Assuntos
Neoplasias da Glândula Tireoide , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Humanos , Radioisótopos do Iodo/uso terapêutico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
PURPOSE: Patritumab plus cetuximab with platinum as first-line therapy for patients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) was evaluated for safety and to determine the recommended phase II combination dose. PATIENTS AND METHODS: Patients aged ≥18 years with confirmed R/M SCCHN received intravenous patritumab (18 mg/kg loading dose; 9 mg/kg maintenance dose every 3 weeks) + cetuximab (400 mg/m2 loading dose; 250 mg/m2 maintenance dose weekly) + cisplatin (100 mg/m2 every 3 weeks) or carboplatin (AUC of 5) for six cycles or until toxicity, disease progression, or withdrawal. Primary endpoints were dose-limiting toxicities [DLT; grade ≥3 (21-day observation period)] and treatment-emergent adverse events (TEAE). Pharmacokinetics, human antihuman antibodies (HAHA), tumor response, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS: Fifteen patients completed a median (range) of 8.7 (2.0-20.7) patritumab cycles. No DLTs were reported. Serious adverse events were reported in 9 patients (patritumab-related n = 4). TEAEs (N = 15 patients) led to patritumab interruption in 7 patients. Patritumab-related dose reductions were reported in 1 patient. Patritumab (18 mg/kg) pharmacokinetics (N = 15) showed mean (SD) AUC0-21d of 2,619 (560) µg/day/mL and maximum concentration of 499.9 (90.4) µg/mL. All patients were HAHA-negative at study end (single, transient low titer in 1 patient). Tumor response rate (complete plus partial response; N = 15) was 47%. Median (95% confidence interval) PFS and OS (N = 15) were 7.9 (3.7-9.7) and 13.5 (6.6-17.5) months, respectively. CONCLUSIONS: Patritumab (18 mg/kg loading dose, 9 mg/kg maintenance dose) plus cetuximab/platinum was tolerable, active in SCCHN, and selected as the phase II dose regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Anticorpos Amplamente Neutralizantes/administração & dosagem , Cetuximab/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Platina/administração & dosagem , Prognóstico , Recidiva , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: Thyroid cancer among children is a very rare disease. Although survival is favourable, morbidity caused by the treatment remains considerable, so there is a great need to optimize management by international cooperation. For this reason, the 2016 European Thyroid Association-Cancer Research Network (ETA-CRN) meeting in Copenhagen, Denmark, paid considerable attention to this topic and aimed to give an overview of the care for this paediatric patient group in different European countries. METHODS: An inventory of data on thyroid cancer treatment among children in Europe was generated by questionnaires focused on treatment and organization of care. RESULTS: The treatment of paediatric thyroid cancer appears to be scattered in each European country with limited centralization of care, and different European countries use different treatment and follow-up protocols. CONCLUSION: Collaboration in a European network to optimize treatment and minimize long-term consequences for paediatric thyroid cancer survivors is necessary. During this meeting, the ETA-CRN has endorsed the initiative to collaborate on this rare endocrine cancer within a European network.
Assuntos
Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/terapia , Adolescente , Criança , Pré-Escolar , Congressos como Assunto , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , MasculinoRESUMO
PURPOSE: To determine the 3-dimensional (3D) intrafractional motion of head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Dynamic contrast-enhanced magnetic resonance images from 56 patients with HNSCC in the treatment position were analyzed. Dynamic contrast-enhanced magnetic resonance imaging consisted of 3D images acquired every 2.9 seconds for 4 minutes 50 seconds. Intrafractional tumor motion was studied in the 3 minutes 43 seconds of images obtained after initial contrast enhancement. To assess tumor motion, rigid registration (translations only) was performed using a region of interest (ROI) mask around the tumor. The results were compared with bulk body motion from registration to all voxels. Motion was split into systematic motion and random motion. Correlations between the tumor site and random motion were tested. The within-subject coefficient of variation was determined from 8 patients with repeated baseline measures. Random motion was also assessed at the end of the first week (38 patients) and second week (25 patients) of radiation therapy to investigate trends of motion. RESULTS: Tumors showed irregular occasional rapid motion (eg, swallowing or coughing), periodic intermediate motion (respiration), and slower systematic drifts throughout treatment. For 95% of the patients, displacements due to systematic and random motion were <1.4 mm and <2.1 mm, respectively, 95% of the time. The motion without an ROI mask was significantly (P<.0001, Wilcoxon signed rank test) less than the motion with an ROI mask, indicating that tumors can move independently from the bony anatomy. Tumor motion was significantly (P=.005, Mann-Whitney U test) larger in the hypopharynx and larynx than in the oropharynx. The within-subject coefficient of variation for random motion was 0.33. The average random tumor motion did not increase notably during the first 2 weeks of treatment. CONCLUSIONS: The 3D intrafractional tumor motion of HNSCC is small, with systematic motion <1.4 mm and random motion <2.1 mm 95% of the time.
