De-escalated adjuvant radiotherapy versus standard adjuvant treatment for human papillomavirus-associated oropharyngeal squamous cell carcinoma (MC1675): a phase 3, open-label, randomised controlled trial.

We aimed to compare toxicity of a 30-36 Gy regimen of de-escalated adjuvant radiotherapy and standard of care treatment.

我们旨在比较降阶辅助性放疗（30-36 Gy）方案与标准治疗的毒性反应。

Methods

We did this phase 3, open-label, randomised controlled trialin two academic sites in the USA.

我们在美国的两个学术场所进行了这项第3阶段、开放标签、随机对照试验。

Eligible participants were adults aged 18 years or older, with American Joint Committee on Cancer 7th edition pathological stage III-IV HPV-associated oropharyngeal squamous cell carcinoma and had more than 70% p16-immunoreactivity on immunohistochemistry evaluation of the surgical specimen.

符合条件的参与者为18岁或以上的成年人，患有美国癌症联合委员会第7版病理分期III-IV期的人乳头瘤病毒相关性口咽鳞状细胞癌，并且在手术标本的免疫组织化学评估中p16免疫反应性超过70%。

All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less and at least one intermediate pathological risk factor.

所有患者均具有东部肿瘤协作组（ECOG）表现状态1或更低，并且至少有一个中度病理风险因素。

Patients were stratified by the presence of extranodal extension and smoking status (<10 packs per year vs ≥10 packs per year) Eligible patients were randomly assigned (2:1) using a minimisation method with a random element to receive de-escalated adjuvant radiotherapy (30-36 Gy in 1·5-1·8 Gy fractions twice per day over 2 weeks plus intravenous docetaxel 15 mg/m2 on days 1 and 8 of treatment) or standard of care (60 Gy in 2 Gy fractions once daily over 6 weeks plus intravenous cisplatin 40 mg/m2 once a week).

患者根据是否存在淋巴结外扩展和吸烟状态（<10包年 vs ≥10包年）进行分层。符合条件的患者使用最小化方法随机分配（2:1），并加入一个随机元素，以接受降阶辅助放疗（在2周内，每天两次，每次1.5-1.8 Gy，总剂量30-36 Gy，加上治疗第1天和第8天静脉注射多西他赛15 mg/m2）或标准治疗（在6周内，每天一次，每次2 Gy，总剂量60 Gy，加上每周一次静脉注射顺铂40 mg/m2）。

The primary endpoint was cumulative, chronic grade 3 or higher toxicity rate 3-24 months after radiotherapy.

主要终点是放疗后3-24个月累积的、慢性3级或更高级别的毒性发生率。

Primary analysis was done in patients who received treatment and had no missing data.

主要分析是在接受治疗且无缺失数据的患者中进行的。

This trial is registered with ClinicalTrials.gov, NCT02908477, and is complete.

该试验已在ClinicalTrials.gov注册，注册号为NCT02908477，且已完成。

Results

Between Oct 11, 2016, and Aug 20, 2020, 254 patients with newly diagnosed oropharyngeal squamous cell carcinoma were assessed for inclusion.

在2016年10月11日至2020年8月20日期间，共有254名新诊断的口咽鳞状细胞癌患者被评估以纳入研究。

Nine did not meet inclusion criteria and 17 declined to participate. 228 patients were enrolled, with 194 proceeding to protocol treatment and analysis (130 in the de-escalated adjuvant radiotherapy group and 64 in the standard of care group).

9名患者未满足纳入标准，17名患者拒绝参与。共有228名患者被纳入研究，其中194名患者进入方案治疗和分析（130名患者在降阶辅助放疗组，64名患者在标准治疗组）。

Median patient age was 59·4 years (range 37·9-81·6). 173 (89%) of 194 patients were male and 21 (11%) were female. 183 (95%) of 194 patients were White, four (2%) were Hispanic, three (2%) were Asian, and one (1%) was Native American.

患者的中位年龄为59.4岁（范围37.9-81.6岁）。在194名患者中，173名（89%）为男性，21名（11%）为女性。在194名患者中，183名（95%）为白人，4名（2%）为西班牙裔，3名（2%）为亚洲人，1名（1%）为美洲原住民。

Median follow-up was 37·3 months (IQR 27·6-49·2).

中位随访时间为37.3个月（四分位数间距27.6-49.2）。

Seven patients were excluded from analysis of the primary late toxicity endpoint (five patients in the de-escalated adjuvant radiotherapy group and two patients in the standard of care group).

有七名患者在主要晚期毒性终点分析中被排除（去强化辅助放疗组有五名患者，标准治疗组有两名患者）。

The cumulative chronic grade 3 or higher toxicity rate at 3-24 months was 3% (four of 125 patients) in the de-escalated adjuvant radiotherapy group and 11% (seven of 62 patients) in the standard of care group (p=0·042) with a cumulative chronic percutaneous endoscopic gastric (PEG) tube rate of 2% (two of 125 patients) in the de-escalated adjuvant radiotherapy group and 8% (five of 62 patients) in the standard of care group (p=0·039).

在3-24个月期间，降量辅助放疗组的累积慢性3级或更高级别毒性发生率为3%（125名患者中有4名），而标准治疗组为11%（62名患者中有7名）（p=0·042），累积慢性经皮内镜下胃造口术（PEG）管使用率为降量辅助放疗组2%（125名患者中有2名），标准治疗组为8%（62名患者中有5名）（p=0·039）。

The most common grade 3 or higher toxic effects in the de-escalated adjuvant radiotherapy group were dysphagia (two [2%] of 125 patients), oesophagitis (one patient [1%]) and hearing impairment (one patient [1%]).

降量辅助放疗组中最常见的3级或更高级别的毒性效应是吞咽困难（125名患者中有2名[2%]），食管炎（1名患者[1%]）和听力损害（1名患者[1%]）。

The most common grade 3 or higher toxic effects in the standard of care group were dysphagia (five [8%] of 61 patients), oesophagitis (one patient [2%]), fatigue (one patient [2%]), pain (one patient [2%]), and osteonecrosis of the jaw (one patient [2%]).

标准治疗组中最常见的3级或更高级别的不良反应包括吞咽困难（61名患者中有5名[8%]）、食管炎（1名患者[2%]）、疲劳（1名患者[2%]）、疼痛（1名患者[2%]）以及颌骨坏死（1名患者[2%]）。

interpretation

De-escalated adjuvant radiotherapy was a more tolerable treatment in terms of chronic toxicities, demonstrating less cumulative grade 3 or higher toxicity compared with standard of care.

降阶辅助放疗在慢性毒性方面是一种更易耐受的治疗方式，与标准治疗相比，显示出较低的累积3级或更高级别的毒性。

Further clinical trials exploring indications for the DART regimen are warranted.

进一步探索DART方案适应症的临床试验是必要的。

funding

The Department of Radiation Oncology, Mayo Clinic, Minnesota and Arizona, the Braillier Family Research Fund, and the Matteson Family Research Fund.

明尼苏达州和亚利桑那州梅奥诊所放射肿瘤科、Braillier家族研究基金和Matteson家族研究基金。