Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial
Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial
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DOI：
10.1016/s0140-6736(18)32779-x
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发表时间：
2019-01-05
期刊：
影响因子：
168.9
通讯作者：
Quynh Thu Le
中科院分区：
文献类型：
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作者：
Gillison, Maura L.;Trotti, Andy M.;Quynh Thu Le
背景：人乳头瘤病毒（HPV）阳性的口咽部鳞状细胞癌患者接受放疗加顺铂治疗后生存率较高。用西妥昔单抗（一种抗表皮生长因子受体的抗体）替代顺铂是否能保持较高的生存率并降低治疗毒性尚不清楚。我们调查西妥昔单抗是否会保持高比例的患者生存率，并减少急性和晚期toxicity.Methods RTOG 1016是一个随机，多中心，非劣效性试验在182个卫生保健中心在美国和加拿大。合格标准包括组织学证实的HPV阳性口咽癌;美国癌症联合委员会第7版临床分类T1-T2、N2 a-N3 M0或T3-T4、N 0-N3 M0; Zubrod体力状态0或1;年龄至少18岁;以及足够的骨髓、肝和肾功能。我们将患者随机分配（1：1）接受放疗加西妥昔单抗或放疗加顺铂。通过使用随机排列区组平衡随机化，并按T类别（T1-T2 vs T3-T4）、N类别（N 0-N2 a vs N2 b-N3）、Zubrod体能状态（0 vs 1）和吸烟史（10包-年）对患者进行分层。患者被分配在放疗开始前5-7天接受负荷剂量400 mg/m2的西妥昔单抗静脉给药，随后接受每周250 mg/m2的西妥昔单抗共7次给药（共2150 mg/m2），或在放疗第1天和第22天接受顺铂100 mg/m2（共200 mg/m2）。所有患者均接受加速调强放疗，剂量为70戈伊，分35次，6周，每周6次（每天2次，间隔至少6小时）。主要终点是总生存期，定义为从随机化到全因死亡的时间，非劣效性界值为1.45。主要分析基于改良的意向治疗方法，其中包括所有符合合格标准的患者。该研究注册于ClinicalTrials.gov，编号NCT 01302834。结果在2011年6月9日至2014年7月31日期间，987例患者入组，其中849例随机分配接受放疗加西妥昔单抗（n=425）或放疗加顺铂（n=424）。399例分配接受西妥昔单抗治疗的患者和406例分配接受顺铂治疗的患者随后合格。中位随访时间为4.5年后，放疗加西妥昔单抗不符合总生存期的非劣效性标准（风险比[HR] 1.45，单侧95% CI上限1.94;非劣效性p=0.5056;单侧对数秩p=0.0163）。西妥昔单抗组的5年总生存率估计为77.9%（95%CI 73.4-82.5），顺铂组为84.6%（80.6-88.6）。与顺铂组相比，西妥昔单抗组的无进展生存率显著降低（HR 1.72，95% CI 1.29-2.29; p=0.0002; 5年无进展生存期67.3%，95% CI 62.4-72.2 vs 78.4%，73.8-83.0），与顺铂组相比，西妥昔单抗组的局部失败率显著较高（HR 2.05，95% CI 1.35-3.10; 5年比例17.3%，95% CI 13.7-21.4 vs 9.9%，6.9-13.6）。急性中度至重度毒性比例（77.4%，95% CI 73.0-81.5 vs 81.7%，77.5-85.3; p=0.1586）和晚期中度至重度毒性（16.5%，95%CI 12.9-20.7 vs 20.4%，16.4-24.8; p=0.1904）西妥昔单抗组和顺铂组之间相似。解释对于HPV阳性口咽癌患者，与放疗加顺铂相比，放疗加西妥昔单抗的总生存率和无进展生存率较低。放射治疗加顺铂是HPV阳性口咽癌患者的标准治疗方法，由美国国家癌症研究所、礼来公司和口腔癌基金会资助。版权所有（c）2018 Elsevier Ltd.保留所有权利。
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). 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. Copyright (c) 2018 Elsevier Ltd. All rights reserved.