TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.•There is a strong translational component within TORPEdO. Imaging and physics data along with blood, tissue collection will inform future studies in refining patient selection for IMPT.

Methodology for the development of National Multidisciplinary Management Recommendations using a multi-stage meta-consensus initiative.

BACKGROUND: Methods for developing national recommendations vary widely. The successful adoption of new guidance into routine practice is dependent on buy-in from the clinicians delivering day-to-day patient care and must be considerate of existing resource constraints, as well as being aspirational in its scope. This initiative aimed to produce guidelines for the management of head and neck squamous cell carcinoma of unknown primary (HNSCCUP) using a novel methodology to maximise the likelihood of national adoption. METHODS: A voluntary steering committee oversaw 3 phases of development: 1) clarification of topic areas, data collection and assimilation, including systematic reviews and a National Audit of Practice; 2) a National Consensus Day, presenting data from the above to generate candidate consensus statements for indicative voting by attendees; and 3) a National Delphi Exercise seeking agreement on the candidate consensus statements, including representatives from all 58 UK Head and Neck Multidisciplinary Teams (MDT). Methodology was published online in advance of the Consensus Day and Delphi exercise. RESULTS: Four topic areas were identified to frame guideline development. The National Consensus Day was attended by 227 participants (54 in-person and 173 virtual). Results from 7 new systematic reviews were presented, alongside 7 expert stakeholder presentations and interim data from the National Audit and from relevant ongoing Clinical Trials. This resulted in the generation of 35 statements for indicative voting by attendees which, following steering committee ratification, led to 30 statements entering the National Delphi exercise. After 3 rounds (with a further statement added after round 1), 27 statements had reached 'strong agreement' (n = 25, 2, 0 for each round, respectively), a single statement achieved 'agreement' only (round 3), and 'no agreement' could be reached for 3 statements (response rate 98% for each round). Subsequently, 28 statements were adopted into the National MDT Guidelines for HNSCCUP. CONCLUSIONS: The described methodology demonstrated an effective multi-phase strategy for the development of national practice recommendations. It may serve as a cost-effective model for future guideline development for controversial or rare conditions where there is a paucity of available evidence or where there is significant variability in management practices across a healthcare service.

Voice burden in teachers and non-teachers in a UK population: A questionnaire-based survey.

OBJECTIVE: To characterise the burden of voice disorders in teachers in a UK population, compare it with non-teachers and identify groups of teachers who may be particularly at risk of developing a voice problem. DESIGN: Questionnaire-based survey of primary and secondary school teachers and non-teachers. Questions consisted of general demographics, VHI-10 and questions relating to voice problems. METHODS: Distribution of questionnaires to teachers and non-teachers and statistical analysis of the responses. SETTING: University teaching hospital. PARTICIPANTS: Teachers and non-teachers in a region of North West England. MAIN OUTCOME MEASURES: Identification of risk factors for voice problems in teachers, compared to non-teachers. RESULTS: A total of 210 primary and 244 secondary school teachers and 304 non-teachers participated in the questionnaire survey. Response rates were 67.9% from primary schools, 41.2% from secondary schools and 40.0% from the non-teachers. 30.0% of teachers and 9.0% of non-teachers had reported problems with their voice. 12.8% of teachers and 2.0% of non-teachers had missed work due to voice problems. 14.1% of teachers and 5.3% non-teachers had seen a general practitioner for voice-related problems, whilst 7.1% of teachers and 6.3% of non-teachers had been referred to an otolaryngologist or speech therapist for voice problems. Factors related to VHI-10 (P < .05) were identified. CONCLUSIONS: Voice disorders are an occupational health problem for teachers, with a significant burden of these disorders in this group of teachers in the UK. We have identified risk factors that could be exploited to identify groups of teachers who would benefit from early intervention.

Pre-treatment tumour perfusion parameters and initial RECIST response do not predict long-term survival outcomes for patients with head and neck squamous cell carcinoma treated with induction chemotherapy.

