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1.
Med Oncol ; 36(11): 93, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595355

RESUMO

In patients with locally advanced human papillomavirus (HPV)-unrelated head and neck squamous-cell carcinoma (HNSCC), cisplatin and radiation therapy (CisRT) resulted in a local-regional recurrence (LRR) rate of 35%, progression-free survival (PFS) of 49%, and overall survival (OS) of 60%. We, and others, showed that nab-paclitaxel is an active agent in metastatic and locally advanced HNSCC. The aim of this report was to assess the efficacy of nab-paclitaxel-based induction chemotherapy and CisRT in HPV-unrelated HNSCC. We performed a retrospective single-institution analysis of patients treated with nab-paclitaxel-based chemotherapy and CisRT. Key inclusion criteria included stage III-IV HPV-unrelated HNSCC. Induction chemotherapy included nab-paclitaxel and cisplatin (AP), AP + 5-fluorouracil (APF), or APF + Cetuximab (APF-C). Endpoints included LRR, overall relapse, PFS, and OS. Thirty-eight patients were the subject of this analysis. Patient characteristics included median age 59 years (IQR: 54-64) and smoking history in 36 patients (95%). Primary tumor sites included larynx/hypopharynx (27), p16 negative oropharynx (10), and oral cavity (1). Most patients had bulky disease: 82% T3-4 (n = 31) and 74% N2b-3 (n = 28). Median follow-up was 44 months (IQR: 23-59). The three-year LRR rate was 16% (95% confidence interval [CI] 7-34) and the overall relapse rate was 22% (95% CI 11-41). The three-year PFS was 64% (95% CI 46-77) and OS was 72% (95% CI 54-84). Among patients with HPV-unrelated HNSCC, nab-paclitaxel-based induction chemotherapy and CisRT resulted in a lower-than-expected rate of LRR and more favorable PFS and OS compared to historical results with CisRT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Albuminas/administração & dosagem , Quimiorradioterapia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Infecções por Papillomavirus/patologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
2.
Cancer Radiother ; 23(6-7): 496-499, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31471251

RESUMO

Stereotactic radiotherapy of oligometastases, mono- or hypofractionated, represents a fundamental change in the practice of the specialty as it was developed for a century. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Four main phase II and III trials are underway in France. Future research concerns the association of stereotactic radiotherapy with immunotherapy or different conventional chemotherapy protocols, the identification of the best clinical presentations, and optimization of fractionation and biological dose for poor prognosis localizations.


Assuntos
Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias/radioterapia , Radiocirurgia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Terapia Combinada/métodos , Previsões , França , Humanos , Imunoterapia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/terapia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
3.
Cancer Radiother ; 23(6-7): 559-564, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31451359

RESUMO

Despite progress in the management of head and neck squamous cell carcinoma (HNSCC), a significant proportion of patients previously irradiated for head-and-neck cancer will develop locoregional recurrence or a second primary. Because of the heterogeneity of this population with respect to disease-related factors (localization, volume, recurrence or second primary, time interval from previous irradiation…) and patient-related factors (comorbidities, sequelae of previous irradiation…), the optimal reirradiation treatment remains to be defined. Salvage therapy using reirradiation, despite some encouraging results, has historically been avoided because of concerns regarding toxicity. The results of more recent studies using contemporary treatment techniques and conformal delivery methods such as intensity modulated radiation therapy (IMRT) or stereotactic radiotherapy (SBRT) have been somewhat more promising. The aim of this review is to discuss the reirradiation of HNSCC in terms of patient selection and modern radiotherapy techniques.


Assuntos
Recidiva Local de Neoplasia/radioterapia , Segunda Neoplasia Primária/radioterapia , Seleção de Pacientes , Radiocirurgia , Radioterapia de Intensidade Modulada , Reirradiação/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Braquiterapia , Humanos , Cuidados Pós-Operatórios , Terapia com Prótons , Lesões por Radiação/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fatores de Tempo
4.
Cancer Radiother ; 23(5): 439-448, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31358445

