title: De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials.
abstract: Iatrogenic complications associated with current treatment protocols for oropharyngeal squamous cell carcinoma are noted to cause high rates of acute and chronic morbidity. The aims of this study are to provide an overview of the current de-escalation trials for human papillomavirus positive (HPV+) oropharyngeal carcinoma and to evaluate the evidence supporting improved response to treatment of patients within this viral cohort. This study reviewed all completed or in progress randomised controlled trials (RCTs) assessing clinical interventions for human papillomavirus-associated locally advanced oropharyngeal squamous cell carcinoma. We utilised a validated 'risk of bias' tool to assess study quality. We identified nine RCTs that met the full inclusion criteria for this review (all of which are currently on-going and will report from 2015 onwards). Five RCTs performed a post hoc analysis by HPV status, which allowed meta-analysis of 1130 patients. The data reveal a significant difference in overall survival (hazard ratio (HR) 0.49 [95% confidence interval (CI) 0.35-0.69]), loco-regional failure (HR 0.43 [95% CI 0.17-1.11]) and disease specific survival (0.41 [95% 0.3-0.56]) in favour of the HPV+ category. In considering de-escalation treatment protocols, nine studies are currently ongoing. Our meta-analysis provides strong evidence for an improved prognosis in the viral associated cohort when treated by platinum based chemotherapy in combination with radiotherapy or primary radiotherapy. So far, one trial (with moderate to high risk of bias) suggests a reduced survival outcome for the HPV+ population when using the epidermal growth factor receptor (EGFR) inhibitor cetuximab.
authors.affiliation: ENT Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Pathology, University of Cambridge, UK. Electronic address: lmm398@doctors.org.uk.
authors.forename: Liam
authors.initials: L
authors.lastname: Masterson
authors.affiliation: ENT Department, Milton Keynes Hospital NHS Foundation Trust, Milton Keynes, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moualed
authors.affiliation: ENT Department, Barts Health NHS Trust, London, UK.
authors.forename: Zi Wei
authors.initials: ZW
authors.lastname: Liu
authors.affiliation: Oncology Centre, University College Hospital NHS Trust, London, UK.
authors.forename: James E F
authors.initials: JE
authors.lastname: Howard
authors.affiliation: ENT Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Raghav C
authors.initials: RC
authors.lastname: Dwivedi
authors.affiliation: ENT Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Tysome
authors.affiliation: Oncology Centre, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Benson
authors.affiliation: Department of Pathology, University of Cambridge, UK.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sterling
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Bielefeld Academic Teaching Hospital, Bielefeld, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sudhoff
authors.affiliation: ENT Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Piyush
authors.initials: P
authors.lastname: Jani
authors.affiliation: Department of Pathology, University of Cambridge, UK.
authors.forename: Peter K C
authors.initials: PK
authors.lastname: Goon
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods; D002985:Clinical Protocols; D006801:Humans; D009959:Oropharyngeal Neoplasms / Q000150:complications / Q000628:therapy*; D027383:Papillomaviridae / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D030361:Papillomavirus Infections / Q000150:complications / Q000628:therapy* / Q000821:virology; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D016896:Treatment Outcome
keywords: De-escalation of treatments; Human papillomavirus; Oropharyngeal carcinoma