Institute for Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK.
Newcastle University, Newcastle, UK.
Lancet. 2019 Jan 5;393(10166):51-60. doi: 10.1016/S0140-6736(18)32752-1. Epub 2018 Nov 15.
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.
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/m on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m loading dose followed by seven weekly infusions of 250 mg/m). 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.
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).
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.
Cancer Research UK.
人乳头瘤病毒（HPV）阳性口咽癌的发病率迅速上升，这种疾病影响年轻患者。表皮生长因子受体抑制剂西妥昔单抗已被提议用于这种情况下的治疗降级，以降低标准顺铂治疗的毒性，但没有随机证据证明这种策略的疗效。
我们在爱尔兰、荷兰和英国的 32 个头颈部治疗中心进行了一项开放标签随机对照 3 期试验，纳入年龄在 18 岁及以上的 HPV 阳性低危口咽癌（不吸烟者或终生吸烟但吸烟史<10 包年）患者。符合条件的患者按 1:1 随机分配（随机分配）接受放疗（70Gy 分 35 次）加静脉用顺铂（100mg/m2，放疗第 1、22 和 43 天）或静脉用西妥昔单抗（400mg/m2 负荷剂量，然后每周输注 7 次 250mg/m2）。主要终点是治疗结束后 24 个月时的总体严重（3-5 级）毒性事件。主要结局通过意向治疗和方案分析进行评估。该试验在 ISRCTN 注册中心注册，编号 ISRCTN33522080。
2012 年 11 月 12 日至 2016 年 10 月 1 日期间，共招募了 334 名患者（顺铂组 166 名，西妥昔单抗组 168 名）。治疗 24 个月时，两组总体（急性和迟发性）严重（3-5 级）毒性无显著差异（顺铂组每名患者平均发生事件数为 4.8[95%CI4.2-5.4]，西妥昔单抗组为 4.8[4.2-5.4]；p=0.98）。同样，24 个月时总体所有级别毒性也无显著差异（顺铂组每名患者平均发生事件数为 29.2[95%CI27.3-31.0]，西妥昔单抗组为 30.1[28.3-31.9]；p=0.49）。然而，顺铂与西妥昔单抗的 2 年总生存率（97.5%vs89.4%，风险比 5.0[95%CI1.7-14.7]；p=0.001）和 2 年复发率（6.0%vs16.1%，3.4[1.6-7.2]；p=0.0007）存在显著差异。
与标准顺铂方案相比，西妥昔单抗在降低毒性方面没有优势，反而在肿瘤控制方面存在显著的不良影响。对于能够耐受顺铂的 HPV 阳性低危患者，顺铂和放疗应作为标准治疗。
英国癌症研究中心。