RESUMO

Intensity-modulated radiation therapy (IMRT) is presently the recommended technique for the treatment of locally advanced head and neck carcinomas. Proton therapy would allow to reduce the volume of irradiated normal tissue and, thus, to decrease the risk of late dysphagia, xerostomia, dysgeusia and hypothyroidism. An exhaustive research was performed with the search engine PubMed by focusing on the papers about the physical difficulties that slow down use of proton therapy for head and neck carcinomas. Range uncertainties in proton therapy (±3 %) paradoxically limit the use of the steep dose gradient in distality. Calibration uncertainties can be important in the treatment of head and neck cancer in the presence of materials of uncertain stoichiometric composition (such as with metal implants, dental filling, etc.) and complex heterogeneities. Dental management for example may be different with IMRT or proton therapy. Some uncertainties can be somewhat minimized at the time of optimization. Inter- and intrafractional variations and uncertainties in Hounsfield units/stopping power can be integrated in a robust optimization process. Additional changes in patient's anatomy (tumour shrinkage, changes in skin folds in the beam patch, large weight loss or gain) require rescanning. Dosimetric and small clinical studies comparing photon and proton therapy have well shown the interest of proton therapy for head and neck cancers. Intensity-modulated proton therapy is a promising treatment as it can reduce the substantial toxicity burden of patients with head and neck squamous cell carcinoma compared to IMRT. Robust optimization will allow to perform an optimal treatment and to use proton therapy in current clinical practice.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Física Sanitária , Terapia com Prótons , Lesões por Radiação/prevenção & controle , Radioterapia (Especialidade) , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Pesquisa Médica Translacional , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/prevenção & controle , Disgeusia/etiologia , Disgeusia/prevenção & controle , Humanos , Hipotireoidismo/etiologia , Hipotireoidismo/prevenção & controle , Modelos Teóricos , Órgãos em Risco , Lesões por Radiação/etiologia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia Guiada por Imagem , Radioterapia de Intensidade Modulada/efeitos adversos , Incerteza , Xerostomia/etiologia , Xerostomia/prevenção & controle
5.
Photochem Photobiol Sci ; 18(7): 1621-1637, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31197302

RESUMO

Photobiomodulation (PBM) therapy is an effective method for preventing and managing oral mucositis (OM) in head and neck squamous cell carcinoma (HNSCC) patients undergoing radiotherapy alone or in combination with chemotherapy. However, the potential effects of PBM therapy on premalignant and malignant cells eventually present in the treatment site are yet unknown. The aim of this systematic review was to analyze the effects of PBM therapy on HNSCC. A literature search was conducted in four indexed databases as follows: MEDLINE/PubMed, EMBASE, Web of Science, and Scopus. The databases were reviewed for papers published up to and including in October 2018. In vitro and in vivo studies that investigated the effects of PBM therapy on HNSCC were selected. From the 852 initially gathered studies, 15 met the inclusion criteria (13 in vitro and 2 in vivo). Only three in vitro studies were noted to have a low risk of bias. The included data demonstrated wide variations of study designs, PBM therapy protocols, and study outcomes. Cell proliferation and viability were the primary evaluation outcome in the in vitro studies. Of the 13 in vitro studies, seven noted a positive effect of PBM therapy on inhibiting or preventing an effect on HNSCC tumor cells, while six studies saw increased proliferation. One in vivo study reported increased oral SCC (OSCC) progression, while the other observed reduced tumor progression. Overall, the data from the studies included in the present systematic review do not support a clear conclusion about the effects of PBM therapy on HNSCC cells.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Lasers de Gás/uso terapêutico , Terapia com Luz de Baixa Intensidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Proliferação de Células/efeitos da radiação , Bases de Dados Factuais , Humanos
6.
Med Oncol ; 36(8): 68, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31190132

RESUMO

This study was designed to evaluate the objective response after hypofractionated radiotherapy (HFRT) combined with cetuximab (HFBRT) in vulnerable elderly patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Vulnerable elderly patients with histologically proven HNSCC received HFRT (total dose 60 Gy, 3 Gy/fraction) with concurrent cetuximab (250 mg/m2 with a loading dose of 400 mg/m2 1 week before HFRT). Elderly patients were categorized as vulnerable based on mini-cog test and adult comorbidity evaluation-27 score. All patients completed the programmed HFRT and two patients received the planned cetuximab infusion. Severe acute toxicity, observed in four patients, was gastrointestinal (oral mucositis in four cases; nausea/vomiting in one case) and dermatological (acneiform eruption in three cases; radiation dermatitis in one case). Three serious adverse events were recorded in three out of six patients Overall, three patients had a partial response and three patients had progression disease 3 months after the end of the treatment. No complete response was observed. HFBRT seems to be not a safer alternative approach for vulnerable elderly patients with locally advanced HNSCC. Further prospective trials are needed to define better tumor control with less incidence of toxic effects in vulnerable elderly HNSCC patients.


