RESUMO
BACKGROUND: Gut microbiome modulation to boost antitumor immune responses is under investigation. METHODS: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis. RESULTS: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics. CONCLUSIONS: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.
Assuntos
Quimiorradioterapia , Microbioma Gastrointestinal , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/microbiologia , Neoplasias Orofaríngeas/virologia , Masculino , Feminino , Pessoa de Meia-Idade , Quimiorradioterapia/métodos , Idoso , Infecções por Papillomavirus/complicações , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/microbiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Adulto , Fezes/microbiologiaRESUMO
BACKGROUND: Oral and gut microbiomes have emerged as potential biomarkers in cancer. We characterised the oral and gut microbiomes in a prospective observational cohort of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients and evaluated the impact of chemoradiotherapy (CRT). METHODS: Saliva, oropharyngeal swabs over the tumour site and stool were collected at baseline and post-CRT. 16S RNA and shotgun metagenomic sequencing were used to generate taxonomic profiles, including relative abundance (RA), bacterial density, α-diversity and ß-diversity. RESULTS: A total of 132 samples from 22 patients were analysed. Baseline saliva and swabs had similar taxonomic composition (R2 = 0.006; p = 0.827). Oropharyngeal swabs and stool taxonomic composition varied significantly by stage, with increased oral RA of Fusobacterium nucleatum observed in stage III disease (p < 0.05). CRT significantly reduced the species richness and increased the RA of gut-associated taxa in oropharyngeal swabs (p < 0.05), while it had no effect in stool samples. These findings remained significant when adjusted by stage, smoking status and antibiotic use. CONCLUSIONS: Baseline oral and gut microbiomes differ by stage in this HPV+ cohort. CRT caused a shift towards a gut-like microbiome composition in oropharyngeal swabs. Stage-specific features and the transitions in oral microbiome might have prognostic and therapeutic implications.
Assuntos
Quimiorradioterapia/efeitos adversos , Microbioma Gastrointestinal , Mucosa Bucal/microbiologia , Neoplasias Orofaríngeas/terapia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Saliva/microbiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Feminino , Seguimentos , Humanos , Masculino , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/efeitos da radiação , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/virologia , Prognóstico , Estudos Prospectivos , Saliva/efeitos dos fármacos , Saliva/efeitos da radiaçãoRESUMO
BACKGROUND: The treatment of head and neck cancer (HNC) may cause significant financial toxicity to patients. Herein, the authors have presented the development and validation of the Financial Index of Toxicity (FIT) instrument. METHODS: Items were generated using literature review and were based on expert opinion. In item reduction, items with factor loadings of a magnitude <0.3 in exploratory factor analysis and inverse correlations (r < 0) in test-retest analysis were eliminated. Retained items constituted the FIT. Reliability tests included internal consistency (Cronbach α) and test-retest reliability (intraclass correlation). Validity was tested using the Spearman rho by comparing FIT scores with baseline income, posttreatment lost income, and the Financial Concerns subscale of the Social Difficulties Inventory. Responsiveness analysis compared change in income and change in FIT between 12 and 24 months. RESULTS: A total of 14 items were generated and subsequently reduced to 9 items comprising 3 domains identified on exploratory factor analysis: financial stress, financial strain, and lost productivity. The FIT was administered to 430 patients with HNC at 12 to 24 months after treatment. Internal consistency was good (α = .77). Test-retest reliability was satisfactory (intraclass correlation, 0.70). Concurrent validation demonstrated mild to strong correlations between the FIT and Social Difficulties Inventory Money Matters subscale (Spearman rho, 0.26-0.61; P < .05). FIT scores were found to be inversely correlated with baseline household income (Spearman rho, -0.34; P < .001) and positively correlated with lost income (Spearman rho, 0.24; P < .001). Change in income was negatively correlated with change in FIT over time (Spearman rho, -0.25; P = .04). CONCLUSIONS: The 9-item FIT demonstrated internal and test-retest reliability as well as concurrent and construct validity. Prospective testing in patients with HNC who were treated at other facilities is needed to further establish its responsiveness and generalizability.
