Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.

PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.

Current management of xerostomia in head and neck cancer patients.

Radiotherapy (RT) continues to play a key role in the management of head and neck cancer (HNC). Xerostomia remains a principal detriment to the quality of life (QoL) for 80 % of surviving patients receiving head and neck radiation. Radiation-induced injury to the salivary glands is dose-dependent, and thus efforts have been focused on decreasing radiation to the salivary glands. Decreased saliva production reduces both short-term and long-term quality of life in head and neck survivors by impacting on taste and contributing to dysphagia. Several radioprotective agents to the salivary gland have been investigated. Although not widely practiced, surgical transfer of the submandibular gland prior to RT is the mainstay of surgical options in preventing xerostomia. This review focuses on the strategies to improve xerostomia following radiation therapy in head and neck cancers.

Using immersive technology and architectural design to assist head and neck cancer patients' recovery from treatment: A focus group and technology acceptance study.

PURPOSE: Head and neck cancer patients can face debilitating treatment related side-effects, resulting in requirement for support and negatively impacting on care outcomes. This study aimed to develop a digital recovery support package and assess its acceptability with head and neck cancer patients to support their information needs and assist with their self-management. It provided additional support through development of a WebXR platform 'recovery' package, which allowed patients to live a 'virtual reality' experience, entering and moving inside a 'virtual room', accessing targeted resources and specific learning materials related to their cancer. METHOD: A qualitative intervention development study consisting of three phases. This study followed the COREQ checklist for qualitative research. Phase 1- Focus groups with seven head and neck cancer patients and six healthcare professionals. Phase 2- Development of 'recovery' package based on the focus group data which informed the content and design of the WebXR recovery platform. Phase 3- Technology acceptance study. Once developed, the platform's acceptability of the experience lived inside the virtual room was assessed via qualitative interviews with six different patient participants. RESULTS: Most participants felt comfortable using the virtual reality platform, finding it a realistic and useful support for identifying resources and signposting to relevant materials. Participants agreed the WebXR platform was a feasible tool for the head and neck cancer setting and helped reduce anxiety. CONCLUSIONS: Head and neck cancer patients welcome specific targeted, information and advice to support their ability to self-manage their rehabilitation and thus focus their nursing care. The platform was implemented during the Covid-19 pandemic, demonstrating its versatility and accessibility in providing complementary support to head and neck cancer patients, to empower them to adjust to their 'new' normal as part of their ongoing cancer journeys.

Patient and physiotherapist perceptions of the Getting Recovery Right After Neck Dissection (GRRAND) rehabilitation intervention: a qualitative interview study embedded within a feasibility trial.

OBJECTIVE: The Getting Recovery Right After Neck Dissection (GRRAND) intervention is a physiotherapy programme for patients with head and neck cancer who have undergone neck dissection. The aim of this qualitative study was to understand if the intervention was useful, acceptable and whether it was feasible to conduct a randomised controlled trial (RCT). DESIGN: This qualitative study was embedded within the GRRAND-Feasibility (GRRAND-F) Study. SETTING: Participants were recruited from four acute National Health Service hospitals in England between 2020 and 2021. PARTICIPANTS: We interviewed four usual care and four intervention patient-participants from a single study site (Oxford). Six were male, two were female. All were white British ethnicity. We interviewed two physiotherapists from Oxford who delivered the GRRAND-F intervention, and physiotherapists from Birmingham, Poole and Norwich who were trained to deliver the intervention but were not able to deliver it within the study time frame. RESULTS: The analysis identified five themes: (1) Acceptability, (2) Adherence, (3) Outcomes, (4) Feasibility and (5) Stand-alone themes (prehabilitation, video consultations, healthcare use).Patient-participants and physiotherapist-participants agreed that usual care was not meeting patients' rehabilitation needs. The GRRAND intervention provided biopsychosocial support. In comparison to the usual care group, patient-participants who received the intervention were more confident that they could perform rehabilitation exercises and were more motivated to engage in long-term adaptive behaviour change. Physiotherapists felt they needed more administrative support to participate in an RCT. CONCLUSION: Participants felt that usual care was insufficient. GRRAND provided much needed, biopsychosocial support to patients. Participants were supportive that it would be feasible to test GRRAND in an RCT. TRIAL REGISTRATION NUMBER: ISRCTN11979997.

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.

Functional Outcomes Following Total Laryngectomy and Pharyngolaryngectomy: A 20-Year Single Center Study.