Assuntos
Cetuximab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Projetos Piloto
7.
Oxid Med Cell Longev ; 2019: 7187128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944696

RESUMO

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 µM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.


Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Cisplatino/uso terapêutico , Melatonina/uso terapêutico , Mitocôndrias/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Autofagia , Cisplatino/farmacologia , Humanos , Melatonina/farmacologia , Espécies Reativas de Oxigênio , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
8.
Med Phys ; 46(5): 2204-2213, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887523

RESUMO

PURPOSE: This study suggests a lifelong learning-based convolutional neural network (LL-CNN) algorithm as a superior alternative to single-task learning approaches for automatic segmentation of head and neck (OARs) organs at risk. METHODS AND MATERIALS: Lifelong learning-based convolutional neural network was trained on twelve head and neck OARs simultaneously using a multitask learning framework. Once the weights of the shared network were established, the final multitask convolutional layer was replaced by a single-task convolutional layer. The single-task transfer learning network was trained on each OAR separately with early stoppage. The accuracy of LL-CNN was assessed based on Dice score and root-mean-square error (RMSE) compared to manually delineated contours set as the gold standard. LL-CNN was compared with 2D-UNet, 3D-UNet, a single-task CNN (ST-CNN), and a pure multitask CNN (MT-CNN). Training, validation, and testing followed Kaggle competition rules, where 160 patients were used for training, 20 were used for internal validation, and 20 in a separate test set were used to report final prediction accuracies. RESULTS: On average contours generated with LL-CNN had higher Dice coefficients and lower RMSE than 2D-UNet, 3D-Unet, ST- CNN, and MT-CNN. LL-CNN required ~72 hrs to train using a distributed learning framework on 2 Nvidia 1080Ti graphics processing units. LL-CNN required 20 s to predict all 12 OARs, which was approximately as fast as the fastest alternative methods with the exception of MT-CNN. CONCLUSIONS: This study demonstrated that for head and neck organs at risk, LL-CNN achieves a prediction accuracy superior to all alternative algorithms.


Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Órgãos em Risco/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Automação , Humanos , Órgãos em Risco/efeitos da radiação , Radioterapia Guiada por Imagem , Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
9.
Med Oncol ; 36(5): 42, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30927146

RESUMO

The purpose of this study is to evaluate if, in elderly HNC patients, loco-regional control (LRC) is influenced by average weekly radiation dose (AWD). From 2009 to 2017, 150 consecutive HNC elderly patients were analyzed. AWD was calculated by dividing total dose in Gray by overall treatment time in weeks. Patients were divided in 2 groups: Group 1 (70-75 years) and Group 2 (> 75 years). Primary endpoint was LRC; secondary endpoints were overall survival (OS) and compliance to treatment. The median age was 76 years (range 70-92), the distribution of patients by age was 72 and 78 patients in Group 1 and in Group 2, respectively; overall median follow-up was 23 months. Optimal cut-off of AWD for LRC was 9.236 (p = 0.018). Median OS was 73 months. In univariate survival analysis low PS (p = 0.005), T3-T4 (p = 0.021), Stage III-IV (p = 0.046) and AWDLow (< 9.236) (p = 0.018) were significantly associated with lower LRC; low PS (p < 0.001) and Group 2 (p = 0.006) were also associated with lower OS. Considering patients treated with radiotherapy alone AWDLow was significantly associated with lower LRC (p = 0.04) whereas among patient treated with chemoradiotherapy AWD did not affected LRC (p = 0.18). The multivariate analysis confirmed the significant value of PS for the prediction of LRC and OS (p = 0.035 and p < 0.001, respectively). In elderly patients an AWD of > 9.236 Gy was found to be beneficial for RT alone regimen. When radiotherapy alone is indicated in elderly patients an effort should be made to maintain an increased AWD in order to improve LRC.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Idoso , Idoso de 80 Anos ou mais , Cetuximab/uso terapêutico , Quimiorradioterapia/normas , Cisplatino/uso terapêutico , Progressão da Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Cooperação do Paciente , Doses de Radiação , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida
10.
Molecules ; 24(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813269