Assuntos
Estresse Financeiro/psicologia , Neoplasias de Cabeça e Pescoço/economia , Neoplasias de Cabeça e Pescoço/psicologia , Psicometria , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estresse Financeiro/economia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida/psicologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: In the wake of the coronavirus disease 2019 (COVID-19) pandemic, access to surgical care for patients with head and neck cancer (HNC) is limited and unpredictable. Determining which patients should be prioritized is inherently subjective and difficult to assess. The authors have proposed an algorithm to fairly and consistently triage patients and mitigate the risk of adverse outcomes. METHODS: Two separate expert panels, a consensus panel (11 participants) and a validation panel (15 participants), were constructed among international HNC surgeons. Using a modified Delphi process and RAND Corporation/University of California at Los Angeles methodology with 4 consensus rounds and 2 meetings, groupings of high-priority, intermediate-priority, and low-priority indications for surgery were established and subdivided. A point-based scoring algorithm was developed, the Surgical Prioritization and Ranking Tool and Navigation Aid for Head and Neck Cancer (SPARTAN-HN). Agreement was measured during consensus and for algorithm scoring using the Krippendorff alpha. Rankings from the algorithm were compared with expert rankings of 12 case vignettes using the Spearman rank correlation coefficient. RESULTS: A total of 62 indications for surgical priority were rated. Weights for each indication ranged from -4 to +4 (scale range; -17 to 20). The response rate for the validation exercise was 100%. The SPARTAN-HN demonstrated excellent agreement and correlation with expert rankings (Krippendorff alpha, .91 [95% CI, 0.88-0.93]; and rho, 0.81 [95% CI, 0.45-0.95]). CONCLUSIONS: The SPARTAN-HN surgical prioritization algorithm consistently stratifies patients requiring HNC surgical care in the COVID-19 era. Formal evaluation and implementation are required. LAY SUMMARY: Many countries have enacted strict rules regarding the use of hospital resources during the coronavirus disease 2019 (COVID-19) pandemic. Facing delays in surgery, patients may experience worse functional outcomes, stage migration, and eventual inoperability. Treatment prioritization tools have shown benefit in helping to triage patients equitably with minimal provider cognitive burden. The current study sought to develop what to the authors' knowledge is the first cancer-specific surgical prioritization tool for use in the COVID-19 era, the Surgical Prioritization and Ranking Tool and Navigation Aid for Head and Neck Cancer (SPARTAN-HN). This algorithm consistently stratifies patients requiring head and neck cancer surgery in the COVID-19 era and provides evidence for the initial uptake of the SPARTAN-HN.
Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Neoplasias de Cabeça e Pescoço/cirurgia , Recursos em Saúde , Pneumonia Viral/epidemiologia , Triagem/métodos , Algoritmos , COVID-19 , Tomada de Decisão Clínica , Consenso , Infecções por Coronavirus/virologia , Humanos , Cooperação Internacional , Pandemias , Pneumonia Viral/virologia , Reprodutibilidade dos Testes , Projetos de Pesquisa , SARS-CoV-2 , CirurgiõesRESUMO
PURPOSE: To characterize outcomes of total laryngectomy for the dysfunctional larynx after radiation. METHODS: Retrospective case series of all subjects who underwent total laryngectomy for the irradiated dysfunctional larynx between 2000 and 2018 at an NCI-designated comprehensive cancer center at a single tertiary care academic medical center. Main outcomes included enteral tube feeding dependency, functional tracheoesophageal speech, and number and timing of postoperative pharyngeal dilations. RESULTS: Median time from radiation to laryngectomy was 2.8 years (range 0.5-27 years). Functional outcomes were analyzed for the 32 patients with 1-year follow-up. Preoperatively, 81% required at least partial enteral tube feeding, as compared to 34% 1-year postoperatively (p = 0.0003). At 1 year, 81% had achieved functional tracheoesophageal speech, which was associated with cricopharyngeal myotomy (p = 0.04, HR 0.04, 95% CI 0.002-0.949). There were 34% of subjects who required at least one pharyngeal dilation for stricture by 1 year postoperatively. Over half (60%) of the cohort were dilated over the study period. CONCLUSIONS: Laryngectomy for the dysfunctional larynx improves speech and swallowing outcomes in many patients. Cricopharyngeal myotomy is associated with improved postoperative voice. While the need for enteral feeding is decreased, persistent postoperative swallowing dysfunction is common. Careful patient selection and education regarding functional expectations are paramount.