BACKGROUND: Laryngeal cancer accounts for 1% of all cancers in men and 0.3% of all cancers in women. Pharyngolaryngectomy (TPL) and total laryngectomy (TL) are central surgical techniques in the management of advanced laryngeal malignancies but are associated with significant morbidity. In addition, optimal reconstruction following TPL remains an area of active research. METHODS: Here, we compared speech and swallowing outcomes following circumferential and partial pharyngeal resection alongside total laryngectomy in patients with laryngeal and hypolaryngeal tumors. We performed a systemic analysis of patient demographics, tumor characteristics, treatment modality, and pharyngeal reconstruction technique following TPL and TL, leveraging data collected over a 20-year period at a large tertiary referral center. RESULTS: Analyzing 155 patients the results show circumferential pharyngeal defects and prior radiotherapy have a significant impact on surgical complications. CONCLUSION: Pharyngeal resection carries a substantial risk of incurring impaired speech and swallowing in patients. Moreover, our results support poorer functional outcomes with more radical pharyngeal resections and show a clear trend toward worse swallowing outcomes in salvage surgery.

Getting Recovery Right After Neck Dissection (GRRAND-F): mixed-methods feasibility study to design a pragmatic randomised controlled trial protocol.

INTRODUCTION: We will evaluate the feasibility of a randomised controlled trial to estimate the effectiveness and cost-effectiveness of a rehabilitation intervention on pain, function and health-related quality of life following neck dissection (ND) after head and neck cancer (HNC). METHODS AND ANALYSIS: This is a pragmatic, multicentred, feasibility study. Participants are randomised to usual care (control) or usual care plus an individualised, rehabilitation programme (Getting Recovery Right After Neck Dissection, GRRAND intervention). Adults aged over 18 with HNC for whom ND is part of their care will be recruited from specialist clinics. Participants are randomised in 1:1 ratio using a web-based service. The target sample size is 60 participants. Usual care will be received by all participants during their postoperative inpatient stay consisting standard National Health Service care supplemented with a booklet advising on postoperative self-management strategies. The GRRAND intervention programme consists of usual care plus up to six individual physiotherapy sessions including neck and shoulder range of motion (ROM) and progressive resistance exercises, advice and education. Between sessions participants will be advised to complete a home exercise programme. The primary outcome is to determine recruitment and retention rates from study participants across sites. Outcomes will be measured at 6 and 12 months. Participants and physiotherapists will be invited to an optional qualitative interview at the completion of their involvement in the study. The target qualitative sample size is 15 participants and 12 physiotherapists. Interviews aim to further investigate the feasibility and acceptability of the intervention and to determine wider experiences of the study design and intervention from patient and physiotherapist perspectives. ETHICS AND DISSEMINATION: Ethical approval was given on 29 October 2019 (National Research Ethics Committee Number: 19/SC/0457). Results will be reported at conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN11979997. STATUS: Trial recruitment is ongoing and is expected to be completed by 30 August 2021.

Trans-cutaneous electrical nerve stimulation to treat dry mouth (xerostomia) following radiotherapy for head and neck cancer. A systematic review.

BACKGROUND: A dry mouth or xerostomia is one of the most common long-term complications following radiotherapy for head and neck cancer and has a negative impact on quality of life in cancer survivors. Transcutaneous electrical nerve stimulation (TENS) is a novel approach to improving saliva flow in these patients. OBJECTIVE: To perform a systematic review of studies evaluating TENS in the treatment of radiotherapy induced xerostomia in head and neck cancer patients. DATA COLLECTION AND ANALYSIS: A comprehensive electronic search was performed in PubMed/MEDLINE, the Cochrane Library, and Google Scholar databases for appropriate published studies. The last search was conducted in January 2020. Two review authors assessed all studies identified by the search strategy and carried out data extraction. RESULTS: Five studies were included in the systematic review which analysed a total of 280 patients with head and neck cancer. Methodological quality and outcomes were evaluated in every study included. The outcome measure was either subjectively assessed or objectively measured. Three studies used conventional TENS therapy to stimulate parotid glands which produced a significant increase in saliva production following therapy. Two studies used acupunctured TENS type to electrically stimulate acupuncture points scattered in the body and they reported improvement in saliva production at the same level as medical treatment. No reported adverse effect of TENS was identified. CONCLUSIONS: This systematic review confirms the safety and feasibility of TENS in the treatment of xerostomia. It is established that commencing daily TENS therapy simultaneously with radiotherapy has the most efficacy. Given the nonspecific parameters used in the included studies, further evidence is needed in order to establish optimal settings and parameters of TENS for treatment of xerostomia.

COVID-19 and the return to head and neck outpatient activity in the United Kingdom: what is the new normal?

