Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA.
Lancet. 2019 Jan 5;393(10166):40-50. doi: 10.1016/S0140-6736(18)32779-X. Epub 2018 Nov 15.
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.
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 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m weekly for seven doses (total 2150 mg/m), or cisplatin 100 mg/m on days 1 and 22 of radiotherapy (total 200 mg/m). 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.
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.
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.
National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.
接受放化疗联合顺铂治疗的 HPV 阳性口咽鳞状细胞癌患者生存率较高。用针对表皮生长因子受体的西妥昔单抗替代顺铂能否保持高生存率并降低治疗毒性尚不清楚。我们旨在研究西妥昔单抗是否能维持高比例的患者生存并降低急性和晚期毒性。
RTOG 1016 是在美国和加拿大的 182 家医疗中心进行的一项随机、多中心、非劣效性试验。纳入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 版临床分期 T1-T2、N2a-N3 M0 或 T3-T4、N0-N3 M0；Zubrod 体能状态 0 或 1；年龄至少 18 岁；以及骨髓、肝和肾功能充足。我们采用随机化区组（block randomization）和按 T 分期（T1-T2 与 T3-T4）、N 分期（N0-N2a 与 N2b-N3）、Zubrod 体能状态（0 与 1）和吸烟史（≤10 包年与>10 包年）分层，将患者随机分配（1:1）接受放化疗联合西妥昔单抗或放化疗联合顺铂治疗。随机分组采用随机排列区组（random permuted blocks），患者被随机分为两组：一组接受静脉注射西妥昔单抗（负荷剂量 400 mg/m2，放疗前 5-7 天），随后每周一次给予西妥昔单抗 250 mg/m2，共 7 次（总剂量 2150 mg/m2）；另一组在放疗第 1 和 22 天接受顺铂 100 mg/m2（总剂量 200 mg/m2）。所有患者均接受加速强度调制放疗（accelerated intensity-modulated radiotherapy），70 Gy 分 35 次，每周 6 次，每次 2 次（间隔至少 6 小时）。主要终点是总生存期（overall survival），定义为自随机分组至任何原因死亡的时间，非劣效性边界为 1.45。主要分析采用改良意向治疗（modified intention-to-treat）分析，所有符合纳入标准的患者均纳入分析。该研究在 ClinicalTrials.gov 注册，编号为 NCT01302834。
2011 年 6 月 9 日至 2014 年 7 月 31 日，共纳入 987 例患者，其中 849 例患者被随机分配接受放化疗联合西妥昔单抗（n=425）或放化疗联合顺铂（n=424）治疗。399 例分配接受西妥昔单抗治疗，406 例分配接受顺铂治疗的患者符合条件。中位随访时间为 4.5 年，放化疗联合西妥昔单抗未达到总生存期的非劣效性标准（风险比[HR] 1.45，单侧 95%置信区间[CI] 1.94；p=0.5056 用于非劣效性；单侧对数秩检验 p=0.0163）。西妥昔单抗组 5 年总生存率为 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期（progression-free survival）显著降低（HR 1.72，95%CI 1.29-2.29；p=0.0002；5 年无进展生存率为 67.3%，95%CI 62.4-72.2 vs 78.4%，95%CI 73.8-83.0），局部区域失败率（locoregional failure rate）显著升高（HR 2.05，95%CI 1.35-3.10；5 年比例为 17.3%，95%CI 13.7-21.4 vs 9.9%，95%CI 6.9-13.6）。急性中重度毒性（77.4%，95%CI 73.0-81.5 与 81.7%，95%CI 77.5-85.3；p=0.1586）和晚期中重度毒性（16.5%，95%CI 12.9-20.7 与 20.4%，95%CI 16.4-24.8；p=0.1904）在西妥昔单抗组和顺铂组之间相似。
对于 HPV 阳性口咽癌患者，放化疗联合西妥昔单抗的总生存期和无进展生存期均低于放化疗联合顺铂。放化疗联合顺铂是 HPV 阳性口咽癌患者的标准治疗方法。
美国国立癌症研究所、礼来公司和口腔癌基金会。