Assuntos
Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Meios de Contraste , Humanos , Aumento da Imagem , Movimento (Física) , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagemRESUMO
OBJECTIVE: To assess the optimal timing and predictive value of early intra-treatment changes in multimodality functional and molecular imaging (FMI) parameters as biomarkers for clinical remission in patients receiving chemoradiation for head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-five patients with stage III-IVb (AJCC 7th edition) HNSCC prospectively underwent 18F-FDG-PET/CT, and diffusion-weighted (DW), dynamic contrast-enhanced (DCE) and susceptibility-weighted MRI at baseline, week 1 and week 2 of chemoradiation. Patients with evidence of persistent or recurrent disease during follow-up were classed as non-responders. Changes in FMI parameters at week 1 and week 2 were compared between responders and non-responders with the Mann-Whitney U test. The significance threshold was set at a p value of <0.05. RESULTS: There were 27 responders and 8 non-responders. Responders showed a greater reduction in PET-derived tumor total lesion glycolysis (TLG40%; p = 0.007) and maximum standardized uptake value (SUVmax; p = 0.034) after week 1 than non-responders but these differences were absent by week 2. In contrast, it was not until week 2 that MRI-derived parameters were able to discriminate between the two groups: larger fractional increases in primary tumor apparent diffusion coefficient (ADC; p < 0.001), volume transfer constant (Ktrans; p = 0.012) and interstitial space volume fraction (Ve; p = 0.047) were observed in responders versus non-responders. ADC was the most powerful predictor (∆ >17%, AUC 0.937). CONCLUSION: Early intra-treatment changes in FDG-PET, DW and DCE MRI-derived parameters are predictive of ultimate response to chemoradiation in HNSCC. However, the optimal timing for assessment with FDG-PET parameters (week 1) differed from MRI parameters (week 2). This highlighted the importance of scanning time points for the design of FMI risk-stratified interventional studies.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Imagem Multimodal , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Idoso , Carcinoma de Células Escamosas/terapia , Imagem de Difusão por Ressonância Magnética , Feminino , Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de PósitronsRESUMO
Purpose In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). This prespecified subanalysis investigated the effect of age on the efficacy and safety of lenvatinib. Patients and Methods This randomized, double-blind, phase III study enrolled patients with histologically confirmed RR-DTC stratified by age (≤ 65 or > 65 years). Patients (N = 392) received lenvatinib 24 mg/day (n = 261) or placebo (n = 131). The primary end point was PFS; secondary end points included overall survival (OS), objective response rate, and safety. Results In both treatment arms, median ages were 56 (younger group) and 71 years (older group). PFS benefit was maintained with lenvatinib versus placebo in the younger and older age groups, with median PFS of 20.2 versus 3.2 months (hazard ratio [HR], 0.19; 95% CI, 0.13 to 0.27; P < .001) and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17 to 0.43; P < .001), respectively. PFS did not differ with age in either treatment arm. OS was improved in older lenvatinib-treated patients versus placebo (HR, 0.53; 95% CI, 0.31 to 0.91; P = .020). Younger lenvatinib-treated patients showed significantly higher ORR (72% v 55%; P = .0038), longer time to first dose reduction (3.7 v 1.5 months), and lower proportion of grade ≥ 3 treatment-related adverse events (67% v 89%; P < .001) compared with older patients. Conclusion This subanalysis demonstrated improved PFS with lenvatinib treatment versus placebo in both age groups, although higher toxicity was observed in older patients. Despite the allowance of crossover after disease progression, the OS benefit was observed in older patients, suggesting that lenvatinib should be considered for treatment of patients of any age with RR-DTC.
