Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial
Authors: Hisham Mehanna, Max Robinson, Andrew Hartley, Anthony Kong, Bernadette Foran, Tessa Fulton-Lieuw, Matthew Dalby, Pankaj Mistry, Mehmet Sen, Lorcan O'Toole, Hoda Al Booz, Karen Dyker, Rafael Moleron, Stephen Whitaker, Sinead Brennan, Audrey Cook, Matthew Griffin, Eleanor Aynsley, Martin Rolles, Emma De Winton, Andrew Chan, Devraj Srinivasan, Ioanna Nixon, Joanne Grumett, C René Leemans, Jan Buter, Julia Henderson, Kevin Harrington, Christopher McConkey, Alastair Gray, Janet Dunn, Rafael Moleron, Orla McArdle, Karen Dyker, Hoda Al Booz, Lorcan O'Toole, Audrey Cook, David Husband, Vivienne Loo, Win Soe, Eleanor Aynsley, Thiagarajan Sridhar, Petra Jankowska, Mano Joseph, Konstantinos Geropantas, Deepali Vaidya, Matthew Griffin, Andrew Hartley, Rengarajan Vijayan, David Hwang, Kevin Harrington, Laura Pettit, Stephen Whitaker, Emma De Winton, Martin Rolles, Sinéad Brennan, Mehmet Sen, Ruheena Mendes, Martin Forster, Andrew Chan, Mererid Evans, Jan Buter, Devraj Srinivasan, Bernie Foran, Paul Nankivell, Jennifer Bryant, Neil Sharma, Rachel Spruce, Jill Brooks, Nikos Batis, Tom Roques, Margaret Bidmead, Huiqi Yang, Christopher Nutting, Justine Tyler, Julia Henderson, Helen Baines, Anne Gasnier, Elizabeth Miles, Catharine Clark, Mererid Evans
Journal: The Lancet (2018)

BackgroundThe 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.MethodsWe 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.FindingsBetween 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).InterpretationCompared 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.FundingCancer Research UK.