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BACKGROUND: Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with chemoradiotherapy with curative intent but at the consequence of adverse effects on quality of life. We aimed to investigate if dysphagia-optimised intensity-modulated radiotherapy (DO-IMRT) reduced radiation dose to the dysphagia and aspiration related structures and improved swallowing function compared with standard IMRT. METHODS: DARS was a parallel-group, phase 3, multicentre, randomised, controlled trial done in 22 radiotherapy centres in Ireland and the UK. Participants were aged 18 years and older, had T1-4, N0-3, M0 oropharyngeal or hypopharyngeal cancer, a WHO performance status of 0 or 1, and no pre-existing swallowing dysfunction. Participants were centrally randomly assigned (1:1) using a minimisation algorithm (balancing factors: centre, chemotherapy use, tumour type, American Joint Committee on Cancer tumour stage) to receive DO-IMRT or standard IMRT. Participants and speech language therapists were masked to treatment allocation. Radiotherapy was given in 30 fractions over 6 weeks. Dose was 65 Gy to primary and nodal tumour and 54 Gy to remaining pharyngeal subsite and nodal areas at risk of microscopic disease. For DO-IMRT, the volume of the superior and middle pharyngeal constrictor muscle or inferior pharyngeal constrictor muscle lying outside the high-dose target volume had a mandatory 50 Gy mean dose constraint. The primary endpoint was MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after radiotherapy, analysed in the modified intention-to-treat population that included only patients who completed a 12-month assessment; safety was assessed in all randomly assigned patients who received at least one fraction of radiotherapy. The study is registered with the ISRCTN registry, ISRCTN25458988, and is complete. FINDINGS: From June 24, 2016, to April 27, 2018, 118 patients were registered, 112 of whom were randomly assigned (56 to each treatment group). 22 (20%) participants were female and 90 (80%) were male; median age was 57 years (IQR 52-62). Median follow-up was 39·5 months (IQR 37·8-50·0). Patients in the DO-IMRT group had significantly higher MDADI composite scores at 12 months than patients in the standard IMRT group (mean score 77·7 [SD 16·1] vs 70·6 [17·3]; mean difference 7·2 [95% CI 0·4-13·9]; p=0·037). 25 serious adverse events (16 serious adverse events assessed as unrelated to study treatment [nine in the DO-IMRT group and seven in the standard IMRT group] and nine serious adverse reactions [two vs seven]) were reported in 23 patients. The most common grade 3-4 late adverse events were hearing impairment (nine [16%] of 55 in the DO-IMRT group vs seven [13%] of 55 in the standard IMRT group), dry mouth (three [5%] vs eight [15%]), and dysphagia (three [5%] vs eight [15%]). There were no treatment-related deaths. INTERPRETATION: Our findings suggest that DO-IMRT improves patient-reported swallowing function compared with standard IMRT. DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers. FUNDING: Cancer Research UK.
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Transtornos de Deglutição , Neoplasias de Cabeça e Pescoço , Radioterapia de Intensidade Modulada , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Radioterapia de Intensidade Modulada/efeitos adversos , Transtornos de Deglutição/etiologia , Qualidade de Vida , Neoplasias de Cabeça e Pescoço/radioterapia , Quimiorradioterapia/efeitos adversosRESUMO
OBJECTIVES: To report clinical outcomes of relapsed oropharyngeal squamous cell carcinoma (OPSCC) after definitive intensity-modulated (chemo)radiotherapy [(C)RT]. MATERIALS AND METHODS: Data for all relapsed patients treated for OPSCC with definitive (C)RT between 2010 and 2016 were collected. Primary end-point was post-failure survival (PFS). RESULTS: Overall, 273 OPSCC patients completed definitive (C)RT. Of these, 42 cases (n = 26 human papilloma virus (HPV)-negative; n = 16 HPV-positive) had relapsed (n = 23 persistent disease; n = 19 recurrent disease) and were included in the final analysis. Two-year PFS for the entire population was 30.6%; 20.5% for HPV-negative and 43.8% for HPV-positive patients. Salvage curative surgery was associated with a significantly higher 2 years PFS rate (56.2%) compared with palliative treatment (22.9%) and best supportive care (0%) (p < 0.001). A positive trend in 2 years PFS was recorded in the early complete response cases (49.5%) versus patients who did not achieve a complete response within 3 months of the end of (C)RT (23.0%) (p = 0.11). CONCLUSION: A higher PFS rate is achieved when relapsed OPSCC cases are treated with salvage curative intent. HPV-positive disease and early complete response within 3 months from the end of (C)RT may be related to better PFS.
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Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Infecções por Papillomavirus/complicações , Neoplasias Orofaríngeas/tratamento farmacológico , Neoplasias Orofaríngeas/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias Bucais/complicações , Papillomavirus Humano , Doença Crônica , Neoplasias de Cabeça e Pescoço/complicações , Prognóstico , Estudos RetrospectivosAssuntos
Carcinoma de Células Escamosas , Transtornos de Deglutição , Neoplasias de Cabeça e Pescoço , Neoplasias Faríngeas , Radioterapia (Especialidade) , Radioterapia de Intensidade Modulada , Humanos , Radioterapia de Intensidade Modulada/efeitos adversos , Transtornos de Deglutição/etiologia , Neoplasias Faríngeas/radioterapia , Carcinoma de Células Escamosas/radioterapia , Dosagem RadioterapêuticaRESUMO
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).