Assuntos
Neoplasias Laríngeas , Laringe , Deglutição , Humanos , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirurgia , Laringectomia , Estudos Retrospectivos , FalaRESUMO
PURPOSE: The incidence of oropharyngeal squamous cell carcinoma continues to rise with the majority of patients receiving definitive or adjunctive radiation. For patients with locoregional recurrence after radiation, optimal treatment involves salvage surgery. The aim of this study is to identify factors that predict survival to ultimately improve patient selection for salvage surgery. METHODS: Retrospective cohort study at an NCI-designated cancer center. We analyzed patients with a history of head and neck radiation who presented with persistent/recurrent or second primary disease requiring salvage oropharyngeal resection from 1998-2017 (n = 120). Patients were stratified into three classes based on time to recurrence and presence of laryngopharyngeal dysfunction. Primary outcomes were 5-year overall survival (OS) and disease specific survival (DSS). RESULTS: Median OS was 27 months (median follow-up 20 months). Five-year OS was 47% for class I (recurrence > 2 years), 26% for class II (recurrence ≤ 2 years), and 0% for class III (recurrence ≤ 2 years and laryngopharyngeal dysfunction), (p < 0.0001). Five-year DSS showed significant differences between classes (p < 0.0001). On multivariate analysis, class remained predictive of OS (p = 0.04- < 0.001) and DSS (p = 0.04-0.001). Adjuvant radiation after salvage surgery with negative margins showed superior OS (71% vs. 28%, p = 0.01) and DSS (83% vs 37%, p = 0.02) compared to surgery alone and was a significant predictor of improved survival on multivariate analysis (HR 0.1, p = 0.04). CONCLUSION: This study identified a subset of patients with oropharyngeal cancer recurrence within two years of initial treatment and with laryngopharyngeal dysfunction who have poor outcomes for salvage surgery.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Humanos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/cirurgia , Estudos Retrospectivos , Terapia de Salvação , Taxa de SobrevidaRESUMO
BACKGROUND: Indications for and efficacy of paratracheal nodal dissection (PTND) in patients undergoing laryngectomy (salvage) for persistent or recurrent laryngeal squamous cell carcinoma are not well-defined. METHODS: A retrospective cohort study was performed for patients undergoing salvage laryngectomy with clinically and radiographically negative neck disease between 1998 and 2015 (n = 210). Univariate and multivariate Cox regression analyses were performed. RESULTS: PTND was performed on 77/210 patients (36%). The PTND cohort had a greater proportion of advanced T classification (rT3/rT4) tumors (78%) than subjects without PTND (55%; p = 0.001). There was a 14% rate of occult nodal metastases in the paratracheal basin; of these, 55% did not have pathologic lateral neck disease. Multivariate analysis controlling for tumor site, tumor stage, and pathologic lateral neck disease demonstrated that PTND was associated with improved overall survival [OS] (p = 0.03; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.38-0.96), disease-free survival [DFS] (p = 0.03; HR 0.55, 95% CI 0.31-0.96), and distant DFS survival (p = 0.01; HR 0.29, 95% CI 0.11-0.77). The rate of hypocalcemia did not differ between subjects who underwent bilateral PTND, unilateral PTND, or no PTND (p = 0.19 at discharge, p = 0.17 at last follow-up). CONCLUSIONS: PTND at the time of salvage laryngectomy was more common in patients with rT3/rT4 tumors and was associated with improved OS and DFS, with no effect on hypocalcemia. In patients undergoing PTND, the finding of occult paratracheal metastases was often independent of lateral neck metastases.
