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

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; De-ESCALaTE HPV Trial Group; Laura Pettit; Paul Nankivell; Jennifer Bryant; Neil Sharma; Rachel Spruce; Jill Brooks

doi:10.1016/S0140-6736(18)32752-1

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

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 WintonAndrew Chan, Devraj Srinivasan, Ioanna Nixon, Joanne Grumett, C. René Leemans, Jan Buter, Julia Henderson, Kevin Harrington, Christopher McConkey, Alastair Gray, Janet Dunn, De-ESCALaTE HPV Trial Group, Laura Pettit (Contributor), Paul Nankivell (Contributor), Jennifer Bryant (Contributor), Neil Sharma (Contributor), Rachel Spruce (Contributor), Jill Brooks (Contributor)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

286 Citations (Scopus)

289 Downloads (Pure)

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.

FUNDING: Cancer Research UK.

Original language	English
Pages (from-to)	51-60
Number of pages	10
Journal	The Lancet
Volume	393
Issue number	10166
Early online date	15 Nov 2018
DOIs	https://doi.org/10.1016/S0140-6736(18)32752-1
Publication status	Published - 5 Jan 2019

Bibliographical note

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1016/S0140-6736(18)32752-1Licence: Creative Commons: Attribution (CC BY)

CRUK/11/043 (via Uni of Warwick): De-ESCALaTE-HPV: Determination of Epidermal growth factor receptor-inhibitor (cetuximab) vs Standard Chemotherapy early and Late Toxicity Events in Human Papilloma Virus Positive oropharyngeal carcinoma
Mehanna, H. (Principal Investigator)
Cancer Research UK
1/09/12 → 31/08/17
Project: Research

Cite this

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., ... Brooks, J. (2019). Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. The Lancet, 393(10166), 51-60. https://doi.org/10.1016/S0140-6736(18)32752-1

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

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.FUNDING: Cancer Research UK.",

keywords = "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",

author = "Hisham Mehanna and Max Robinson and Andrew Hartley and Anthony Kong and Bernadette Foran and Tessa Fulton-Lieuw and Matthew Dalby and Pankaj Mistry and Mehmet Sen and Lorcan O'Toole and {Al Booz}, Hoda and Karen Dyker and Rafael Moleron and Stephen Whitaker and Sinead Brennan and Audrey Cook and Matthew Griffin and Eleanor Aynsley and Martin Rolles and {De Winton}, Emma and Andrew Chan and Devraj Srinivasan and Ioanna Nixon and Joanne Grumett and Leemans, {C. Ren{\'e}} and Jan Buter and Julia Henderson and Kevin Harrington and Christopher McConkey and Alastair Gray and Janet Dunn and {De-ESCALaTE HPV Trial Group} and Laura Pettit and Paul Nankivell and Jennifer Bryant and Neil Sharma and Rachel Spruce and Jill Brooks",

year = "2019",

month = jan,

day = "5",

doi = "10.1016/S0140-6736(18)32752-1",

language = "English",

volume = "393",

pages = "51--60",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier",

number = "10166",

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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, Pettit, L, Nankivell, P, Bryant, J, Sharma, N, Spruce, R & Brooks, J 2019, 'Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial', The Lancet, vol. 393, no. 10166, pp. 51-60. https://doi.org/10.1016/S0140-6736(18)32752-1

TY - JOUR

T1 - Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV)

T2 - an open-label randomised controlled phase 3 trial

AU - Mehanna, Hisham

AU - Robinson, Max

AU - Hartley, Andrew

AU - Kong, Anthony

AU - Foran, Bernadette

AU - Fulton-Lieuw, Tessa

AU - Dalby, Matthew

AU - Mistry, Pankaj

AU - Sen, Mehmet

AU - O'Toole, Lorcan

AU - Al Booz, Hoda

AU - Dyker, Karen

AU - Moleron, Rafael

AU - Whitaker, Stephen

AU - Brennan, Sinead

AU - Cook, Audrey

AU - Griffin, Matthew

AU - Aynsley, Eleanor

AU - Rolles, Martin

AU - De Winton, Emma

AU - Chan, Andrew

AU - Srinivasan, Devraj

AU - Nixon, Ioanna

AU - Grumett, Joanne

AU - Leemans, C. René

AU - Buter, Jan

AU - Henderson, Julia

AU - Harrington, Kevin

AU - McConkey, Christopher

AU - Gray, Alastair

AU - Dunn, Janet

AU - De-ESCALaTE HPV Trial Group

A2 - Pettit, Laura

A2 - Nankivell, Paul

A2 - Bryant, Jennifer

A2 - Sharma, Neil

A2 - Spruce, Rachel

A2 - Brooks, Jill

PY - 2019/1/5

Y1 - 2019/1/5

N2 - 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.

AB - 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.

KW - Acute Disease

KW - Antineoplastic Agents/administration & dosage

KW - Cetuximab/administration & dosage

KW - Chemoradiotherapy/adverse effects

KW - Cisplatin/administration & dosage

KW - Drug Administration Schedule

KW - Female

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Neoplasm Staging

KW - Oropharyngeal Neoplasms/pathology

KW - Papillomavirus Infections/complications

KW - Radiotherapy, Intensity-Modulated/adverse effects

KW - Risk Assessment

KW - Squamous Cell Carcinoma of Head and Neck/pathology

KW - Treatment Outcome

UR - http://www.scopus.com/inward/record.url?scp=85059501338&partnerID=8YFLogxK

UR - http://europepmc.org/abstract/med/30449623

U2 - 10.1016/S0140-6736(18)32752-1

DO - 10.1016/S0140-6736(18)32752-1

M3 - Article

C2 - 30449623

SN - 0140-6736

VL - 393

SP - 51

EP - 60

JO - The Lancet

JF - The Lancet

IS - 10166

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Fingerprint

Projects

CRUK/11/043 (via Uni of Warwick): De-ESCALaTE-HPV: Determination of Epidermal growth factor receptor-inhibitor (cetuximab) vs Standard Chemotherapy early and Late Toxicity Events in Human Papilloma Virus Positive oropharyngeal carcinoma

Cite this