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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
BACKGROUND AND PURPOSE: To evaluate the inter-observer variation (IOV) in pharyngeal constrictor muscle (PCM) contouring, and resultant impact on dosimetry and estimated toxicity, as part of the pre-trial radiotherapy trial quality assurance (RTQA) within DARS, a multicenter phase III randomized controlled trial investigating the functional benefits of dysphagia-optimized intensity-modulated radiotherapy (Do-IMRT) in pharyngeal cancers. METHODS AND MATERIALS: Outlining accuracy of 15 clinicians' superior and middle PCM (SMPCM) and inferior PCM (IPCM) were retrospectively assessed against gold standards (GS) using volume, location, and conformity indices (CIs) on a pre-trial benchmark case of oropharyngeal cancer. The influence of delineation variability on dose delivered to the constrictor muscles with Do-IMRT and resultant normal tissue complication probability (NTCP) for physician-scored radiation-associated dysphagia at 6 months was evaluated. RESULTS: For GS, SMPCM, and IPCM volumes were 13.51 and 1.67 cm3; corresponding clinician mean volumes were 12.18 cm3 (SD 3.0) and 2.40 cm3 (SD 0.9) respectively. High IOV in SMPCM and IPCM delineation was observed by the low DICE similarity coefficient value, along with high geographical miss index and discordance index values. Delineation variability did not significantly affect the mean dose delivered to the constrictors, relative to the GS plan. Mean clinician NTCP was 24.6% (SD 0.6), compared to the GS-NTCP of 24.7%. CONCLUSIONS: Results from this benchmark case demonstrate that inaccurate PCM delineation existed, even with protocol guidelines. This did not impact on delivered dose to this structure with Do-IMRT, or on estimated swallowing toxicity, in this single benchmark case.
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This study aimed to assess the impact of the margin applied to the clinical target volume, to create the planning target volume, on plan quality of a novel dysphagia-optimised intensity modulated radiotherapy technique developed within a head and neck cancer multicentre randomised controlled trial. Protocol compliant plans were used for a single benchmark planning case. Larger margins were associated with higher doses to adjacent organs at risk, particularly the inferior pharyngeal constrictor muscle, but coincided with some improved low dose target coverage. A 3 mm margin is recommended for this technique if local practices allow.
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PURPOSE: To assess TNM 8 staging in discriminating overall survival (OS) amongst patients with locally advanced oral cavity squamous cell carcinoma (OCSCC) treated with surgery and post-operative radiotherapy (PORT), compared to TNM 7. MATERIAL AND METHODS: Data from OCSCC patients treated with surgery and PORT between January 2010 and December 2018 were reviewed. Demographics, tumour characteristics and treatment response data were collected, and patients staged according to both TNM 7 and TNM 8. OS and disease free survival (DFS) were estimated using the Kaplan Meier method. Univariate and multivariable analyses were conducted for factors affecting OS, DFS and early disease recurrence within 12 months. RESULTS: Overall 172 patients were analyzed. Median follow up was 32 months for all patients and 48 months for surviving patients. TNM 8 staging demonstrated significant stratification of OS and DFS amongst the entire cohort, whereas TNM 7 staging did not. On multivariable analysis, TNM 8 stage, performance status (PS) and a positive surgical margin were prognostic for OS. Looking at disease recurrence within 12 months, TNM 8 stage IVB, presence of lymphovascular invasion (LVSI), younger age and lesser smoking history were predictive factors on multivariable analysis. CONCLUSION: TNM 8 is a good development of its predecessor in terms of predicting survival for patients with locally advanced OCSCC. We have also identified younger age (<60 years) and a smoking history of <10 pack years as risk factors for early disease recurrence, potentially representing a separate biological cohort within OCSCC patients.
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Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/radioterapia , Neoplasias Bucais/cirurgia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.
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Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Neoplasias de Cabeça e Pescoço/microbiologia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/microbiologia , Fusobacterium/isolamento & purificação , Carcinoma de Células Escamosas , Infecções por Fusobacterium/complicações , Infecções por Fusobacterium/microbiologia , Masculino , FemininoRESUMO
OBJECTIVE: Advances in radiation delivery, imaging techniques, and chemotherapy have significantly improved treatment options for non-metastatic nasopharyngeal cancers (NPC). However, their impact on the practice in the United Kingdom (UK), where this tumour is rare, is unknown. This study examined the current attitudes of UK head and neck oncologists to the treatment of NPC. METHODS: UK head and neck oncologists representing 19/23 cancer networks were sent an invitation email with a personalised link to a web-based survey designed to identify the influence of tumour and nodal staging on current NPC management practices. RESULTS: 26/42 (61%) of clinicians responded. Induction chemotherapy followed by concomitant chemoradiation was the treatment of choice for Stage III (69%) and IVa/b (96%), with cisplatin and 5-fluorouracil combination being the most commonly used induction chemotherapy regimen (88%). 16 centres (61%) used a geometric approach, adding variable margins of 0-10 mm to the gross tumour volume to define their therapeutic dose clinical target volume. 54% of respondents used 3 radiotherapy (RT) prescription doses to treat NPC. Retropharyngeal nodal region irradiation policy was inconsistent, with nearly one-quarter treating the entire group to a radical dose. CONCLUSION: Significant heterogeneity currently exists in the RT practice of NPC in the UK. A consensus regarding the optimal curative, function-sparing treatment paradigm for NPC is necessary to ensure cancer survivors have satisfactory long-term health-related quality of life. Advances in knowledge: This is the first study to highlight the significant variation in RT practice of NPC in the UK.
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Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Oncologistas , Padrões de Prática Médica , Cabeça/patologia , Humanos , Neoplasias Nasofaríngeas/patologia , Pescoço/patologia , Estadiamento de Neoplasias , Reino UnidoAssuntos
Radioterapia Guiada por Imagem , Radioterapia de Intensidade Modulada , Humanos , Ensaios Clínicos Fase I como Assunto , Estudos de Viabilidade , Estudos Multicêntricos como Assunto , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem/métodos , Radioterapia de Intensidade Modulada/métodosRESUMO
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.