for worse survival are not well characterized., Objective: To identify prognostic factors associated with cancer recurrence and death in patients with PTC-TCM., Design, Setting, and Participants: All patients treated for PTC-TCM at a single tertiary-level academic health care institution from January 1, 1997, through July 31, 2018, were included. Tall cell variant (TCV) was defined as PTC with TCM of 30% or more; and tall cell features (TCF) was defined as PTC with TCM of less than 30%. Patients with other coexisting histologic findings and/or nonsurgical management were excluded. Clinicopathologic features associated with worse outcomes were identified using Kaplan-Meier and Cox proportional-hazards model. Data were analyzed from March 1, 2018, to August 15, 2018., Main Outcomes and Measures: Locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and overall survival (OS) after surgery., Results: A total of 365 patients (median [range] age, 51.8 [15.9-91.6] years; 242 [66.3%] female) with PTC-TCM (TCV, 32%; TCF, 68%) were evaluable. Total thyroidectomy was performed in 336 (92%) patients; 19 (5.2%) received radiotherapy; and 15 (4.1%) received radioactive iodine. Clinical features were pT3 or T4, 65%; node-positive, 53%; and positive surgical margins, 24%. LRRFS at 1-, 3-, 5-, and 10-year was 95%, 87%, 82%, and 73%, respectively. On multivariable analysis, male sex and age were not independent predictors of inferior 5-year LRRFS, whereas positive surgical margins (HR, 3.5; 95% CI, 2.0-6.3), positive lymph nodes (HR, 2.8; 95% CI, 1.4-5.8), and primary tumor size of 3 cm or more (HR, 3.3; 95% CI, 1.4-7.8) were strongly associated with worse LRRFS. Age 55 years or older (HR, 3.2; 95% CI, 1.5-7.0), male sex (HR 4.5; 95% CI, 2.1-10.0), positive surgical margins (HR, 2.7; 95% CI, 1.2-6.0), nodal positivity (HR, 3.1; 95% CI, 1.3-7.7), tumor diameter of 1.5 cm or more (HR, 20.6; 95% CI, 2.8-152.1), and TCV vs TCF (HR, 3.1; 95% CI, 1.5-6.7) were associated with worse DRFS. Male sex (HR, 3.1; 95% 1.4-6.8) and tumor diameter of 1.5 cm or more (HR, 2.8; 95% CI, 1.0-7.4) were associated with worse OS. A findings-based nomogram was constructed to predict 10-year LRRFS (C index, 0.8)., Conclusions and Relevance: This retrospective cohort study found that in patients with PTC-TCM, positive surgical margins, node positive disease, and tumor size of 3 cm or more were risk factors for worse LRRFS. Intensified locoregional therapy, including adjuvant radiation, may be considered for treating these patients.

Background: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings., Methods: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events., Results: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%)., Conclusions: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)., (Copyright © 2022 Massachusetts Medical Society.)