RESUMO

Boron neutron capture therapy (BNCT) is a binary cancer treatment modality where two different agents (10B and thermal neutrons) have to be present to produce an effect. A dedicated trial design is necessary for early clinical trials. The concentration of 10B in tissues is an accepted surrogate to predict BNCT effects on tissues. Tissue, blood, and urines were sampled after infusion of two different boron carriers, namely BSH and BPA in the frame of the European Organisation for Research and Treatment of Cancer (EORTC) trial 11001. In this study, urine samples were used to identify protein profiles prior and after drug infusion during surgery. Here, an approach that is based on the mass spectrometry (MS)-based proteomic analysis of urine samples from head and neck squamous cell carcinoma (HNSCC) and thyroid cancer patients is presented. This method allowed the identification of several inflammation- and cancer-related proteins, which could serve as tumor biomarkers. In addition, changes in the urinary proteome during and after therapeutic interventions were detected. In particular, a reduction of three proteins that were involved in inflammation has been observed: Galectin-3 Binding Protein, CD44, and osteopontin. The present work represents a proof of principle to follow proteasome changes during complex treatments based on urine samples.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Proteômica/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Neoplasias da Glândula Tireoide/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/urina , Biomarcadores Tumorais/urina , Terapia por Captura de Nêutron de Boro/métodos , Proteínas de Transporte/urina , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glicoproteínas/urina , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/urina , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Pessoa de Meia-Idade , Osteopontina/urina , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/urina , Neoplasias da Glândula Tireoide/metabolismo , Resultado do Tratamento
11.
Cancer Genomics Proteomics ; 16(2): 139-146, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850365

RESUMO

BACKGROUND/AIM: Head and neck cancers are a heterogenous group of epithelial tumors represented mainly by squamous cell carcinomas (HNSCC), which are the sixth most common type of cancer worldwide. Surgery together with radiotherapy (RT) is among the basic treatment modalities for most HNSCC patients. Various biomarkers aiming to predict patients' response to RT are currently investigated. The reason behind this effort is, on one hand, to distinguish radioresistant patients that show weak benefit from RT and, on the other hand, reduce the ionizing radiation dose in less aggressive radiosensitive HNSCC with possibly less acute or late toxicity. MATERIALS AND METHODS: A total of 94 HNSCC patients treated by definitive intensity-modulated radiotherapy were included in our retrospective study. We used a global expression analysis of microRNAs (miRNAs) in 43 tumor samples and validated a series of selected miRNAs in an independent set of 51 tumors. RESULTS: We identified miR-15b-5p to be differentially expressed between patients with short and long time of locoregional control (LRC). Kaplan-Meier analysis confirmed that HNSCC patients with higher expression of miR-15b-5p reach a significantly longer locoregional relapse-free survival compared to patients expressing low levels. Finally, multivariable Cox regression analysis revealed that miR-15b-5p is an independent predictive biomarker of LRC in HNSCC patients (HR=0.25; 95% CI=0.05-0.78; p<0.016). CONCLUSION: miR-15b-5p represents a potentially helpful biomarker for individualized treatment decisions concerning the management of HNSCC patients.