Assuntos
Procedimentos Cirúrgicos Eletivos/mortalidade , Neoplasias Laríngeas/cirurgia , Laringectomia/mortalidade , Excisão de Linfonodo/mortalidade , Linfonodos/cirurgia , Terapia de Salvação , Neoplasias da Traqueia/cirurgia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Laríngeas/patologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Traqueia/patologiaRESUMO
BACKGROUND: Patients undergoing salvage laryngectomy are predisposed to radiation-induced hypothyroidism and impaired wound healing secondary to the tissue effects of prior treatment. The impact of hypothyroidism on postoperative wound healing is not established. METHODS: A single-institution retrospective case series was performed. The inclusion criteria specified preoperatively euthyroid adults who underwent salvage laryngectomy with concurrent neck dissection between 1997 and 2015 for persistent or recurrent laryngeal squamous cell carcinoma after radiation or chemoradiation therapy (n = 182). The principal explanatory variable was postoperative hypothyroidism, defined as thyroid-stimulating hormone (TSH) higher than 5.5 mIU/L. The primary end points of the study were pharyngocutaneous fistulas and wounds requiring reoperation. Multivariate analysis was performed. RESULTS: The fistula rate was 47% among hypothyroid patients versus 23% among euthyroid patients. In the multivariate analysis, the patients who experienced hypothyroidism in the postoperative period had a 3.6-fold greater risk of fistula [95% confidence interval (CI) 1.8-7.1; p = 0.0002]. The hypothyroid patients had an 11.4-fold greater risk for a required reoperation (24.4 vs 5.4%) than the euthyroid patients (95% CI 2.6-49.9; p = 0.001). The risk for fistula (p = 0.003) and reoperation (p = 0.001) increased with increasing TSH. This corresponds to an approximate 12.5% incremental increase in the absolute risk for fistula and a 10% increase in the absolute risk for reoperation with each doubling of the TSH. CONCLUSION: Postoperative hypothyroidism independently predicts postoperative wound-healing complications. The association of hypothyroidism with fistula formation may yield opportunities to modulate wound healing with thyroid supplementation or to provide a biomarker of wound progression.
Assuntos
Carcinoma de Células Escamosas/cirurgia , Fístula Cutânea/etiologia , Hipotireoidismo/epidemiologia , Neoplasias Laríngeas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Doenças Faríngeas/etiologia , Fístula do Sistema Respiratório/etiologia , Idoso , Carcinoma de Células Escamosas/terapia , Fístula Cutânea/cirurgia , Feminino , Humanos , Hipotireoidismo/fisiopatologia , Neoplasias Laríngeas/terapia , Laringectomia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Esvaziamento Cervical/efeitos adversos , Doenças Faríngeas/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Período Pós-Operatório , Reoperação , Fístula do Sistema Respiratório/cirurgia , Estudos Retrospectivos , Fatores de Risco , Terapia de Salvação/efeitos adversos , Tireotropina/sangue , CicatrizaçãoRESUMO
BACKGROUND: AT-101 is a BCL-2 Homolog domain 3 mimetic previously demonstrated to have tumoricidal effects in advanced solid organ malignancies. Given the evidence of activity in xenograft models, treatment with AT-101 in combination with docetaxel is a therapeutic doublet of interest in metastatic head and neck squamous cell carcinoma. PATIENTS AND METHODS: Patients included in this trial had unresectable, recurrent, or distantly metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to curative radiation or surgery. This was an open label randomized, phase II trial in which patients were administered AT-101 in addition to docetaxel. The three treatment arms were docetaxel, docetaxel plus pulse dose AT-101, and docetaxel plus metronomic dose AT-101. The primary endpoint of this trial was overall response rate. RESULTS: Thirty-five patients were registered and 32 were evaluable for treatment response. Doublet therapy with AT-101 and docetaxel was well tolerated with only 2 patients discontinuing therapy due to treatment related toxicities. The overall response rate was 11 % (4 partial responses) with a clinical benefit rate of 74 %. Median progression free survival was 4.3 months (range: 0.7-13.7) and overall survival was 5.5 months (range: 0.4-24). No significant differences were noted between dosing strategies. CONCLUSION: Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Gossipol/análogos & derivados , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Taxoides/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Feminino , Gossipol/administração & dosagem , Gossipol/efeitos adversos , Gossipol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: [(99m)Tc]Tilmanocept, a novel CD206 receptor-targeted radiopharmaceutical, was evaluated in an open-label, phase III trial to