Assuntos
Fatores Etários , Antineoplásicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Tolerância a Radiação , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
Purpose: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients.Experimental Design: Quantitation of the transverse relaxation rate, R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin in human CALR xenografts and patients with HNSCC at 3T. Autocovariance and power spectrum analysis of variations in R2* was performed for each imaged voxel, to assess statistical significance and frequencies of cycling changes in tumor blood oxygenation. Pathologic correlates with tumor perfusion (Hoechst 33342), hypoxia (pimonidazole), and vascular density (CD31) were sought in the xenografts, and dynamic contrast-enhanced (DCE) MRI was used to assess patient tumor vascularization. The prevalence of fluctuations within patient tumors, DCE parameters, and treatment outcome were reported.Results: Spontaneous R2* fluctuations with a median periodicity of 15 minutes were detected in both xenografts and patient tumors. Spatially, these fluctuations were predominantly associated with regions of heterogeneous perfusion and hypoxia in the CALR xenografts. In patients, R2* fluctuations spatially correlated with regions of lymph nodes with low Ktrans values, typically in the vicinity of necrotic cores.Conclusions: IS-MRI can be used to monitor variations in levels of paramagnetic deoxyhemoglobin, associated with cycling hypoxia. The presence of such fluctuations may be linked with impaired tumor vasculature, the presence of which may impact treatment outcome. Clin Cancer Res; 23(15); 4233-41. ©2017 AACR.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neovascularização Patológica/diagnóstico por imagem , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral , Meios de Contraste/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Linfonodos/patologia , Masculino , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Nitroimidazóis/administração & dosagem , Tolerância a Radiação/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT is frequently ineffective in patients with advanced disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on CCRT in HNSCC. Here, we evaluated the HSP90 inhibitor, AUY922, combined with CCRT. METHODS: The ability of AUY922 to sensitize to CCRT was assessed in p53 mutant head and neck cell lines by clonogenic assay. Modulation of the CCRT induced DNA damage response (DDR) by AUY922 was characterized by confocal image analysis of RAD51, BRCA1, 53BP1, ATM and mutant p53 signaling. The role of FANCA depletion by AUY922 was examined using shRNA. Cell cycle checkpoint abrogation and chromosomal fragmentation was assessed by western blot, FACS and confocal. The role of ATM was also assessed by shRNA. AUY922 in combination with CCRT was assessed in vivo. RESULTS: The combination of AUY922 with cisplatin, radiation and CCRT was found to be synergistic in p53 mutant HNSCC. AUY922 leads to significant alterations to the DDR induced by CCRT. This comprises inhibition of homologous recombination through decreased RAD51 and pS1524 BRCA1 with a corresponding increase in 53BP1 foci, activation of ATM and signaling into mutant p53. A shift to more error prone repair combined with a loss of checkpoint function leads to fragmentation of chromosomal material. The degree of disruption to DDR signalling correlated to chromosomal fragmentation and loss of clonogenicity. ATM shRNA indicated a possible rationale for the combination of AUY922 and CCRT in cells lacking ATM function. CONCLUSIONS: This study supports future clinical studies combining AUY922 and CCRT in p53 mutant HNSCC. Modulation of the DDR and chromosomal fragmentation are likely to be analytical points of interest in such trials.
Assuntos
Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Isoxazóis/farmacologia , Compostos Organoplatínicos/farmacologia , Resorcinóis/farmacologia , Animais , Proteína BRCA1/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular Tumoral , Quimiorradioterapia/métodos , Cromossomos/genética , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Reparo do DNA/efeitos da radiação , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Recombinação Homóloga/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Proteína Supressora de Tumor p53/genéticaRESUMO
AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by the clonogenic assay. Radiosensitization by AZD6738 to clinically relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell-cycle checkpoint and inhibiting homologous recombination. Mitosis with damaged DNA resulted in mitotic catastrophe as measured by micronucleus formation by live-cell fluorescent-ubiquitination cell-cycle imaging of cell-cycle progression and nuclear morphology. Induction of micronuclei was significantly more prominent for AZD6738 compared with inhibition of the downstream kinase CHK1 alone at isoeffective doses. Micronuclei were characterized as acentric chromosomal fragments, which displayed characteristics of increased DNA damage and cell-cycle dyssynchrony when compared with the primary nucleus. Mol Cancer Ther; 16(1); 25-34. ©2016 AACR.