Assuntos
MicroRNAs/genética , Recidiva Local de Neoplasia/radioterapia , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Biomarcadores Tumorais/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Resultado do Tratamento
12.
Ann Otol Rhinol Laryngol ; 128(7): 595-600, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30808209

RESUMO

OBJECTIVES: The aim of this study was to investigate the utility of pretreatment and 3-month 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) standardized uptake value (SUV) in predicting and assessing recurrence in T3-T4 laryngeal carcinoma treated with definitive radiation therapy (RT). METHODS: Patients with newly diagnosed T3-T4 laryngeal squamous cell carcinoma treated with definitive RT from 2004 to 2014 were reviewed. Patients who underwent pretreatment or 3-month PET/CT 2 to 4 months after treatment were included. Those with prior systemic, surgical, or RT treatment were excluded. The primary objective was to assess whether pretreatment or posttreatment maximum SUV of the primary site (pSUV) of disease was associated with local recurrence-free survival. Overall survival was a secondary end point. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated to assess the accuracy of 3-month PET/CT at the larynx primary. RESULTS: Twenty-eight patients were eligible for analysis. Median follow-up time was 34.7 months (range, 5.3-138.7 months), and median age was 57 years. Most patients had supraglottic (71.4%), T3 (89.3%), N2 (50.0%) disease, received chemotherapy (96.4%), and had histories of tobacco use (96.4%). On univariate analysis, 3-month posttreatment pSUV was associated with local recurrence-free survival ( P < .01), while pretreatment pSUV was not ( P = .41). No other associations were found with local recurrence-free survival. Neither pretreatment nor 3-month pSUV was significantly associated with overall survival. The calculated sensitivity, specificity, positive predictive value, and negative predictive value of 3-month PET/CT at the primary site were 33%, 85%, 40%, and 81%, respectively. CONCLUSIONS: High initial fluorodeoxyglucose uptake in T3-T4 laryngeal primaries did not show an association with the risk for postradiation local relapse or overall survival, while increased fluorodeoxyglucose uptake at 3 months was associated with increased local recurrence. At 3 months, the relatively low sensitivity and positive predictive value may limit the utility of PET/CT in the assessment of persistent advanced laryngeal cancer after definitive radiation.


Assuntos
Neoplasias Laríngeas/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Adulto , Idoso , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
13.
Med Phys ; 46(5): 2526-2537, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30806479

RESUMO

PURPOSE: To describe in detail a dataset consisting of longitudinal fan-beam computed tomography (CT) imaging to visualize anatomical changes in head-and-neck squamous cell carcinoma (HNSCC) patients throughout radiotherapy (RT) treatment course. ACQUISITION AND VALIDATION METHODS: This dataset consists of CT images from 31 HNSCC patients who underwent volumetric modulated arc therapy (VMAT). Patients had three CT scans acquired throughout the duration of the radiation treatment course. Pretreatment planning CT scans with a median of 13 days before treatment (range: 2-27), mid-treatment CT at 22 days after start of treatment (range: 13-38), and post-treatment CT 65 days after start of treatment (range: 35-192). Patients received RT treatment to a total dose of 58-70 Gy, using daily 2.0-2.20 Gy, fractions for 30-35 fractions. The fan-beam CT images were acquired using a Siemens 16-slice CT scanner head protocol with 120 kV and current of 400 mAs. A helical scan with 1 rotation per second was used with a slice thickness of 2 mm and table increment of 1.2 mm. In addition to the imaging data, contours of anatomical structures for RT, demographic, and outcome measurements are provided. DATA FORMAT AND USAGE NOTES: The dataset with DICOM files including images, RTSTRUCT files, and RTDOSE files can be found and publicly accessed in the Cancer Imaging Archive (TCIA, http://www.cancerimagingarchive.net/) as collection Head-and-neck squamous cell carcinoma patients with CT taken during pretreatment, mid-treatment, and post-treatment (HNSCC-3DCT-RT). DISCUSSION: This is the first dataset to date in TCIA which provides a collection of multiple CT imaging studies (pretreatment, mid-treatment, and post-treatment) throughout the treatment course. The dataset can serve a wide array of research projects including (but not limited to): quantitative imaging assessment, investigation on anatomical changes with treatment progress, dosimetry of target volumes and/or normal structures due to anatomical changes occurring during treatment, investigation of RT toxicity, and concurrent chemotherapy and RT effects on head-and-neck patients.