OBJECTIVES: Previously, we showed that pre-treatment tumour plasma perfusion (Fp) predicts RECIST response to induction chemotherapy (ICT) in locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The aim here was to determine whether the pre-treatment tumour Fp estimate, changes in tumour Fp or RECIST response post 2 cycles of ICT were prognostic for long-term survival outcomes. METHODS: A prospective study enrolled patients with high stage HNSCC treated with docetaxel (T), cisplatin (P) and 5-fluorouracil (F) (ICT) followed by synchronous cisplatin and intensity modulated radiotherapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before and after two cycles of ICT was used to measure Fp and RECIST response. RESULTS: Forty-two patients were recruited and 37 underwent two scans. The median follow-up was 36 (range 23-49) months. Pre-treatment tumour Fp (stratified by median) was not prognostic for overall survival (p = 0.42), disease specific survival (p = 0.20) and locoregional control (p = 0.64). Neither change in tumour Fp nor RECIST response post two cycles of ICT was prognostic for any outcome (p>0.21). CONCLUSION: DCE-MRI parameters do not predict long-term survival outcomes following ICT and RECIST response to ICT may not be an appropriate endpoint to determine early efficacy of a treatment in HNSCC patients.

Taxane, platinum and 5-FU prior to chemoradiotherapy benefits patients with stage IV neck node-positive head and neck cancer and a good performance status.

PURPOSE: The benefit of adding docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy to chemoradiotherapy (CRT) in head and neck squamous cell carcinoma (HNSCC) remains uncertain. We aimed to investigate whether ICT is well tolerated when given with prophylactic treatment against predicted adverse effects and which patients benefit most. METHODS: A single-centre audit identified 132 HNSCC patients with stage IVa/b neck node-positive disease, prescribed TPF followed by CRT. TPF involved three cycles of docetaxel (75 mg/m2 IV) and cisplatin (75 mg/m2 IV) on day 1 plus 5-FU (750 mg/m2 IV) on days 2-5. Planned CRT was 66 Gy in 30 fractions of intensity-modulated radiotherapy with concurrent cisplatin (100 mg/m2 IV) at the beginning of week 1 and 4 (days 1 and 22). All patients received prophylactic antibiotics and granulocyte colony-stimulating factor. RESULTS: Median follow-up was 39.5 months. 92.4% of patients completed three cycles of TPF; 95.5% of patients started chemoradiotherapy. Grade 3/4 adverse events were low (febrile neutropenia 3.0%), with no toxicity-related deaths. 3-year overall survival was 67.2%; disease-specific survival was 78.7%; locoregional control was 78.3%. Distant metastases rate was 9.8% (3.0% in those without locoregional recurrence). Good performance status (p = 0.002) and poor tumour differentiation (p = 0.018) were associated with improved overall survival on multivariate analysis. CONCLUSION: With prophylactic antibiotics and granulocyte colony-stimulating factor TPF was well tolerated with good survival outcomes. TPF should remain a treatment option for stage IV neck node-positive patients with a good performance status. The use of tumour grade to aid patient selection for TPF warrants investigation.

Role of 18-Fludeoxyglucose positron emission tomography-computed tomography and subsequent panendoscopy in head and neck squamous cell carcinoma of unknown primary.

OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinomas of unknown primary (HNSCCUP) accounts for up to 10% of presenting head and neck squamous cell carcinomas. Identification of the primary site allows for directed therapy. Where initial investigations have failed to locate the primary site, 18-fludeoxyglucose positron emission tomography-computed tomography (PET/CT) has emerged as a useful tool with improved sensitivity over positron emission tomography alone. Following PET/CT scan, the role of subsequent panendoscopy ± biopsy has not been fully assessed. We aim to evaluate and quantify the role of PET/CT and subsequent panendoscopy in HNSCCUP. STUDY DESIGN: Retrospective cohort study. METHODS: Patients with HNSCCUP presenting between January 2005 and December 2010 at a regional oncology referral center were studied. All patients who presented with a metastatic neck node and unknown primary who had undergone PET/CT prior to panendoscopy were included. The accuracy of PET/CT was calculated and compared with panendoscopy and histopathological findings. RESULTS: Fifty-two patients were included. Twenty-seven PET/CT scans suggested a primary site. Calculated diagnostic parameters were 83% sensitivity, 87% specificity, positive predictive value 89%, and negative predictive value 80%. Three false-positive PET/CT scans were noted after panendoscopy and normal histology. Importantly, three confirmed tongue base tumors were found on panendoscopy, which were undetected on PET/CT. CONCLUSIONS: PET/CT is a valuable resource for locating tumors in HNSCCUP. It helps direct biopsy and aids in the detection of local and distant metastases along with synchronous primary tumors. Importantly, due to both false-positive and false-negative PET/CT rates, panendoscopy and biopsy remains an essential adjunct investigation irrespective of PET/CT results. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1354-1358, 2016.

