Proton versus photon radiotherapy for patients with oropharyngeal cancer in the USA: a multicentre, randomised, open-label, non-inferiority phase 3 trial.

Toxicity from the current state-of-the-art photon radiotherapy, intensity-modulated radiation therapy (IMRT), has prompted the search for alternative, less toxic therapies.

目前最先进的光子放射治疗，即强度调制放射治疗（IMRT），所带来的毒性反应促使人们寻找其他毒性更低的治疗方法。

One such alternative that might de-intensify treatment is proton therapy.

一种可能减轻治疗强度的替代方案是质子治疗。

In this trial, we aimed to directly compare IMRT with intensity-modulated proton therapy (IMPT), both concurrent with systemic therapy, hypothesising comparable disease control and survival and lower toxicity.

在这项试验中，我们旨在直接比较强度调制放射治疗（IMRT）与强度调制质子治疗（IMPT），两者均与系统治疗同时进行，我们假设疾病控制和生存率相当，且毒性更低。

Methods

This randomised, multicentre, open-label, non-inferiority, phase 3 trial was conducted in 21 sites (cancer centres or universities) in the USA.

这是一项随机、多中心、开放标签、非劣效性、III期试验，在美国的21个地点（癌症中心或大学）进行。

Patients (aged ≥18 years) with stage III or stage IV oropharyngeal cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and randomly assigned 1:1 to receive IMPT or IMRT.

招募了年龄≥18岁的III期或IV期口咽癌患者，以及东部肿瘤协作组表现状态为0-2的患者，并按1:1的比例随机分配接受IMPT或IMRT治疗。

All patients were treated with radiotherapy to 70 Gy in 33 fractions to the primary tumour site and cervical lymphadenopathy.

所有患者均接受了对原发肿瘤部位和颈部淋巴结转移的放射治疗，总剂量为70 Gy，分33次进行。

The type, schedule, and dose of induction or concurrent systemic therapy were chosen locally by each institution's multidisciplinary tumour board and were consistent with international guidelines.

诱导或同步全身治疗的类型、方案和剂量由每个机构的多学科肿瘤委员会根据国际指南选择。

The primary endpoint was progression-free survivaland was assessed in the intention-to-treatpopulation; safety outcomes were assessed in the per-protocol population (ie, patients who received the assigned therapy).

主要终点是无进展生存期，并在意向治疗人群中进行评估；安全性结果在按方案人群中进行评估（即接受指定治疗的患者）。

A non-inferiority margin of 9 percentage points for progression-free survivalat 3 years was used.

使用了3年无进展生存期的非劣效性边界为9个百分点。

This trial is registered with ClinicalTrials.gov (NCT01893307) and is closed to further accrual after prespecified interim analysis.

该试验已在ClinicalTrials.gov注册（NCT01893307），并在预先设定的中期分析后停止进一步纳入新患者。

Results

From Oct 10, 2013, to May 1, 2022, 440 patients consented (median age 61 years [IQR 55-68], 399 [91%] male, 409 [93%] White); 221 were allocated to the IMPT group (with 160 [72%] receiving IMPT) and 219 to the IMRT group (136 [62%] receiving IMRT).

从2013年10月10日至2022年5月1日，共有440名患者同意参与（中位年龄61岁[四分位数间距55-68]，399名[91%]为男性，409名[93%]为白人）；其中221名被分配到IMPT组（160名[72%]接受了IMPT治疗），219名被分配到IMRT组（136名[62%]接受了IMRT治疗）。

At a median follow-up time of 3·2 years, progression-free survivalrates for the IMPT group were 82·5% (95% CI 76·1-87·3) at 3 years and 81·3% (74·5-86·5) at 5 years; corresponding rates for the IMRT group were 83·0% (76·7-87·7) and 76·2% (68·0-82·6; hazard ratio[HR] 0·88 [95% CI 0·57-1·35]; p=0·005 for non-inferiority of IMPT).

在中位随访时间为3.2年时，IMPT组的无进展生存率在3年时为82.5%（95%置信区间76.1-87.3），在5年时为81.3%（74.5-86.5）；IMRT组相应的生存率在3年时为83.0%（76.7-87.7），在5年时为76.2%（68.0-82.6；风险比[HR] 0.88 [95%置信区间0.57-1.35]；p=0.005，显示IMPT的非劣效性）。

Overall survivalrates after IMPT were 90·9% at 5 years versus 81·0% after IMRT (HR 0·58 [95% CI 0·34-0·99]; p=0·045).

IMPT后的总生存率在5年时为90.9%，而IMRT后的总生存率为81.0%（HR 0.58 [95%置信区间0.34-0.99]；p=0.045）。

Treatment-related deaths occurred in nine patients; six in the IMRT group and three in the IMPT group.

治疗相关死亡发生在九名患者中；六名在IMRT组，三名在IMPT组。

Deaths from disease progression occurred in 27 patients; 18 in the IMRT group and nine in the IMPT group. 5-year disease control rates for IMPT versus IMRT were similar between treatment groups (local recurrences 2·9% vs 5·6%, p=0·474; regional recurrences 3·4% vs 3·2%, p=0·860; and distant metastases 9·1% vs 8·9%, p=0·897).

疾病进展导致的死亡发生在27名患者中；IMRT组18名，IMPT组9名。IMPT与IMRT的5年疾病控制率在治疗组之间相似（局部复发2·9%对比5·6%，p=0·474；区域复发3·4%对比3·2%，p=0·860；远处转移9·1%对比8·9%，p=0·897）。

Severe lymphopenia was more common in the IMRT group (89% vs 76%), as were dysphagia (49% vs 31%), xerostomia (45% vs 33%), and gastrostomy tube dependence (40·2% vs 26·8%; p=0·018).

在调强放疗（IMRT）组中，严重的淋巴细胞减少症更为常见（89%对比76%），同时吞咽困难（49%对比31%）、口干（45%对比33%）以及胃造口管依赖性（40.2%对比26.8%；p=0.018）的情况也更为普遍。

interpretation

IMPT showed non-inferiority to IMRT for progression-free survival, improvement in overall survival, similar disease control, and reduced high-grade toxicity relative to IMRT.

对于无进展生存期，质子束调强放疗（IMPT）显示出与IMRT相当的非劣效性，总生存期有所改善，疾病控制相似，并且与IMRT相比，高级别毒性有所减少。

Treatment-related and post-progression deaths occurred more frequently with IMRT.

使用IMRT的患者中，治疗相关和疾病进展后的死亡发生更为频繁。

IMPT is a new standard-of-care treatment option for patients with oropharyngeal cancer.

对于口咽癌患者，IMPT已成为新的标准治疗方案。

funding

MD Anderson Cancer Center, Massachusetts General Hospital, National Institutes of Health, Hitachi America.

德克萨斯大学MD安德森癌症中心、马萨诸塞州总医院、美国国家卫生研究院、日立美国公司。