PURPOSE: As surgical specialties now begin the graduated return to elective activity and face-to-face clinics, this paper investigates the current head and neck outpatient practices across the United Kingdom. METHODS: A cross-sectional study comprised of an online 20-item survey was distributed to members of the British Association of Head & Neck Oncologists (BAHNO). The survey was open on a web-based platform and covered topics including safety measures for patients, protective equipment for healthcare staff and protocols for the use of flexible nasendoscopy in the clinic. RESULTS: The survey was completed by 117 participants covering 66 NHS Trusts across the UK. There was a significant reduction in face-to-face Otolaryngology, Maxillofacial and Speech and Language clinic patients when compared to pre-pandemic numbers (p < 0.0001). Risk assessments for flexible nasendoscopy were done for 69% of clinics and 58% had an established protocol. Room downtime after flexible nasendoscopy ranged from 0 to 6 h and there was a significant increase in allocated downtime after a patient had coughed/sneezed (p < 0.001). Natural ventilation existed in 36% of clinics and the majority of responders didn't know the Air Change Per Hour (ACPH) of the clinic room (77%). Where ACPH was known, it often did not match the allocated room downtime. CONCLUSION: There is a wide variation in outpatient activity across the United Kingdom, but adaptations are being made to try and maintain staff and patient safety. However, more can still be done by liaising with allied teams to clarify outpatient protocols.

Timing and volume of information produced for the Otolaryngologist during the COVID-19 pandemic in the UK: A review of the volume of online literature.

BACKGROUND: The SARS-CoV-2 was first reported in December 2019 in Wuhan, China and has been declared a pandemic in March 2020. COVID-19 has caused unprecedented and lasting biopsychosocial effects worldwide. All healthcare professionals have faced life-threatening risks by attending their daily jobs. The daily emergence of advice and guidelines was necessary to ensure the safety of patients and staff. To this effect, all elective services came to a halt to preserve hospitals' capacity for dealing with the sickest. This retrospective, descriptive review aims to assess the volume and timing of the advice released specifically relevant to UK ENT specialists. METHODS: Two separate searches were performed. One involved online advice published in English by international, national and ENT-specific organisations between January 1 and May 31. The date, title, source, type of advice and link to the advice were recorded in Excel. The resources were analysed per week of publication. A second separate search for peer-reviewed publications was conducted using PubMed Central and Cochrane databases. FINDINGS: COVID-19-related guidance was considered, of which 175 were identified. 52/175 (29.7%) articles were published by international organisations. 56/175 (32%) were produced by national organisations, and 67/175 (38.28%) were produced by ENT specific organisations. The peak guidance production took place in the third and fourth week of March (16/03/2020-29/03/2020) with 72/175 publications. Of these, 27/70 came from the international category, 17/70 from national bodies and 26/70 from ENT-specific organisations. 13 863 total publications relating to COVID-19 were found using PubMed and Cochrane search strategies; 76% were relevant to ENT. CONCLUSION: The challenges faced by ENT relate to the unprecedented, sudden and daily changes to clinical practice. Multiple bodies interpreted the guidance, giving an opportunity for confusion and delay in treatments for patients. Implementing a system with clear lines of communication and dissemination of information will improve our response to future pandemic events whilst maintaining a commercial awareness to better use the human and financial resources of an already financially restricted NHS.

Radioresistant laryngeal cancers upregulate type 1 IGF receptor and exhibit increased cellular dependence on IGF and EGF signalling.

OBJECTIVES: Patients failing radiotherapy for laryngeal squamous cell carcinoma (LSCC) often require salvage total laryngectomy which has major functional consequences, highlighting a need for biomarkers of radiotherapy resistance. In other tumour types, radioresistance has been linked to epidermal growth factor receptor (EGFR) and type 1 insulin-like growth factor receptor (IGF-1R). Here, we evaluated IGF-1R and EGFR as predictors and mediators of LSCC radioresistance. DESIGN: We compared IGF-1R and EGFR immunohistochemical scores in patients with LSCC achieving long-term remission post-radiotherapy (n = 23), patients treated with primary laryngectomy (n = 22) or salvage laryngectomy following radiotherapy recurrence (n = 18). To model radioresistance in vitro, two LSCC cell lines underwent clinically relevant irradiation to 55 Gy in 2.75 Gy fractions. RESULTS: Type 1 insulin-like growth factor receptor expression was higher in pre-treatment biopsies of radiotherapy failures compared with those in long-term remission and was upregulated post-radiotherapy. Patients undergoing primary laryngectomy had more advanced T/N stage and greater tumour IGF-1R content than those achieving long-term remission. Pre-treatment EGFR did not associate with radiotherapy outcomes but showed a trend to upregulation post-irradiation. In vitro, radiosensitivity was enhanced by inhibition of EGFR but not IGF. Repeated irradiation upregulated IGF-1R in BICR18 and SQ20B cells and EGFR in SQ20B, and enhanced SQ20B radioresistance. Repeatedly irradiated SQ20B_55 cells were not radiosensitised by inhibition of IGF and/or EGFR, but IGF-1R:EGFR co-inhibition suppressed baseline cell survival more effectively than blockade of either pathway alone, and more effectively than in parental cells. CONCLUSIONS: Radiation upregulates IGF-1R and may enhance IGF/EGFR dependence, suggesting that IGF/EGFR blockade may have activity in LSCCs that recur post-radiotherapy.