Assuntos
Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Radiossensibilizantes/farmacologia , Sulfóxidos/farmacologia , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Modelos Animais de Doenças , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Recombinação Homóloga/efeitos dos fármacos , Recombinação Homóloga/efeitos da radiação , Humanos , Indóis , Concentração Inibidora 50 , Camundongos , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Morfolinas , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Sulfonamidas , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: This phase III, non-blinded, parallel-group, randomised controlled study evaluated the efficacy of Caphosol mouthwash in the management of radiation-induced oral mucositis (OM) in patients with head and neck cancer (HNC) undergoing radical (chemo)radiotherapy. PATIENTS AND METHODS: Eligible patients were randomised at 1:1 to Caphosol plus standard oral care (intervention) or standard oral care alone (control), stratified by radiotherapy technique and use of concomitant chemotherapy. Patients in the intervention arm used Caphosol for 7weeks: 6weeks during and 1-week post-radiotherapy. The primary endpoint was the incidence of severe OM (CTCAE ⩾grade 3) during and up to week 8 post-radiotherapy. Secondary endpoints include pharyngeal mucositis, dysphagia, pain and quality of life. RESULTS: The intervention (n=108) and control (n=107) arms were well balanced in terms of patient demographics and treatment characteristics. Following exclusion of patients with missing data, 210 patients were available for analysis. The incidence of severe OM did not differ between the intervention and control arms (64.1% versus 65.4%, p=0.839). Similarly, no significant benefit was observed for other secondary endpoints. Overall, compliance with the recommended frequency of Caphosol was low. CONCLUSION: Caphosol did not reduce the incidence or duration of severe OM during and after radiotherapy in HNC.
Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Antissépticos Bucais/uso terapêutico , Lesões por Radiação/terapia , Estomatite/terapia , Adulto , Idoso , Feminino , Neoplasias de Cabeça e Pescoço/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Lesões por Radiação/epidemiologia , Estomatite/epidemiologiaRESUMO
PURPOSE: To investigate the effects of different time-resolved angiography with stochastic trajectories (TWIST) k-space undersampling schemes on calculated pharmacokinetic dynamic contrast-enhanced (DCE) vascular parameters. METHODS: A digital perfusion phantom was employed to simulate effects of TWIST on characteristics of signal changes in DCE. Furthermore, DCE-MRI was acquired without undersampling in a group of patients with head and neck squamous cell carcinoma and used to simulate a range of TWIST schemes. Errors were calculated as differences between reference and TWIST-simulated DCE parameters. Parametrical error maps were used to display the averaged results from all tumors. RESULTS: For a relatively wide range of undersampling schemes, errors in pharmacokinetic parameters due to TWIST were under 10% for the volume transfer constant, Ktrans, and total extracellular extravascular space volume, Ve. TWIST induced errors in the total blood plasma volume, Vp, were the largest observed, and these were inversely dependent on the area of the fully sampled k-space. The magnitudes of errors were not correlated with Ktrans, Vp and weakly correlated with Ve. CONCLUSIONS: The authors demonstrated methods to validate and optimize k-space view-sharing techniques for pharmacokinetic DCE studies using a range of clinically relevant spatial and temporal patient derived data. The authors found a range of undersampling patterns for which the TWIST sequence can be reliably used in pharmacokinetic DCE-MRI. The parameter maps created in the study can help to make a decision between temporal and spatial resolution demands and the quality of enhancement curve characterization.
