title: PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer.
abstract: BACKGROUND
  Human papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes.
  
  
  METHODS
  The study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint.
  
  
  CONCLUSIONS
  PATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment.
  
  
  BACKGROUND
  This study is registered with ClinicalTrials.gov identifier NCT02215265 .
authors: Velindre NHS Trust, Velindre Road, Cardiff, CF14 2TL, UK. waheedaowadally@nhs.net.
authors: Waheeda
authors: W
authors: Owadally
authors: Wales Cancer Trials Unit, 6th Floor, Neuadd Meirionnydd, Cardiff University, Heath Park, Cardiff, CF14 4YS, UK. HurtCN@cardiff.ac.uk.
authors: Chris
authors: C
authors: Hurt
authors: Wales Cancer Trials Unit, 6th Floor, Neuadd Meirionnydd, Cardiff University, Heath Park, Cardiff, CF14 4YS, UK. TimminsH@cardiff.ac.uk.
authors: Hayley
authors: H
authors: Timmins
authors: Mount Vernon Hospital, Rickmansworth Road, Northwood, HA6 2RN, UK. eparsons1@nhs.net.
authors: Emma
authors: E
authors: Parsons
authors: Research and Development Office, 3rd Floor, Velindre NHS Trust, 14 Cathedral Road, Cardiff, CF11 9LJ, UK. Sarah.Townsend@wales.nhs.uk.
authors: Sarah
authors: S
authors: Townsend
authors: Institute of Health and Society, Newcastle University, The Baddiley-Clark Building, Richardson Road, Newcastle-upon-Tyne, NE2 4AX, UK. joanne.patterson@newcastle.ac.uk.
authors: Joanne
authors: J
authors: Patterson
authors: Speech and Language Therapy, Department of Head and Neck Surgery, Section of Speech Pathology and Audiology, MD Anderson Cancer Centre, Houston, Texas, USA. karnold@mdanderson.org.
authors: Katherine
authors: K
authors: Hutcheson
authors: HPV Research Group, Section of Pathology, Cardiff University School of Medicine, UHW Main Building, Heath Park, Cardiff, CF14 4XN, UK. PowellNG@cardiff.ac.uk.
authors: Ned
authors: N
authors: Powell
authors: Bristol Cancer Institute, University Hospitals Bristol NHS Foundation Trust, Horfield Road, Bristol, BS2 8ED, UK. Matthew.Beasley@UHBristol.nhs.uk.
authors: Matthew
authors: M
authors: Beasley
authors: Velindre NHS Trust, Velindre Road, Cardiff, CF14 2TL, UK. Nachi.Palaniappan@wales.nhs.uk.
authors: Nachi
authors: N
authors: Palaniappan
authors: Centre for Oral Health Research, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4BW, UK. max.robinson@newcastle.ac.uk.
authors: Max
authors: M
authors: Robinson
authors: Head and Neck Surgery, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK. T.M.Jones@liverpool.ac.uk.
authors: Terence M
authors: TM
authors: Jones
authors: Velindre NHS Trust, Velindre Road, Cardiff, CF14 2TL, UK. Mererid.Evans@wales.nhs.trust.
authors: Mererid
authors: M
authors: Evans
mesh_terms: D059186:Chemoradiotherapy, Adjuvant / Q000379:methods*; D003679:Deglutition / Q000528:radiation effects; D006801:Humans; D037981:Neck Dissection / Q000379:methods; D019647:Oral Surgical Procedures / Q000379:methods*; D009959:Oropharyngeal Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D030361:Papillomavirus Infections / Q000473:pathology / Q000628:therapy*; D011446:Prospective Studies; D011788:Quality of Life; D011829:Radiation Dosage; D018714:Radiotherapy, Adjuvant / Q000379:methods*; D016019:Survival Analysis; D016896:Treatment Outcome