Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial

Research output: Contribution to journalArticle


  • De-ESCALaTE HPV Trial Group

External organisations

  • Institute for Head and Neck Studies and Education (InHANSE)
  • Newcastle University
  • University Hospitals Birmingham NHS Trust
  • Weston Park Hospital
  • Birmingham University
  • St James's Institute of Oncology
  • Castle Hill Hospital
  • Bristol Haematology and Oncology Centre
  • St James' Hospital
  • Aberdeen Royal Infirmary
  • Royal Surrey County Hospital
  • St Luke's Hospital, Dublin
  • Cheltenham General Hospital
  • Nottingham University Hospitals NHS Trust
  • The James Cook University Hospital
  • Abertawe Bro Morgannwg University Health Board
  • Royal United Hospitals Bath
  • University Hospitals Coventry and Warwickshire NHS Trust
  • Western General Hospital
  • Beatson West Of Scotland Cancer Centre
  • Section of Gerontology and Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, Netherlands.
  • Royal Marsden Hospital, London
  • Institute for Cancer Research
  • University of Oxford


BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.

METHODS: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080.

FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007).

INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin.

FUNDING: Cancer Research UK.

Bibliographic note

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.


Original languageEnglish
Pages (from-to)51-60
Number of pages10
JournalThe Lancet
Issue number10166
Early online date15 Nov 2018
Publication statusPublished - 5 Jan 2019


  • Acute Disease, Antineoplastic Agents/administration & dosage, Cetuximab/administration & dosage, Chemoradiotherapy/adverse effects, Cisplatin/administration & dosage, Drug Administration Schedule, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Oropharyngeal Neoplasms/pathology, Papillomavirus Infections/complications, Radiotherapy, Intensity-Modulated/adverse effects, Risk Assessment, Squamous Cell Carcinoma of Head and Neck/pathology, Treatment Outcome