determine the false negative rate (FNR) of sentinel lymph node biopsy (SLNB) relative to the pathologic nodal status in patients with intraoral or cutaneous head and neck squamous cell carcinoma (HNSCC) undergoing tumor resection, SLNB, and planned elective neck dissection (END). Negative predictive value (NPV), overall accuracy of SLNB, and the impact of radiopharmaceutical injection timing relative to surgery were assessed. METHODS AND FINDINGS: This multicenter, non-randomized, single-arm trial (ClinicalTrials.gov identifier NCT00911326) enrolled 101 patients with T1-T4, N0, and M0 HNSCC. Patients received 50 µg [(99m)Tc]tilmanocept radiolabeled with either 0.5 mCi (same day) or 2.0 mCi (next day), followed by lymphoscintigraphy, SLNB, and END. All excised tissues were evaluated for tissue type and tumor presence. [(99m)Tc]Tilmanocept identified one or more SLNs in 81 of 83 patients (97.6 %). Of 39 patients identified with any tumor-positive nodes (SLN or non-SLN), one patient had a single tumor-positive non-SLN in whom all SLNs were tumor-negative, yielding an FNR of 2.56 %; NPV was 97.8 % and overall accuracy was 98.8 %. No significant differences were observed between same-day and next-day procedures. CONCLUSIONS: Use of receptor-targeted [(99m)Tc]tilmanocept for lymphatic mapping allows for a high rate of SLN identification in patients with intraoral and cutaneous HNSCC. SLNB employing [(99m)Tc]tilmanocept accurately predicts the pathologic nodal status of intraoral HNSCC patients with low FNR, high NPV, and high overall accuracy. The use of [(99m)Tc]tilmanocept for SLNB in select patients may be appropriate and may obviate the need to perform more extensive procedures such as END.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Dextranos , Linfonodos/diagnóstico por imagem , Mananas , Neoplasias Bucais/diagnóstico por imagem , Compostos Radiofarmacêuticos , Pentetato de Tecnécio Tc 99m/análogos & derivados , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/cirurgia , Dextranos/administração & dosagem , Reações Falso-Negativas , Humanos , Linfonodos/patologia , Metástase Linfática , Linfocintigrafia/métodos , Mananas/administração & dosagem , Neoplasias Bucais/patologia , Neoplasias Bucais/cirurgia , Pescoço , Esvaziamento Cervical , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/administração & dosagem , Biópsia de Linfonodo Sentinela , Pentetato de Tecnécio Tc 99m/administração & dosagem , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
BACKGROUND: Axitinib is an oral, potent, small molecule tyrosine kinase inhibitor with selective inhibition of VEGFR 1,2, 3, as well as inhibition of potential downstream effectors of the EGFR pathway. Given the upregulation of EGFR and VEGFR in head and neck squamous cell carcinoma, treatment with axitinib holds promise as a rational targeted therapy. PATIENTS AND METHODS: Patients with unresectable, recurrent or metastatic head and neck squamous cell carcinoma were included in this open label, single arm, phase II trial. Primary endpoint was 6 month progression free survival. All patients received single agent axitinib with planned dose escalation based on tolerability. A planned interim efficacy analysis was performed after enrollment of 30 patients. RESULTS: Forty-two patients were registered, 30 were evaluable. While treatment was well-tolerated with no severe bleeding events, only 19 patients were able to achieve full planned dose. The best overall response rate was 6.7% (two partial responses) with a disease control rate of 76.7%. Median progression free survival was 3.7 months (95% Confidence Interval (CI): 3.5-5.7) and overall survival was 10.9 months (95% CI: 6.4-17.8). Exploratory analysis demonstrated that patients with a smaller sum of diameter of target lesions experienced improved response rates, and better progression-free and overall survival. CONCLUSION: Treatment with single agent axitinib should be considered due to acceptable toxicity profile and favorable median overall survival compared to standard therapies.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Axitinibe , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Hipertensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Inibidores de Proteínas Quinases/uso terapêutico , Taxa de Sobrevida/tendênciasRESUMO
BACKGROUND: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well-characterized, prospective, cohort of 346 HNSCC patients. METHODS: Kaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status. RESULTS: Methylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95% CI: 1.40-3.94; CD1A HR: 1.31, 95% CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95% CI: 1.88-5.93; RPFT HR: 2.06, 95% CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95% CI: 0.13-0.74). CONCLUSIONS: This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation.