Tumor plasma flow determined by dynamic contrast-enhanced MRI predicts response to induction chemotherapy in head and neck cancer.

OBJECTIVES: Non-response to induction chemotherapy (IC) occurs in 30% of head and neck squamous cell carcinoma (HNSCC) and has been predicted by tumor plasma flow (Fp) derived by perfusion computed tomography. The present study was designed to test whether baseline tumor Fp determined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) would predict IC response. MATERIALS AND METHODS: A prospective open study powered to test the relationship between tumor Fp and response to IC (docetaxel, cisplatin, 5-fluorouracil) enrolled 50 patients with stage IV HNSCC. Response after two IC cycles was measured by MRI using Response Evaluation Criteria in Solid Tumors in 37 patients. Tumor Fp (primary end point) and multiple parameters in tumors and lymph nodes (secondary end points) were generated at baseline. Differences in baseline DCE-MRI parameters according to IC response were assessed by the Mann-Whitney U test, and predictive value by receiver operating characteristic (ROC) analysis. RESULTS: Median baseline tumor Fp was 53.2ml/100ml/min in 25 responders and 23.9 in 12 non-responders (U 82; P=0.027; area under ROC curve (AUC) 0.73). Median baseline Fp in lymph nodes was 25.8ml/100ml/min for 37 nodes in 25 responders and 17.1 for 15 nodes in 12 non-responders (U 186, P=0.066; AUC 0.67). Frequency of IC response in 37 patients was 68% overall, 83% for tumor Fp above the median (40.6ml/100ml/min) and 45% below the median. Other DCE-MRI parameters were not associated with IC response. CONCLUSION: Pre-treatment tumor Fp determined by DCE-MRI predicts IC response in HNSCC.

Computerised objective measurement of strain in voiced speech.

Voice quality assessment is required by healthcare professionals in patients suffering from voice problems. Speech and language therapists (SLTs) use a well-known subjective assessment approach which is called GRBAS, to quantify voice problems. GRBAS is an acronym for a five dimensional scale of measurements of voice properties which were originally recommended by the Japanese Society of Logopeadics and Phoniatrics and the European Research for clinical and research use. The properties are `Grade', `Roughness', `Breathiness', `Asthenia' and `Strain'. In requiring the services of trained SLTs, this subjective assessment make the GRBAS measurement expensive to administer. In this research, computerised objective measurement of `Strain' in voice using two regression prediction models is compared with measurements produced by SLTs according to the GRBAS scale. These regression models are K Nearest Neighbor Regression (KNNR) and Multiple Linear Regression (MLR). These new approaches for prediction of Strain are based on different subsets of features, different sets of data, and different prediction models in comparison with previous approaches in the literature. The best feature subset for predicting Strain objectively was obtained amongst different feature subsets. When compared with the mean of five SLT's scores, over 102 samples, the computerised measurement was found to have a Normalized Root Mean Square Error (NRMSE) averaged over 20 trials, lower than that of each individual SLT. We have achieved a NRMSE of 14.6% and 15.1% for the MLR and KNNR respectively when the best feature subsets were used for predicting Strain objectively.