Assuntos
Angiografia , Meios de Contraste/farmacocinética , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/metabolismo , Imageamento por Ressonância Magnética , Adulto , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagens de Fantasmas , Processos EstocásticosRESUMO
BACKGROUND: Persistent dysphagia following primary chemoradiation (CRT) for head and neck cancers can have a devastating impact on patients' quality of life. Single arm studies have shown that the dosimetric sparing of critical swallowing structures such as the pharyngeal constrictor muscle and supraglottic larynx can translate to better functional outcomes. However, there are no current randomised studies to confirm the benefits of such swallow sparing strategies. The aim of Dysphagia/Aspiration at risk structures (DARS) trial is to determine whether reducing the dose to the pharyngeal constrictors with dysphagia-optimised intensity- modulated radiotherapy (Do-IMRT) will lead to an improvement in long- term swallowing function without having any detrimental impact on disease-specific survival outcomes. METHODS/DESIGN: The DARS trial (CRUK/14/014) is a phase III multicentre randomised controlled trial (RCT) for patients undergoing primary (chemo) radiotherapy for T1-4, N0-3, M0 pharyngeal cancers. Patients will be randomised (1:1 ratio) to either standard IMRT (S-IMRT) or Do-IMRT. Radiotherapy doses will be the same in both groups; however in patients allocated to Do-IMRT, irradiation of the pharyngeal musculature will be reduced by delivering IMRT identifying the pharyngeal muscles as organs at risk. The primary endpoint of the trial is the difference in the mean MD Anderson Dysphagia Inventory (MDADI) composite score, a patient-reported outcome, measured at 12 months post radiotherapy. Secondary endpoints include prospective and longitudinal evaluation of swallow outcomes incorporating a range of subjective and objective assessments, quality of life measures, loco-regional control and overall survival. Patients and speech and language therapists (SLTs) will both be blinded to treatment allocation arm to minimise outcome-reporting bias. DISCUSSION: DARS is the first RCT investigating the effect of swallow sparing strategies on improving long-term swallowing outcomes in pharyngeal cancers. An integral part of the study is the multidimensional approach to swallowing assessment, providing robust data for the standardisation of future swallow outcome measures. A translational sub- study, which may lead to the development of future predictive and prognostic biomarkers, is also planned. TRIAL REGISTRATION: This study is registered with the International Standard Randomised Controlled Trial register, ISRCTN25458988 (04/01/2016).
Assuntos
Carcinoma de Células Escamosas/radioterapia , Transtornos de Deglutição/prevenção & controle , Neoplasias de Cabeça e Pescoço/radioterapia , Lesões por Radiação/prevenção & controle , Quimiorradioterapia , Ensaios Clínicos Fase III como Assunto , Transtornos de Deglutição/etiologia , Humanos , Estudos Multicêntricos como Assunto , Qualidade de Vida , Lesões por Radiação/etiologia , Radioterapia de Intensidade Modulada/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
PURPOSE: Current normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue-sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation. METHODS AND MATERIALS: FDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis were used for dimensionality reduction of the dose-volume histogram data. The reduced dose data were input into functional logistic regression models (functional partial least squares-logistic regression [FPLS-LR] and functional principal component-logistic regression [FPC-LR]) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate-response associations, assessed using bootstrapping. RESULTS: The area under the receiver operating characteristic curve for the PLR, FPC-LR, and FPLS-LR models was 0.65, 0.69, and 0.67, respectively, for mucositis (internal validation) and 0.81, 0.83, and 0.83, respectively, for dysphagia (external validation). The calibration slopes/intercepts for the PLR, FPC-LR, and FPLS-LR models were 1.6/-0.67, 0.45/0.47, and 0.40/0.49, respectively, for mucositis (internal validation) and 2.5/-0.96, 0.79/-0.04, and 0.79/0.00, respectively, for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models. CONCLUSIONS: FPLS and functional principal component analysis marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in normal tissue complication probability modeling.
Assuntos
Transtornos de Deglutição/etiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Modelos Estatísticos , Mucosite/etiologia , Órgãos em Risco/efeitos da radiação , Lesões por Radiação/complicações , Doença Aguda , Área Sob a Curva , Carboplatina/efeitos adversos , Cisplatino/efeitos adversos , Relação Dose-Resposta à Radiação , Humanos , Análise de Componente Principal , Curva ROC , Radiossensibilizantes/efeitos adversos , Dosagem Radioterapêutica , Análise de RegressãoRESUMO
The objective of this study was to assess the predictive value of early assessment (after 1 cycle of induction chemotherapy [IC]) with 18F-FDG PET/CT and diffusion-weighted (DW) MRI for subsequent response to radical chemoradiotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Twenty patients with stage III-IVa HNSCC prospectively underwent 18F-FDG PET/CT and DW MRI before and 2 wk after each cycle of IC (first cycle, IC1; second cycle, IC2). Response was assessed 3 mo after completion of chemoradiotherapy with clinical examination, MRI, and 18F-FDG PET/CT. Patients with persistent disease were classed as nonresponders. Changes in functional and molecular imaging parameters after IC1 were compared between responders and nonresponders with the Mann-Whitney U test. The significance threshold was set at a P value of less than 0.05. RESULTS: Responders showed a significantly greater reduction in metabolic tumor volume (P = 0.03) and total lesion glycolysis (P = 0.04) after IC1 than nonresponders. Responders also showed a tendency toward a larger but statistically nonsignificant increase in apparent diffusion coefficient after IC1. There was no significant difference in the changes from baseline between the IC1 and IC2 for all functional and molecular imaging parameters, indicating that most biologic response to IC measured by 18F-FDG PET/CT and DW MRI was observed early after the first cycle of IC. CONCLUSION: Our preliminary data indicate that the 18F-FDG PET/CT-derived metabolic tumor volume or total lesion glycolysis, acquired after IC1, are early predictive biomarkers for ultimate response to subsequent chemoradiotherapy. These early biomarkers enable identification of patients at risk of treatment failure at an early time point, permitting treatment individualization and consideration of alternative strategies such as radiotherapy dose escalation or surgery.