Assuntos
Antígenos CD1/genética , Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Metilação de DNA , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/virologia , Comorbidade , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Proinflammatory cytokine levels may be associated with cancer stage, recurrence, and survival. The objective of this study was to determine whether cytokine levels were associated with dietary patterns and fat-soluble micronutrients in patients with previously untreated head and neck squamous cell carcinoma (HNSCC). METHODS: This was a cross-sectional study of 160 patients with newly diagnosed HNSCC who completed pretreatment food frequency questionnaires (FFQs) and health surveys. Dietary patterns were derived from FFQs using principal component analysis. Pretreatment serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) were measured using an enzyme-linked immunosorbent assay, and serum carotenoid and tocopherol levels were measured by high-performance liquid chromatography. Multivariable ordinal logistic regression models examined associations between cytokines and quartiles of reported and serum dietary variables. RESULTS: Three dietary patterns emerged: whole foods, Western, and convenience foods. In multivariable analyses, higher whole foods pattern scores were significantly associated with lower levels of IL-6, TNF-α, and IFN-γ (P ≤ .001, P = .008, and P = .03, respectively). Significant inverse associations were reported between IL-6, TNF-α, and IFN-γ levels and quartiles of total reported carotenoid intake (P = .006, P = .04, and P = .04, respectively). There was an inverse association between IFN-γ levels and serum α-tocopherol levels (P = .03). CONCLUSIONS: Consuming a pretreatment diet rich in vegetables, fruit, fish, poultry, and whole grains may be associated with lower proinflammatory cytokine levels in patients with HNSCC.
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Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Citocinas/sangue , Dieta , Neoplasias de Cabeça e Pescoço/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
OBJECTIVE: Limited availability of authentic human adenoid cystic carcinoma (ACC) cell lines has hindered progress in understanding mechanisms underpinning the biology of this disease and the development of safe and effective therapies. STUDY DESIGN: Surgical human ACC specimens (UM-HACC-6, UM-HACC-14) were dissociated into single cell suspensions and cultured in fibronectin-coated flasks. Alternatively, tumor fragments were transplanted subcutaneously into female immunodeficient (SCID) mice to establish patient-derived xenograft tumors (PDX; UM-PDX-HACC-14). RESULTS: Both ACC cell lines showed continuous growth in monolayers for over 100 passages. Total RNA-Seq, RT-PCR, and FISH analysis revealed that both are MYB-NFIB fusion negative. Western blots revealed passage-dependent expression of E-Cadherin, PCNA, p63, phospho-c-MYB, and NFIB. Both, UM-HACC-14 and UM-HACC-6 cells exhibited tumorigenic potential when injected orthotopically into mouse submandibular glands. CONCLUSION: UM-HACC-14, patient-matching UM-PDX-HACC-14, and the UM-HACC-6 cell line are new, authenticated preclinical models of ACC that are well suited for mechanistic and developmental therapeutics studies.