Prognostic value of hypoxia-associated markers in advanced larynx and hypopharynx squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: To determine the prognostic value of hypoxia-associated markers carbonic anhydrase-9 (CA-9) and hypoxia-inducible factor-1α (HIF-1α) in advanced larynx and hypopharynx squamous cell carcinoma (SCCa) treated by organ preservation strategies. STUDY DESIGN: Retrospective cohort study. METHODS: Pretreatment CA-9 and HIF-1α expression, clinicopathologic data, and tumor volume were analyzed in a series of 114 patients with T3-4 SCCa larynx or hypopharynx treated by (chemo)radiation. RESULTS: Adverse prognostic factors for locoregional control were T4 classification (P = 0.008), and for disease-specific survival were CA-9 positivity (P = 0.039), T4 classification (P = 0.001), larger tumor volume (P = 0.004), N1-3 classification (P = 0.002), and pretreatment hemoglobin < 13.0 g/dl (P = 0.014). With increasing CA-9 expression, there was a trend to increasing tumor recurrence (P trend = 0.009) and decreasing survival (P trend = 0.002). On multivariate analysis, independent variables were T4 classification (hazard ratio [HR] 13.54, P = 0.01) for locoregional failure, and CA-9 positivity (HR = 8.02, P = 0.042) and higher tumor volume (HR = 3.33, P = 0.007) for disease-specific mortality. CONCLUSION: This is the first study to look specifically at T3 and T4 SCCa larynx and hypopharynx for a relationship between hypoxia-associated marker expression and clinical outcome. Pretreatment immunohistochemical CA-9 expression is an adverse prognostic factor for disease-specific survival, indicating that CA-9 expression may confer a more aggressive tumor phenotype.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation.

Dynamic contrast-enhanced magnetic resonance imaging biomarkers in head and neck cancer: potential to guide treatment? A systematic review.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) generates microvascular parameters from the tracer kinetic analysis of a series of MRI images obtained in under 15 min. DCE-MRI parameters are associated with tumour hypoxia, which is well-established as a cause of treatment failure in head and neck squamous cell carcinoma (HNSCC). A systematic review was conducted of prospective DCE-MRI parameter studies in HNSCC in the English language literature. Exclusion criteria were case reports and retrospective series. Six DCE-MRI marker studies in HNSCC met the inclusion criteria. Four studies contained 21-74 patients and two studies recruited 13 and 14 patients. In studies measuring the transfer coefficient (K(trans)), higher overall K(trans) or lower skewness of K(trans) were predictive of a good outcome following chemoradiation. DCE-MRI parameters have the potential to guide treatment in HNSCC. Progress in the field requires standardisation of methods, data sharing and large multi-centre collaborative validation studies.

Human papillomavirus infection is rare in nonmalignant tonsil tissue in the UK: implications for tonsil cancer precursor lesions.

The incidence of human papillomavirus (HPV)-associated tonsil cancer is increasing but the prevalence of HPV, and of premalignant precursors, in tonsil tissue is unknown. We aimed to assess prevalence of HPV infection in nonmalignant tonsillar crypt epithelia and to histopathologically characterise positive samples. Formalin-fixed paraffin-embedded (FFPE) tonsil tissue specimens were obtained from an age- and sex-stratified random sample of patients aged 0-69 years whose paired tonsils were archived following elective tonsillectomy at hospitals throughout England and Southern Scotland from 2004 to 2008. Homogenised fresh-frozen tonsil tissue was also obtained from archive for two random subsets of males aged 25-34 and over 44. HPV status was assessed in all samples for 20 mucosal HPV types by GP5+/6+ polymerase chain reaction (PCR) enzyme immunoassay and by HPV16 type-specific PCR targeting the E6 gene. In the homogenised material, HPV status was also assessed for 44 HPV types by SPF10-PCR enzyme immunoassay. Of 4,095 randomly sampled FFPE specimens, amplifiable DNA was extracted from 3,377 (82.5%) and from 511 of 524 (97.5%) homogenised tonsils. HPV DNA was identified in 0 of 3,377 (0%, 95% CI 0-0.089%) fixed samples and 0 of 511 (0%, 95% CI 0-0.58%) homogenised samples. This suggests HPV infection may be rare in tonsil reticulated crypt epithelia. Furthermore, we found no evidence of HPV-associated premalignant neoplasia. These data suggest that if HPV-associated premalignant lesions do occur, they are likely to be rare and may have a high risk of progression to carcinoma.

A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer.

PURPOSE: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types. EXPERIMENTAL DESIGN: Samples were available from 157 T2-T4 laryngeal cancer and 185 T1-T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (≤median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON). RESULTS: Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA-HS high (P=0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P=0.90). TLDA-HS did not predict benefit from CON in bladder cancer. CONCLUSION: The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial.

Molecular and cellular processes underlying the hallmarks of head and neck cancer.