Assuntos
Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/terapia , Quimioterapia de Indução , Imagem Multimodal , Valor Preditivo dos Testes , Idoso , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND AND PURPOSE: Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose (dose-volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100-iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. RESULTS: The dose-volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. CONCLUSIONS: The RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence.
Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Aprendizado de Máquina , Lesões por Radiação/etiologia , Estomatite/etiologia , Doença Aguda , Tomada de Decisão Clínica , Feminino , Humanos , Modelos Logísticos , Masculino , Modelos Teóricos , Probabilidade , Dosagem RadioterapêuticaRESUMO
BACKGROUND AND PURPOSE: Current oral mucositis normal tissue complication probability models, based on the dose distribution to the oral cavity volume, have suboptimal predictive power. Improving the delineation of the oral mucosa is likely to improve these models, but is resource intensive. We developed and evaluated fully-automated atlas-based segmentation (ABS) of a novel delineation technique for the oral mucosal surfaces. MATERIAL AND METHODS: An atlas of mucosal surface contours (MSC) consisting of 46 patients was developed. It was applied to an independent test cohort of 10 patients for whom manual segmentation of MSC structures, by three different clinicians, and conventional outlining of oral cavity contours (OCC), by an additional clinician, were also performed. Geometric comparisons were made using the dice similarity coefficient (DSC), validation index (VI) and Hausdorff distance (HD). Dosimetric comparisons were carried out using dose-volume histograms. RESULTS: The median difference, in the DSC and HD, between automated-manual comparisons and manual-manual comparisons were small and non-significant (-0.024; p=0.33 and -0.5; p=0.88, respectively). The median VI was 0.086. The maximum normalised volume difference between automated and manual MSC structures across all of the dose levels, averaged over the test cohort, was 8%. This difference reached approximately 28% when comparing automated MSC and OCC structures. CONCLUSIONS: Fully-automated ABS of MSC is suitable for use in radiotherapy dose-response modelling.
Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Mucosa Bucal/efeitos da radiação , Órgãos em Risco , Atlas como Assunto , Relação Dose-Resposta à Radiação , Humanos , Radiometria/métodos , Dosagem RadioterapêuticaRESUMO
PURPOSE: To determine whether quantitation of T2* is sufficiently repeatable and sensitive to detect clinically relevant oxygenation levels in head and neck squamous cell carcinoma (HNSCC) at 3T. MATERIALS AND METHODS: Ten patients with newly diagnosed locally advanced HNSCC underwent two magnetic resonance imaging (MRI) scans between 24 and 168 hours apart prior to chemoradiotherapy treatment. A multiple gradient echo sequence was used to calculate T2* maps. A quadratic function was used to model the blood transverse relaxation rate as a function of blood oxygenation. A set of published coefficients measured at 3T were incorporated to account for tissue hematocrit levels and used to plot the dependence of fractional blood oxygenation (Y) on T2* values, together with the corresponding repeatability range. Repeatability of T2* using Bland-Altman analysis, and calculation of limits of agreement (LoA), was used to assess the sensitivity, defined as the minimum difference in fractional blood oxygenation that can be confidently detected. RESULTS: T2* LoA for 22 outlined tumor volumes were 13%. The T2* dependence of fractional blood oxygenation increases monotonically, resulting in increasing sensitivity of the method with increasing blood oxygenation. For fractional blood oxygenation values above 0.11, changes in T2* were sufficient to detect differences in blood oxygenation greater than 10% (Δ T2* > LoA for ΔY > 0.1). CONCLUSION: Quantitation of T2* at 3T can detect clinically relevant changes in tumor oxygenation within a wide range of blood volumes and oxygen tensions, including levels reported in HNSCC. J. Magn. Reson. Imaging 2016;44:72-80.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/metabolismo , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Oxigênio/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Medullary thyroid cancer (MTC) is a rare cancer comprising approximately 5% of all thyroid cancers. The majority arises sporadically but around 25% are hereditary forming part of the Multiple Endocrine Neoplasia (MEN) type 2 syndromes. The initial management is surgical, the extent of resection determined by radiological stage, presence of and specific REarranged during Transfection (RET) oncogene mutation and level of serum calcitonin. External beam radiotherapy may be utilised in the adjuvant setting to improve local control rates. Conventional cytotoxic agents remain essentially futile in the management of advanced MTC with response rates of around 15-20% at best. Over the last decade, alongside a greater understanding of the molecular pathogenesis of MTC we have seen the development of small molecule agents including tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) and RET with activity in advanced MTC. This review will examine the evidence for this therapeutic approach, when to consider initiating and how to manage toxicities arising from such therapies in the treatment of advanced MTC.