Assuntos
Carcinoma Adenoide Cístico , Camundongos SCID , Neoplasias das Glândulas Salivares , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoide Cístico/metabolismo , Animais , Humanos , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/metabolismo , Camundongos , Feminino , Linhagem Celular Tumoral , Western Blotting , Xenoenxertos , Hibridização in Situ FluorescenteRESUMO
Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.
Assuntos
Neoplasias Primárias Desconhecidas , Procedimentos Cirúrgicos Robóticos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/radioterapia , Neoplasias Primárias Desconhecidas/patologia , Idoso , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/radioterapia , Neoplasias Orofaríngeas/cirurgia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Dosagem RadioterapêuticaRESUMO
BACKGROUND: Neck dissections (ND) are a routine procedure in head and neck oncology. Given the postoperative functional impact that some patients experience, it is imperative to identify and track quality of life (QoL) symptomatology to tailor each patient's therapeutic needs. To date, there is no validated French-Canadian questionnaire for this patient-population. We therefore sought to translate and validate the Neck Dissection Impairment Index (NDII) in Canadian French. METHODS: A 3-phased approach was used. Phase 1: The NDII was translated from English to Canadian French using a "forward and backward" translational technique following international guidelines. Phase 2: A cognitive debriefing session was held with 10 Canadian French-speaking otolaryngology patients to evaluate understandability and acceptability. Phase 3: The final version was administered prospectively to 30 patients with prior history of ND and 30 control patients. These patients were asked to complete the questionnaire 2 weeks after their first response. Test-retest reliability was calculated with Spearman's correlation. Internal consistency was elicited using Cronbach's alpha. RESULTS: NDII was successfully translated and validated to Canadian French. Cronbach's alpha revealed high internal consistency (0.92, lower 95% confidence limit 0.89). The correlation for test-retest validity were strong or very strong (0.61-0.91). CONCLUSION: NDII is an internationally recognized QoL tool for the identification of ND-related impairments. This validated Canadian French version will allow clinicians to adequately assess the surgery-related QoL effect of neck surgery in the French-speaking population, while allowing French institutions to conduct and/or participate in multisite clinical trials requiring the NDII as an outcome measure.
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Neoplasias de Cabeça e Pescoço , Esvaziamento Cervical , Qualidade de Vida , Traduções , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Canadá , Inquéritos e Questionários , Neoplasias de Cabeça e Pescoço/cirurgia , Neoplasias de Cabeça e Pescoço/psicologia , Reprodutibilidade dos Testes , Idoso , Adulto , Estudos Prospectivos , Oncologia CirúrgicaRESUMO
PURPOSE: Patients undergoing head and neck cancer surgery after prior radiation or chemoradiation are at high risk for wound complications. Hypothyroidism is a known risk factor for wound complications, especially fistulae after salvage total laryngectomy. The purpose of this phase II clinical trial is to investigate the effect of perioperative intravenous levothyroxine supplementation on wound complications in patients undergoing salvage total laryngectomy. PATIENTS AND METHODS: Euthyroid patients previously treated with radiation/chemoradiation undergoing total laryngectomy were prospectively recruited (n = 72). Postoperatively, intravenous levothyroxine was administered at a weight-based dose (1.3 mcg/kg/d) and transitioned to enteral dosing on day 7. Free T3, T4, and thyroid-stimulating hormones were collected, and dosing was adjusted accordingly. The primary endpoints were rates of fistula formation and fistula requiring reoperation, compared with matched historic controls. All patients were monitored for adverse effects. RESULTS: The rate of postoperative hypothyroidism was 21% compared with 49% in a matched historic cohort. The rate of fistula formation was 18.1%, whereas the rate of fistula requiring reoperation was 4.2%, significantly lower than rates in our historic cohort (34.6% and 14.8%, respectively; P = 0.02 and 0.01). Postoperative hypothyroidism and recurrent clinical stage predicted fistula requiring reoperation in multivariate analysis; other acute phase reactants were not predictive. There were no observed adverse events related to levothyroxine supplementation. CONCLUSIONS: Postoperative intravenous levothyroxine supplementation reduced rates of acute hypothyroidism, fistula formation, and fistula requiring reoperation in patients undergoing salvage total laryngectomy without adverse effects. Intravenous levothyroxine is a viable strategy to reduce wound complications in this high-risk patient population.
