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Gillison ML , Trotti AM , Harris J , Eisbruch A , Harari PM , Adelstein DJ , Sturgis EM , Burtness B , Ridge JA , Ringash J , Galvin J , Yao M , Koyfman SA , Blakaj DM , Razaq MA , Colevas AD , Beitler JJ , Jones CU , Dunlap NE , Seaward SA , Spencer S , Galloway TJ , Phan J , Dignam JJ , Le QT
Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial
Lancet. 2019 Jan 5;393(10166) :40-50
PMID: 30449625    PMCID: PMC6541928    URL: https://www.ncbi.nlm.nih.gov/pubmed/30449625
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Abstract
BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity. METHODS: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (</=10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m(2) 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m(2) weekly for seven doses (total 2150 mg/m(2)), or cisplatin 100 mg/m(2) on days 1 and 22 of radiotherapy (total 200 mg/m(2)). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1.45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834. FINDINGS: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4.5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1.45, one-sided 95% upper CI 1.94; p=0.5056 for non-inferiority; one-sided log-rank p=0.0163). Estimated 5-year overall survival was 77.9% (95% CI 73.4-82.5) in the cetuximab group versus 84.6% (80.6-88.6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1.72, 95% CI 1.29-2.29; p=0.0002; 5-year progression-free survival 67.3%, 95% CI 62.4-72.2 vs 78.4%, 73.8-83.0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2.05, 95% CI 1.35-3.10; 5-year proportions 17.3%, 95% CI 13.7-21.4 vs 9.9%, 6.9-13.6). Proportions of acute moderate to severe toxicity (77.4%, 95% CI 73.0-81.5 vs 81.7%, 77.5-85.3; p=0.1586) and late moderate to severe toxicity (16.5%, 95% CI 12.9-20.7 vs 20.4%, 16.4-24.8; p=0.1904) were similar between the cetuximab and cisplatin groups. INTERPRETATION: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma. FUNDING: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.
Notes
1474-547x Gillison, Maura L Trotti, Andy M Harris, Jonathan Eisbruch, Avraham Harari, Paul M Adelstein, David J Sturgis, Erich M Burtness, Barbara Ridge, John A Ringash, Jolie Galvin, James Yao, Min Koyfman, Shlomo A Blakaj, Dukagjin M Razaq, Mohammed A Colevas, A Dimitrios Beitler, Jonathan J Jones, Christopher U Dunlap, Neal E Seaward, Samantha A Spencer, Sharon Galloway, Thomas J Phan, Jack Dignam, James J Le, Quynh Thu Journal Article U10 CA180822/CA/NCI NIH HHS/ U10 CA180868/CA/NCI NIH HHS/ U24 CA180803/CA/NCI NIH HHS/ UG1 CA189867/CA/NCI NIH HHS/ Comparative Study England Multicenter Study Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Lancet. 2019 Jan 5;393(10166):40-50. doi: 10.1016/S0140-6736(18)32779-X. Epub 2018 Nov 15.