Dose escalation with intraoperative radiotherapy in newly diagnosed glioblastoma (INTRAGO-II): an open-label, multicentre, randomised, controlled, phase 3 trial.

We aimed to evaluate whether additional intraoperative radiotherapy compared with standard of care improves outcomes in patients with newly diagnosed glioblastoma.

我们旨在评估与标准护理相比，额外的术中放疗是否能改善新诊断胶质母细胞瘤患者的治疗结果。

Methods

INTRAGO-II was an open-label, multicentre, randomised, controlled, phase 3 trial enrolling patients aged 18-80 years with supratentorial glioblastoma amenable to resection of the contrast enhancing tumour with Karnofsky performance score (KPS) of ≥60%.

INTRAGO-II 是一项开放标签、多中心、随机对照的 III 期临床试验，招募了年龄在 18-80 岁之间、顶叶胶质母细胞瘤可切除且对比增强肿瘤可进行手术切除、Karnofsky 功能状态评分（KPS）≥60% 的患者。

Patients from 18 centres in Brazil, Canada, China, Germany, Spain, South Korea, and the USA were randomly assigned (1:1) intraoperatively to receive additional kilovoltage intraoperative radiotherapy with 30 Gy (intraoperative radiotherapy group) or surgery alone (standard-of-care group), stratified by age, KPS, and residual tumour.

来自巴西、加拿大、中国、德国、西班牙、韩国和美国的 18 个中心的患者被随机分配（1:1）在手术中接受额外的千伏级术中放疗，剂量为 30 Gy（术中放疗组）或仅接受手术（标准治疗组），根据年龄、KPS 和残余肿瘤进行分层。

Postoperative treatment consisted of external-beam radiotherapy to 60 Gy with concurrent temozolomide (75 mg/m2), followed by six adjuvant cycles of temozolomide (150-200 mg/m2, days 1-5 every 28 days).

术后治疗包括外照射至60 Gy，同时使用替莫唑胺（75 mg/m2），随后进行六周期的辅助性替莫唑胺治疗（150-200 mg/m2，每28天的第1-5天）。

The primary endpoint was median progression-free survivalin the full-analysis set, confirmed by masked, centralised review.

主要终点是全分析集中的中位无进展生存期，通过蒙蔽的中央审查确认。

This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT02685605.

这项正在进行的研究已经停止招募，并已在ClinicalTrials.gov注册，注册号为NCT02685605。

Results

Between Dec 9, 2016, and June 17, 2024, of 411 patients assessed for eligibility, 314 were randomly assigned.

在2016年12月9日至2024年6月17日期间，共有411名患者接受了资格评估，其中314名患者被随机分配。

The full-analysis set comprised 298 patients (intraoperative radiotherapy, n=161; standard-of-care, n=137), of whom 127 (43%) patients were female and 171 (57%) were male.

全分析集包括298名患者（术中放疗组，n=161；标准治疗组，n=137），其中127名（43%）为女性，171名（57%）为男性。

Data on race and ethnicity were not collected.

未收集有关种族和民族的数据。

At a median follow-up of 17·2 months (IQR 10·5-27·1), median progression-free survivalwas 11·0 months (95% CI 9·2-12·6) in the intraoperative radiotherapy group versus 11·4 months (9·7-13·9) in the standard-of-care group (hazard ratio[HR] 1·1, 95% CI 0·85-1·44; p=0·47).

中位随访时间为17.2个月（四分位数间距10.5-27.1），手术中放疗组的中位无进展生存期为11.0个月（95%置信区间9.2-12.6），标准治疗组为11.4个月（95%置信区间9.7-13.9）（风险比[HR] 1.1，95%置信区间0.85-1.44；p=0.47）。

Local recurrence was the predominant pattern of failure in both groups (76 [72%] in the intraoperative radiotherapy group vs 60 [71%] in the standard-of-care group, p=0·87).

局部复发是两组失败的主要模式（手术中放疗组76例[72%]，标准治疗组60例[71%]，p=0.87）。

The most common grade 3-4 adverse events were seizure (21 [13%] in the intraoperative radiotherapy group vs nine [7%] in the standard-of-care group), radiation necrosis (11 [7%] vs three [2%]; p=0·06), thrombocytopenia (seven [4%] vs 11 [8%]), and muscle weakness (12 [7%] vs 19 [14%]).

最常见的3-4级不良事件是癫痫发作（术中放疗组21例[13%]对比标准治疗组9例[7%]），放射性坏死（11例[7%]对比3例[2%]；p=0·06），血小板减少症（七例[4%]对比11例[8%]），以及肌肉无力（12例[7%]对比19例[14%]）。

In total, 252 serious adverse events occurred in 105 (65%) patients in the intraoperative radiotherapy group and 142 serious adverse events in 72 (53%) patients in the standard-of-care group.

总共，术中放疗组有105名（65%）患者发生了252起严重不良事件，而标准治疗组有72名（53%）患者发生了142起严重不良事件。

Of these, 65 (26%) events in 40 (38%) patients in the intraoperative radiotherapy group and 27 (19%) events in 19 (26%) patients in the standard-of-care group were considered possibly related to the treatment.

在这些病例中，接受术中放疗的组别有65个（占26%）事件发生在40名（占38%）患者中，而接受标准治疗的组别有27个（占19%）事件发生在19名（占26%）患者中，这些事件被认为可能与治疗相关。

Of all grade five adverse events reported, 14 in the intraoperative radiotherapy group (CNS toxicity [n=2], myocardial infarction [n=2], sepsis [n=2], and one each cardiac arrest, fever, lung infection, fracture, postoperative haemorrhage, neoplasm, haematoma, and not otherwise specified death) and six in the standard-of-care group (lung infection [n=2], and one each multiorgan failure, encephalitis, neoplasm, and cystitis) were attributable to specific CTCAE terms.

在所有报告的五级不良事件中，术中放疗组有14例（中枢神经系统毒性[n=2]，心肌梗死[n=2]，败血症[n=2]，以及心脏骤停、发热、肺部感染、骨折、术后出血、肿瘤、血肿各1例，以及未具体说明的死亡），标准治疗组有6例（肺部感染[n=2]，以及多器官衰竭、脑炎、肿瘤和膀胱炎各1例），这些不良事件均可归因于特定的CTCAE术语。

interpretation

Instant, spatially precise dose escalation with intraoperative radiotherapy added to standard of care did not improve outcomes, questioning the value of further local dose intensification in resectable glioblastoma.

即时、空间精确的剂量提升，通过术中放疗加入到标准治疗中，并没有改善结果，这质疑了在可切除的胶质母细胞瘤中进一步局部剂量增强的价值。

funding

Universities of Heidelberg and Bonn, Carl Zeiss Meditec, Deutsche Forschungsgemeinschaft.

海德堡大学和波恩大学，卡尔蔡司医疗技术公司，德国研究基金会。