Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.
Date
2019-01-05ICR Author
Author
Mehanna, H
Robinson, M
Hartley, A
Kong, A
Foran, B
Fulton-Lieuw, T
Dalby, M
Mistry, P
Sen, M
O'Toole, L
Al Booz, H
Dyker, K
Moleron, R
Whitaker, S
Brennan, S
Cook, A
Griffin, M
Aynsley, E
Rolles, M
De Winton, E
Chan, A
Srinivasan, D
Nixon, I
Grumett, J
Leemans, CR
Buter, J
Henderson, J
Harrington, K
McConkey, C
Gray, A
Dunn, J
De-ESCALaTE HPV Trial Group,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
De-ESCALaTE HPV Trial Group
Humans
Papillomavirus Infections
Oropharyngeal Neoplasms
Acute Disease
Cisplatin
Antineoplastic Agents
Neoplasm Staging
Treatment Outcome
Drug Administration Schedule
Risk Assessment
Middle Aged
Female
Male
Radiotherapy, Intensity-Modulated
Kaplan-Meier Estimate
Chemoradiotherapy
Cetuximab
Squamous Cell Carcinoma of Head and Neck
Research team
Targeted Therapy
Language
eng
Date accepted
2018-10-18
License start date
2019-01
Citation
Lancet (London, England), 2019, 393 (10166), pp. 51 - 60
Publisher
ELSEVIER SCIENCE INC