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Abstract
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.

Author information

Mehanna H1, Robinson M2, Hartley A3, Kong A4, Foran B5, Fulton-Lieuw T4, Dalby M6, Mistry P6, Sen M7, O'Toole L8, Al Booz H9, Dyker K10, Moleron R11, Whitaker S12, Brennan S13, Cook A14, Griffin M15, Aynsley E16, Rolles M17, De Winton E18, Chan A19, Srinivasan D20, Nixon I21, Grumett J6, Leemans CR22, Buter J22, Henderson J23, Harrington K24, McConkey C6, Gray A25, Dunn J6; De-ESCALaTE HPV Trial Group.
1
Institute for Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK. Electronic address: h.mehanna@bham.ac.uk.
2
Newcastle University, Newcastle, UK.
3
University Hospitals Birmingham, Birmingham, UK.
4
Institute for Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK.
5
Weston Park Hospital, Sheffield, UK.
6
University of Warwick, Coventry, UK.
7
St James's Institute of Oncology, Leeds, UK.
8
Queen's Centre for Oncology, Castle Hill Hospital, Cottingham, UK.
9
Bristol Haematology and Oncology Centre, Bristol, UK.
10
St James' University Hospital, Leeds, UK.
11
Aberdeen Royal Infirmary, Aberdeen, UK.
12
Royal Surrey County Hospital, Surrey, UK.
13
St Luke's Hospital, Cancer Trials Ireland, and St Luke's Institute of Cancer Research, Dublin, Ireland.
14
Cheltenham General Hospital, Cheltenham, UK.
15
Nottingham University Hospitals NHS Trust, Nottingham, UK.
16
James Cook University Hospital, Middlesbrough, UK.
17
Abertawe Bro Morgannwg University Health Board, Port Talbot, UK.
18
Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
19
University Hospital Coventry and Warwickshire NHS Trust, Coventry, UK.
20
Western General Hospital, Edinburgh, UK.
21
Beatson West of Scotland Cancer Centre, Glasgow, UK.
22
VU University Medical Centre, Amsterdam, Netherlands.
23
National RTTQA Group, Royal Marsden Hospital, London, UK.
24
Institute of Cancer Research and Royal Marsden Hospital, London UK.
25
University of Oxford, Oxford, UK.