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This article discusses the challenges in managing head neck squamous cell cancer from an unknown primary (HSCCUP) due to a lack of contemporary evidence and evolving understanding of the role of human papillomavirus (HPV) in head and neck cancer. Despite these limitations, various organizations have produced guidelines for managing HSCCUP using different methodologies. The article presents the results of a consensus process involving multiple stakeholders and centers, which led to the publication of consensus statements in the United Kingdom National Multidisciplinary Guidelines. The authors of the document, Vinidh Paleri, John Hardman, Tom Roques, and Ben O'Leary, made significant contributions to the work and have no conflicts of interest to report. The peer review history of the article is available for further reference. [Extracted from the article]

With the widespread use of 18F‐fluorodeoxyglucose positron emission tomography (FDG PET/CT) in the investigation and staging of cancers, incidental discovery of FDG‐avid thyroid nodules is becoming increasingly common, with a reported incidence in the range 1%–4% of FDG PET/CT scans. The risk of malignancy in an incidentally discovered FDG avid thyroid nodule is not clear due to selection bias in reported retrospective series but is likely to be less than 15%. Even in cases where the nodule is found to be malignant, the majority will be differentiated thyroid cancers with an excellent prognosis even without treatment. If, due to index cancer diagnosis, age and co‐morbidities, it is unlikely that the patient will survive 5 years, further investigation of an incidental FDG avid thyroid nodule is unlikely to be warranted. We provide a consensus statement on the circumstances in which further investigation of FDG avid thyroid nodules with ultrasound and fine needle aspiration might be appropriate. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of centralization of prostate cancer surgery and radiotherapy services on the choice of prostate cancer treatment. Patients and Methods: This national population‐based study used linked cancer registry data and administrative hospital‐level data for all 16 621 patients who were diagnosed between 1 January 2017 and 31 December 2018 with intermediate‐risk prostate cancer and who underwent radical prostatectomy (RP) or radical radiation therapy (RT) in the English National Health Service (NHS). Travel times by car to treating centres were estimated using a geographic information system. We used logistic regression to assess the impact of the relative proximity of alternative treatment options on the type of treatment received, with adjustment for patient characteristics. Results: Of the 78 NHS hospitals that provide RT or RP for prostate cancer, 41% provide both, 36% provide RT and 23% provide RP. Compared to patients who had both treatment options available at their nearest centre where overall 57% of patients received RT and 43% RP, patients were less likely to receive RT if their nearest centre offered RP only and the extra travel time to a hospital providing RT was >15 min (52% of patients received RT and 48% RP%, odds ratio [OR] 0.70 (0.58–0.85); P < 0.001). Conversely, patients were more likely to receive RT if their nearest centre offered RT and the extra travel time to a hospital providing RP was >15 min (63% of patients received RT and 37% RP, OR 1.23 (1.08–1.40); P < 0.001). There was a negligible impact on the type of treatment received if centres providing alternative treatment options were ≤15‐min travel time from each other. Conclusion: The relative proximity of prostate cancer treatment options to a patient's residence is an independent predictor for the type of radical treatment received. Centralization policies for prostate cancer should not focus on one treatment modality but should consider all treatments to avoid a negative impact on treatment choice. [ABSTRACT FROM AUTHOR]

Background: Treatment of the uninvolved neck in well‐lateralized tonsillar squamous cell carcinoma is controversial. We became concerned after a number of contralateral neck recurrences (CNRs) in patients receiving ipsilateral radiotherapy (RT). Methods: This is a single center retrospective series including patients with well‐lateralized tonsillar cancer treated with ipsilateral neck RT between 2004 and 2011. Results: We identified 53 patients treated with ipsilateral neck RT during the study period. The rate of CNR was 7.5% (4 of 53). All four patients had p16‐positive, T1, N2b, M0 tumors. The subgroup of patients with N2b disease (28 of 53) had a CNR of 14.3%. We subsequently switched to treat patients with N2b with bilateral neck RT. We analyzed the outcomes of 23 patients with N2b treated with bilateral neck intensity‐modulated RT (IMRT) and observed no CNRs. Conclusions: We observed a higher than expected rate of CNR in the N2b population. Bilateral neck IMRT for these patients represents a safe alternative. [ABSTRACT FROM AUTHOR]

Objectives To identify the most cost-effective treatment strategy in patients with early stage (T1 and T2) cancers of the laryngeal glottis. Design A Markov decision model populated using data from updated systematic reviews and meta-analyses, with attributable costs from NHS sources. Data on local control and mortality were obtained from updates of existing systematic reviews conducted for the NICE guideline on cancer of the upper aerodigestive tract. Procedure costs were sourced from NHS reference costs 2013/14 by applying tariffs associated with the appropriate health resource group code Setting The UK National Health Service. Population Patients with early stage (T1 and T2) cancers of the laryngeal glottis. Interventions Transoral laser microsurgery ( TLM) and radiation therapy ( RT). Main outcome measures Total costs, incremental costs and quality adjusted life years ( QALYs) over a 10-year time horizon. Results Radiation therapy as the initial treatment strategy was found to be more expensive (£2654 versus £623) and less effective ( QALY reduction of 0.141 and 0.04 in T1a and T1b-T2 laryngeal cancers, respectively) than TLM. The dominance of TLM for T1a cancers was unchanged in most scenarios modelled in sensitivity analysis. For T1b-T2 laryngeal cancers, the result changed in numerous scenarios. In probabilistic sensitivity analysis, TLM was found to have a 71% and 58% probability of being cost-effective in T1a and T1b-T2 laryngeal cancers, respectively. Conclusions Transoral laser microsurgery is a cost-effective strategy to adopt in the management of T1a laryngeal cancers. Uncertainty remains over the optimal strategy to adopt in T1b-T2 laryngeal cancers. [ABSTRACT FROM AUTHOR]

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 diseasespecific 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, locoregional 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. [ABSTRACT FROM AUTHOR]

See article on page 3468–3469, in this issue [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. Cancer Research UK. [ABSTRACT FROM AUTHOR]

Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5–60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74–1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375. • This phase III RCT does not support dose escalation using accelerated hypofractionation. • No benefit in local tumour control or survival was seen. • Two-year local tumour failure rate was approximately 30% in both treatment groups. • The larynx was preserved in about 90% patients in both treatment groups. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: (a) To determine which of two values clarification exercises (VCE), based on theoretical decision rules used naturally by people, would be more helpful to patients making a treatment decision and (b) to evaluate the convergent validity of the most helpful VCE when part of a decision aid for the treatment of early-stage prostate cancer. Methods: Two studies were completed. Study 1: Ninety community volunteers were assigned at random to one of three groups and all made a hypothetical treatment decision. Two groups received VCEs, one with a summary and one without, and the third was a control group. Study 2: In a multi-centre phase II trial, 69 patients used the decision aid that included the exercise ranked most helpful in Study 1. Decision aid assessments included the decisional conflict scale, treatment valuation assessment and regret. Results: Study 1: Most participants in each group ranked the VCE with the summary as most helpful. Study 2: VCE outputs, such as the size of the summary, were associated in predictable ways with the decision aid assessments. Conclusion: The VCE ranked most helpful in Study 1 showed convergent validity with decision aid assessments. Practice implications: With the interpretation of the VCE outputs now validated, a randomized controlled trial is required to determine if the exercise helps patients more than the aid without the exercise. [Copyright &y& Elsevier]