Assuntos
Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Planejamento da Radioterapia Assistida por Computador , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
14.
Int J Radiat Oncol Biol Phys ; 104(2): 365-373, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776452

RESUMO

PURPOSE: The "PRAVACUR" phase 2 trial (NCT01268202) assessed the efficacy of pravastatin as an antifibrotic agent in patients with established cutaneous and subcutaneous radiation-induced fibrosis (RIF) after head and neck squamous cell carcinoma (HNSCC) radiation therapy and/or radiochemotherapy. METHODS AND MATERIALS: The main inclusion criteria were: NSCC in remission, grade ≥2 cutaneous and subcutaneous neck RIF (National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0), and no current treatment with statins or fibrates. Patients received pravastatin 40 mg/d for 12 months. The primary endpoint was reduction of RIF thickness by more than 30% at 12 months, as measured by cutaneous high-frequency ultrasonography. Secondary endpoints included RIF severity reduction, pravastatin tolerance, and quality of life. RESULTS: Sixty patients with grade 2 (n = 37), grade 3 (n = 22), or grade 4 (n = 1) RIF were enrolled from February 2011 to April 2016. The mean interval between RIF diagnosis and pravastatin initiation was 17.1 months. Pravastatin was stopped before 11 months of treatment in 18 patients (because of grade ≥2 adverse events related to pravastatin in 8 patients [13%]). In the 40 patients in whom pravastatin efficacy was assessed by high-frequency ultrasonography at baseline and at 12 months of treatment, a reduction of RIF thickness ≥30% was observed in 15 of 42 patients (35.7%; 95% confidence interval, 21.6%-52.0%). At the 12-month clinical evaluation, RIF severity was decreased in 50% of patients (n = 21; 95% confidence interval, 34.2%-65.8%), and the patients' self-perception, mood state, and social functioning were significantly improved. Pravastatin was well tolerated, with a very low occurrence of grade 3 toxicities (myalgia, n = 1) and grade 2 toxicities (myalgia/arthralgia or esophagitis, n = 3). CONCLUSIONS: This phase 2 prospective study supports the notion of radioinduced fibrosis reversibility. It showed that pravastatin (40 mg/d for 12 months) is an efficient antifibrotic agent in patients with grade ≥2 cutaneous and subcutaneous fibrosis after HNSCC radiation therapy.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/radioterapia , Pravastatina/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Pele/efeitos da radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Intervalos de Confiança , Fármacos Dermatológicos/efeitos adversos , Fibrose , Humanos , Pravastatina/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Lesões por Radiação/patologia , Pele/patologia
15.
Radiother Oncol ; 131: 127-134, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30773179

RESUMO

BACKGROUND AND PURPOSE: Classical robust optimization considers uncertainties in patient setup and particle range. However, anatomical changes occurring during the treatment are neglected. Our aim was to compare classical robust optimization (cRO) with anatomical robust optimization (aRO), to quantify the influence of anatomical variations during the treatment course, and to assess the need of adaptation. MATERIALS AND METHODS: Planning CT and weekly control CTs (cCTs) from 20 head and neck patients were analysed. Three intensity-modulated proton therapy (IMPT) plans were compared: conventional PTV-based plan; cRO, using solely the planning CT, and aRO, including additionally the first 2 cCTs in the optimization. Weekly and total cumulative doses, considering anatomical variations during the treatment, were calculated and compared with the nominal plans. RESULTS: Nominal plans fulfilled clinical specifications for target coverage (D98% ≥95% of prescribed dose). The PTV-based and cRO approaches were not sufficient to account for anatomical changes during the treatment in 10 and 5 patients, respectively, resulting in the need of plan adaptation. With the aRO approach, in all except one patient the target coverage was conserved, and no adaptations were necessary. CONCLUSION: In 25% of the investigated cases, classical robust optimization is not sufficient to account for anatomical changes during the treatment. Adding additional information of random anatomical variations in the optimization improves plan robustness.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Terapia com Prótons/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Cabeça/anatomia & histologia , Cabeça/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Pescoço/anatomia & histologia , Pescoço/diagnóstico por imagem , Órgãos em Risco/anatomia & histologia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/normas , Radioterapia de Intensidade Modulada/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Incerteza
16.
Anticancer Res ; 39(2): 713-720, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711949