Transoral tongue base mucosectomy for the identification of the primary site in the work-up of cancers of unknown origin: Systematic review and meta-analysis.

BACKGROUND: The use of transoral robotic surgery (TORS) and laser microsurgery (TLM) in the diagnosis and identification of the site of the unknown primary has become increasingly common. This systematic review and meta-analysis aims to assess the use and efficacy of TORS and TLM for this indication. METHOD: Systematic review and meta-analysis of studies employing TORS or TLM in diagnosis of the unknown primary tumor site in patients with cervical nodal metastases of squamous cell origin. MEDLINE, EMBASE and CINHAL were searched from inception to July 2018 for all studies that used TORS and or TLM in identifying the unknown primary. RESULTS: 251 studies were identified, of which 21 were eligible for inclusion. The primary tumour was identified by TORS/TLM in 78% of patients (433 out of 556). Tongue base mucosectomy (TBM) identified the primary in 222 of 427 cases (53%). In patients with negative physical examination, diagnostic imaging and PETCT, TBM identified the primary in 64% (95% CI 50, 79) cases. In patients who had negative CT/MRI imaging, negative PETCT and negative EUA and tonsillectomy, TBM identified a tongue base primary in 78% (95% CI 41, 92) cases. Haemorrhage, the commonest complication, was reported in 4.9% cases. Mean length of stay varied between 1.4 and 6.3 days. CONCLUSION: Tongue base mucosectomy, performed by TORS or TLM, is highly efficacious in identifying the unknown primary in the head and neck region.

Incidental findings on 18-FDG PET-CT in head and neck cancer. A retrospective case-control study of incidental findings on 18-FDG PET-CT in patients with head and neck cancer.

PURPOSE: Use of 18-FDG PET-CT is increasing in patients with head and neck cancer, enabling the identification of metastases or synchronous malignancies, but also 'incidental' disease. We aimed to establish the rate of 'incidental' findings resulting from 18-FDG PET-specific imaging, that would not have been otherwise identified on other imaging, in patients with head and neck cancer undergoing staging or surveillance of disease. METHODS: 18-FDG PET-CT was performed for investigation or surveillance. Case notes were reviewed retrospectively. Unexpected findings identifiable on CT imaging alone, or by FDG-PET were recorded. For those only identifiable with FDG-PET, findings were divided into either 'incidental' or 'intentional', and benign or malignant. RESULTS: 93 patients underwent 18- FDG PET-CT. 86.0% had new pathology identified. 3.2% had a new malignancy identified. 37.6% had new findings on FDG-PET that would not have been identified on CT alone: 5.4% had 'intentional findings' (metastasis), and 32.3% had 'incidental findings' (synchronous malignancy or benign). 1.1% had a new malignancy on FDG-PET alone. CONCLUSIONS: Intentional and incidental findings are likely on 18-FDG PET-CT. Whilst important for patient management, there is an associated emotional and financial cost, which needs acknowledgement and further investigation.

Use of the self-retaining Alexis ring retractor in transoral robotic surgery.

BACKGROUND: Ring retractors, such as the Alexis® wound retractor, are simple devices used in a wide range of surgical settings to provide atraumatic exposure while protecting wound edges. METHODS: Here, we describe the application of the Alexis® to provide access during transoral robotic surgery (TORS). CONCLUSION: Its ease of application and many benefits, including maximization of intraoral space and protection of perioral soft tissues, make this device an excellent adjunct for TORS procedures.

Mucosal melanoma of the upper airways tract mucosal melanoma: A systematic review with meta-analyses of treatment.

BACKGROUND: Mucosal melanoma of the upper aerodigestive tract (MM-UADT) occurs in a complex anatomic region. It represents a small number of tumors of the head and neck and a small number of melanoma cases. METHODS: Search strategies initially identified 600, 11 of which were included in this study. RESULTS: All studies involved surgery and radiotherapy. None were randomized, and all were assessed as having a high risk of selection and performance bias. No studies reported quality of life, treatment-related mortality, or morbidity. The results indicate that the addition of radiotherapy to surgery reduces the rate of locoregional recurrence (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.42-0.87). There was no statistically significant difference in overall survival (HR, 1.16; 95% CI, 0.98-1.37). CONCLUSION: Surgical resection with postoperative radiotherapy remains the optimal treatment strategy for locoregional control. More robust studies and the use of molecular targeted therapies need to be undertaken to improve overall survival. © 2016 Wiley Periodicals, Inc. Head Neck 39: 819-825, 2017.