The hallmarks of cancer were updated by Hanahan and Weinberg in 2011. Here we discuss the updated hallmarks in relation to what is known of the molecular and cellular processes underlying the development of head and neck squamous cell carcinoma (HNSCC). Several mechanisms are described, and recent surveys of HNSCC suggest a limited number of mutations, from which more mechanisms may emerge. There are also epigenetic changes to the control of normal processes. More than one mechanism underlies each hallmark. Processes essential to the development of HNSCC need not be essential to the proliferation of the fully developed tumour. Attention is paid to the emerging hallmarks, deregulation of cellular energy metabolism and evasion of immune destruction, and enabling characteristics, genome instability and mutation and tumour-promoting inflammation. HNSCC may adapt to hypoxia, suppress HLA expression, and express Toll-like receptors to facilitate inflammation, which support the proliferation of the tumour.

Prospective technical validation and assessment of intra-tumour heterogeneity of a low density array hypoxia gene profile in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Tumour hypoxia is associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC), however there is no accepted method for assessing hypoxia clinically. We aimed to conduct a technical validation of a hypoxia gene expression signature using the TaqMan Low Density Array (TLDA) platform to investigate if this approach reliably identified hypoxic tumours. MATERIALS AND METHODS: Tumour samples (n=201) from 80 HNSCC patients were collected prospectively from two centres. Fifty-three patients received pimonidazole prior to surgery. TaqMan Low Density Array-Hypoxia Scores (TLDA-HS) were obtained by quantitative real-time PCR (qPCR) using a 25-gene signature and customised TLDA cards. Assay performance was assessed as coefficient of variation (CoV). RESULTS: The assay was sensitive with linear reaction efficiencies across a 4 log(10) range of inputted cDNA (0.001-10 ng/µl). Intra- (CoV=6.9%) and inter- (CoV=2.0%) assay reproducibility were excellent. Intra-tumour heterogeneity was lower for TLDA-HS (23.2%) than for pimonidazole (67.2%) or single gene measurements of CA9 (62.2%), VEGFA (45.0%) or HIG2 (39.4%). TLDA-HS in HNSCC cell lines increased with decreasing pO(2). TLDA-HS correlated with Affymetrix U133 Plus 2.0 microarray HS (p<0.01) and positive pimonidazole scores (p=0.005). CONCLUSIONS: Gene expression measurements of hypoxia using a 25-gene signature and TLDA cards are sensitive, reproducible and associated with lower intra-tumour heterogeneity than assaying individual genes or pimonidazole binding. The approach is suitable for further assessment of prognostic and predictive capability in clinical trial material.

Use of Pre-Ablation Radioiodine-131 Scan to Assess the Impact of Surgical Volume and Specialisation following Thyroidectomy for Differentiated Thyroid Carcinoma.

BACKGROUND: We evaluated the relationship between thyroid remnant size following thyroidectomy for differentiated thyroid carcinoma and surgical volume and specialisation by assessing pre-ablation radioiodine-131 ((131)I) thyroid bed uptake (TBU) scanning as a surrogate for residual thyroid tissue. METHODS: We analysed data of 651 patients in our thyroid cancer database. Patients' data were included if the following criteria were met: (1) diagnosis of differentiated thyroid carcinoma, (2) total or near-total thyroidectomy, (3) pre-ablation (131)I scan prior to radioiodine ablation (RAI), (4) no distant metastasis, and (5) >3,000 MBq ablative dose of (131)I. (131)I diagnostic whole-body scans and measurement of thyroglobulin levels were carried out 3-9 months after RAI. 305 patients were included in the final analysis. RESULTS: Four endocrine, 19 otolaryngology and 25 general surgeons performed thyroidectomies with median pre-ablation (131)I TBU values of 1.0, 1.8 and 2.9%, respectively (p = 0.0031). There was a statistically significant relationship between number of thyroidectomies performed and median pre-ablation (131)I TBU values up to the optimal number of 11 operations beyond which there was no further significant difference between surgeons. There were differences in remnant size between endocrine and general surgeons (p = 0.001), otolaryngology and general surgeons (p = 0.023) but not between endocrine and otolaryngology surgeons (p = 0.167). CONCLUSION: Using the pre-ablation (131)I uptake scan as a surrogate for thyroid remnant quantification following thyroidectomy demonstrates the relationship between the surgical volume and size of thyroid remnant. The study also demonstrated beneficial effects of specialisation with specialist surgeons achieving the smallest thyroid remnant.