RESUMO

BACKGROUND: Radiotherapy (RT) combined with a radiosensitizer represents an important treatment for head and neck squamous cell carcinoma (HNSCC). Only few chemotherapy agents are currently approved as radiosensitizers for targeted therapy. In this study, the potent cyclin-dependent kinase 4/6 (CDK4/6) inhibitor LEE011 was tested for potential to act as a radiosensitizer during RT. MATERIALS AND METHODS: RT enhancement by LEE011 was assessed by in vitro clonogenic assay, flow cytometry, and western blot in a variety of HNSCC cell lines. The HNSCC cell line OML1 and its radiation-resistant clone OML1-R were used. RESULTS: LEE011 induced cell-cycle arrest in SCC4/SCC25 cells during the G1/M phase through inhibition of retinoblastoma protein phosphorylation. LEE011 enhanced the effects of radiation in OML1 cells and overcame radiation resistance in OML1-R cells. CONCLUSION: LEE011 is a potential radiosensitizer that can enhance the cytotoxic effects of RT. Clinical trials including LEE011 during RT for HNSCC should be considered.


Assuntos
Aminopiridinas/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Purinas/farmacologia , Radiossensibilizantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Apoptose/efeitos dos fármacos , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/radioterapia , Fosforilação , Proteínas de Ligação a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
17.
Radiat Oncol ; 14(1): 32, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744643

RESUMO

BACKGROUND: Concurrent chemoradiotherapy with cisplatin is standard for patients (pts) with loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) and for patients with resected SCCHN with high-risk features. The standard regimen includes 3-weekly cisplatin, but weekly regimens are often used to lower toxicity. Reaching a cumulative dose of ≥200 mg/m2 cisplatin was shown being associated with improved outcome. We herein investigated cumulative dose reached and toxicities between the 3-weekly and weekly cisplatin regimens with concurrent radiotherapy. METHODS: Multicentre, retrospective analysis of all patients undergoing combined RCT with cisplatin treated at 3 centres in Switzerland between 06/2008 and 12/2015. RESULTS: Three hundred fourteen pts. were included (3-weekly, N = 127; weekly, N = 187). Median cumulative cisplatin dose was 200 mg/m2 (IQR 150-300) for pts. treated with a 3-weekly schedule and 160 mg/m2 (120-240) for the weekly schedule, consequently more pts. treated with a 3-weekly schedule reached a cumulative dose ≥200 mg/m2 (75.6% vs. 47.1%, p < 0.001). This association was also observed in multivariable analysis adjusted for age and sex (OR 3.46, 95% confidence interval [CI], 2.1-5.7). The 3-weekly regimen led to a higher rate of acute renal toxicity (33.1% vs. 20.9%, p = 0.022). In the landmark analysis, we could not confirm that a cisplatin dose ≥200 mg/m2 is associated with better survival (HR 1.3, 95% CI 0.8-1.9). CONCLUSIONS: Significantly more patients receive a cumulative cisplatin dose of ≥200 mg/m2, when treated with a 3-weekly schedule compared to weekly dosing. The previously reported association between a cumulative cisplatin dose ≥200 mg/m2 and improved outcome could not be shown in our study.


Assuntos
Antineoplásicos/administração & dosagem , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
Radiat Oncol ; 14(1): 34, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782197

RESUMO

PURPOSE: Salvage surgery of recurrent hypopharyngeal and laryngeal squamous cell carcinoma (SCC) results in limited local control and survival rates. As a result of recent technological progress, radiotherapy (RT) has become a valuable, potentially curative therapeutic option. Thus, we aimed to determine prognostic factors for survival outcome in order to optimize patient selection for salvage radiotherapy after failure of first-line treatment with surgery alone in this special patient cohort. METHODS: Seventy-five patients (85% male, median age of 64 years) underwent salvage RT in a secondary setting for recurrent hypopharyngeal or laryngeal SCC after prior surgery alone between 2007 and 2017. On average, patients were treated with one prior surgery (range 1-4 surgeries). Median time between surgery and salvage RT was 7 months (range 1-47 months) for initially advanced tumors (T3/4, N+, extracapsular spread) and 18 months (range 5-333 months) for initially early stage tumors. The majority of patients received concomitant chemotherapy (n = 48; 64%) or other kind of systemic treatment concurrent to radiotherapy (n = 10; 13%). RESULTS: Median follow-up was 41 months (range 3-120 months). Overall, fifteen patients were diagnosed with local failure (all were in-field) at last follow-up (20%). Median time to recurrence was 35 months (range 3-120 months) and 3-year local progression-free survival (LPFS) was 75%, respectively. Dose-escalated RT with 70.4 Gy applied in 2.1 Gy or 2.2 Gy fractions corresponding an EQD2 > 70 Gy (p = 0.032) and the use of concomitant cisplatin weekly chemotherapy (p = 0.006) had a significant positive impact on LPFS. 3-year OS and DPFS were 76 and 85%, respectively. No toxicity-related deaths occurred. Reported grade > 3 side effects were rare (n = 4/70, 6%). CONCLUSION: Salvage radiotherapy resulted in excellent local control rates while radiation dose and the use of cisplatin weekly chemotherapy were identified as prognostic factors for LPFS. Nevertheless, patient selection for curative salvage treatment remains challenging.