RESUMO
OBJECTIVES: We previously described dose-escalated intensity-modulated radiotherapy (IMRT) in squamous cell cancer of the larynx/hypopharynx (SCCL/H) to offer improved locoregional control with a low incidence of toxicity at 2 years. We now present outcome and safety data at 5 years. MATERIALS AND METHODS: A sequential cohort Phase I/II trial design was used. Patients with SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. RESULTS: Between 09/2002 and 01/2008, 60 patients (29 DL1, 31 DL2) with stage III (41% DL1, 52% DL2) and stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 5.7 (1.0-10.2) years and for DL2 was 6.0 (0.3-8.4) years. Five-year local control rates (95% confidence interval) for DL1 and DL2, respectively, were 68% (50.6-85.4%) and 75% (58.9-91.1%), locoregional progression-free survival rates were 54% (35.6-72.4%) and 62.6% (44.8-80.4%), and overall survival was 61.9% (44.1-79.7) and 67.6 (51.1-84.1%). Five-year laryngeal preservation rates were 66.7% (37.4-87.9%) and 71.4% (44.4-85.8%), respectively. Cumulative toxicities reported were: one patient in DL1 and 2 in DL2 developed benign pharyngeal strictures. No other G3/4 toxicities were reported. CONCLUSIONS: Dose-escalated IMRT at DL2 achieves higher 5-year local control, larynx preservation and survival rates with acceptable late toxicity. Recruitment into a Cancer Research UK Phase III study (ART-DECO), with DL2 as the experimental arm, is ongoing.
Assuntos
Neoplasias Hipofaríngeas/radioterapia , Neoplasias Laríngeas/radioterapia , Radioterapia de Intensidade Modulada , HumanosRESUMO
PURPOSE: To describe the dose-response relationships for the different measures of salivary gland recovery following radical radiotherapy for locally advanced head and neck squamous cell cancers (LA-HNSCC). METHODS AND MATERIALS: Dosimetric analysis of data from the PARSPORT trial, a Phase III study of conventional RT (RT) and intensity modulated radiotherapy (IMRT) for LA-HNSCC was undertaken to determine the relationship between parotid gland mean dose and toxicity endpoints: high-grade subjective and objective xerostomia and xerostomia-related quality of life scores. LKB-NTCP parameters (TD50, m and n) were generated and tolerance doses (D50) reported using non-linear logistic regression analysis. RESULTS: Data were available on 63 patients from the PARSPORT trial. Parotid saliva flow rate provided the strongest association between mean dose and recovery, D50=23.4 Gy (20.6-26.2) and k=3.2 (1.9-4.5), R(2)=0.85. Corresponding LKB parameters were TD50=26.3 Gy (95% CI: 24.0-30.1), m=0.25 (0.18-1.0 and n=1). LENTSOMA subjective xerostomia also demonstrated a strong association D50=33.3 Gy (26.7-39.8), k=2.8 (91.4-4.4), R(2)=0.77). CONCLUSION: We recommend using the LENT SOMA subjective xerostomia score to predict recovery of salivation due to its strong association with dosimetry and ease of recording.