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Fístula Cutânea , Hipotireoidismo , Laringectomia , Complicações Pós-Operatórias , Terapia de Salvação , Tiroxina , Humanos , Masculino , Laringectomia/efeitos adversos , Feminino , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Idoso , Tiroxina/administração & dosagem , Tiroxina/efeitos adversos , Tiroxina/uso terapêutico , Fístula Cutânea/etiologia , Fístula Cutânea/prevenção & controle , Hipotireoidismo/etiologia , Hipotireoidismo/tratamento farmacológico , Complicações Pós-Operatórias/prevenção & controle , Fístula/etiologia , Fístula/prevenção & controle , Administração Intravenosa , Adulto , Doenças Faríngeas/etiologia , Doenças Faríngeas/prevenção & controle , Doenças Faríngeas/tratamento farmacológico , Estudos ProspectivosRESUMO
PURPOSE: Locoregionally advanced HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has excellent cure rates, although current treatment regimens are accompanied by acute and long-term toxicities. We designed a phase II deescalation trial for patients with HPV+ OPSCC to evaluate the feasibility of an upfront neck dissection to individualize definitive treatment selection to improve the quality of life without compromising survival. PATIENTS AND METHODS: Patients with T1-3, N0-2 HPV+ OPSCC underwent an upfront neck dissection with primary tumor biopsy. Arm A included patients with a single lymph node less than six centimeters, with no extracapsular spread (ECS) and no primary site adverse features underwent transoral surgery. Arm B included patients who had two or more positive lymph nodes with no ECS, or those with primary site adverse features were treated with radiation alone. Arm C included patients who had ECS in any lymph node and were treated with chemoradiation. The primary endpoint was quality of life at 1 year compared with a matched historical control. RESULTS: Thirty-four patients were enrolled and underwent selective neck dissection. On the basis of pathologic characteristics, 14 patients were assigned to arm A, 10 patients to arm B, and 9 to arm C. A significant improvement was observed in Head and Neck Quality of Life (HNQOL) compared with historical controls (-2.6 vs. -11.9, P = 0.034). With a median follow-up of 37 months, the 3-year overall survival was 100% and estimated 3-year estimated progression-free survival was 96% [95% confidence interval (CI), 76%-99%]. CONCLUSIONS: A neck dissection-driven treatment paradigm warrants further research as a deintensification strategy.
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Esvaziamento Cervical , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Qualidade de Vida , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/cirurgia , Idoso , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Adulto , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estadiamento de Neoplasias , Quimiorradioterapia/métodos , Resultado do Tratamento , Papillomaviridae/isolamento & purificaçãoRESUMO
BACKGROUND: To address the rehabilitative barriers to frequency and precision of care, we conducted a pilot study of a biofeedback electropalatography (EPG) device paired with telemedicine for patients who underwent primary surgery +/- adjuvant radiation for oral cavity carcinoma. We hypothesized that lingual optimization followed by telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER) would further improve speech and swallowing outcomes after "standard-of-care" SOC rehabilitation. METHOD: Pilot prospective 8-week (TEBER) program following 8 weeks of (SOC) rehabilitation. RESULTS: Twenty-seven patients were included and 11 completed the protocol. When examining the benefit of TEBER independent of standard of care, "range-of-liquids" improved by +0.36 [95% CI, 0.02-0.70, p = 0.05] and "range-of-solids" improved by +0.73 [95% CI, 0.12-1.34, p = 0.03]. There was a positive trend toward better oral cavity obliteration; residual volume decreased by -1.2 [95% CI, -2.45 to 0.053, p = 0.06], and "nutritional-mode" increased by +0.55 [95% CI, -0.15 to 1.24, p = 0.08]. CONCLUSION: This pilot suggests that TEBER bolsters oral rehabilitation after 8 weeks of SOC lingual range of motion.