Assuntos
Neoplasias Hipofaríngeas/radioterapia , Neoplasias Laríngeas/radioterapia , Recidiva Local de Neoplasia/radioterapia , Terapia de Salvação/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Feminino , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/mortalidade , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Terapia de Salvação/efeitos adversos , Terapia de Salvação/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
19.
Oncogene ; 38(19): 3729-3742, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664690

RESUMO

The role of p53 in genotoxic therapy-induced metabolic shift in cancers is not yet known. In this study, we investigated the role of p53 in the glycolytic shift in head and neck squamous cell carcinoma cell lines following irradiation. Isogenic p53-null radioresistant cancer cells established through cumulative irradiation showed decreased oxygen consumption and increased glycolysis with compromised mitochondria, corresponding with their enhanced sensitivity to drugs that target glycolysis. In contrast, radioresistant cancer cells with wild-type p53 preserved their primary metabolic profile with intact mitophagic processes and maintained their mitochondrial integrity. Moreover, we identified a previously unappreciated link between p53 and mitophagy, which limited the glycolytic shift through the BNIP3-dependent clearance of abnormal mitochondria. Thus, drugs targeting glycolysis could be used as an alternative strategy for overcoming radioresistant cancers, and the p53 status could be used as a biomarker for selecting participants for clinical trials.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas de Membrana/metabolismo , Degradação Mitocondrial/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Glicólise/fisiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos NOD , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Oncol Rep ; 41(3): 1658-1668, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628709

RESUMO

Electrochemotherapy is an established local ablative method used for the treatment of different tumor types, including tumors of the head and neck area. Clinical studies have demonstrated a lower response rate of tumors that recur in pre­irradiated area. The aim of the present study was to explore the response of experimentally induced radioresistant cells and tumors to electrochemotherapy with cisplatin or bleomycin. The radioresistant cells (FaDu­RR) were established by fractionated irradiation of parental human squamous cell carcinoma cell line, FaDu. We compared the 2 cell lines in response to chemotherapy and electrochemotherapy with cisplatin or bleomycin in vitro and in vivo. Using specific mass spectrometry­based analytical methods we determined the difference in the uptake of chemotherapeutics in tumors after electrochemotherapy. Additionally, we compared the capacity of the cells to repair DNA double­strand breaks (DSB) after exposure to the drugs used in electrochemotherapy with the γH2AX foci resolution determined by immunofluorescence microscopy. Our results indicate radio­ and cisplatin cross­resistance, confirmed with the lower response rate of radioresistant tumors after electrochemotherapy with cisplatin. On the other hand, the sensitivity to electrochemotherapy with bleomycin was similar in both cell lines and tumors. While the uptake of chemotherapeutics after electrochemotherapy was comparable in both tumor models, there was a difference between the cell lines in capacity to repair DNA DSB­the radioresistant cells had a lower level of DSB and faster DNA repair rate after exposure to both, cisplatin or bleomycin. Due to the higher complete response rate after electrochemotherapy with bleomycin than with cisplatin, we conclude that the results favor bleomycin­over cisplatin­based electrochemotherapy for treatment of radioresistant tumors and/or tumors that regrow after radiotherapy.


Assuntos
Antineoplásicos/farmacologia , Eletroquimioterapia/métodos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Bleomicina/farmacologia , Bleomicina/uso terapêutico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Camundongos , Camundongos SCID , Tolerância a Radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
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