Concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): final and exploratory analyses of a randomised, open-label, phase 3 trial.

We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours.

我们报告了该研究的长期随访结果，重点关注了携带异柠檬酸脱氢酶(IDH)突变(IDHmt)肿瘤的个体。

Methods

This randomised, open-label, phase 3 study in 137 institutions across Australia, Europe, and North America included participants aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2.

这项在澳大利亚、欧洲和北美137个机构进行的随机、开放标签、III期研究，纳入了年龄在18岁或以上的参与者，他们新诊断为1p/19q非共缺失的间变性胶质瘤，并且WHO表现状态为0-2级。

Participants were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide.

参与者通过中央最小化技术随机分配（1:1:1:1），分别接受单纯放疗（59.4 Gy，33次分割）、放疗联合口服替莫唑胺（每天75 mg/m2）、放疗联合辅助口服替莫唑胺（12个4周周期，第1-5天给予150-200 mg/m2的替莫唑胺）或放疗联合同步和辅助替莫唑胺。

Participants were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status.

参与者根据机构、WHO表现状态评分、年龄、1p杂合性丢失、显微镜下少突胶质细胞成分的存在以及MGMT启动子甲基化状态进行了分层。

The primary endpoint was overall survivaladjusted by stratification factors at randomisation in the intention-to-treatpopulation.

主要终点是意向治疗人群中，根据随机化时的分层因素调整后的总生存期。

The eighth amendment of the study protocol (June 27, 2011) incorporated analysis of IDH mutational status into the study.

研究方案的第八次修订（2011年6月27日）将IDH突变状态的分析纳入研究中。

We report the intention-to-treatanalysis and the exploratory analysis within the population of participants with astrocytoma with an IDH mutation.

我们报告了意向治疗分析和在携带IDH突变的星形细胞瘤患者群体中的探索性分析。

As the safety data have been published previously, no safety data are reported.

由于安全性数据之前已经发表，本报告不再重复报道安全数据。

This trial is registered with ClinicalTrials.gov, NCT00626990, and is completed.

该试验已在ClinicalTrials.gov注册，注册号为NCT00626990，并且已经完成。

Results

Between Dec 4, 2007, and Sept 11, 2015, 1407 participants were registered and 751 participants were randomly allocated, 444 of whom were diagnosed with an IDHmt tumour.

在2007年12月4日至2015年9月11日期间，共有1407名参与者注册登记，其中751名参与者被随机分配，其中444名被诊断为IDHmt肿瘤。

After a median follow-up for overall survivalof 10·9 years (IQR 9·5-12·7), in the intention-to-treatpopulation, adjuvant temozolomide improved overall survivalcompared with no adjuvant temozolomide (hazard ratio[HR] 0·65 [95% CI 0·54-0·77]), but concurrent did not compared with no concurrent temozolomide (HR 0·91 [0·76-1·08]).

在中位随访总生存期为10.9年（四分位数间距9.5-12.7）后，在意向治疗人群中，辅助性替莫唑胺与未使用辅助性替莫唑胺相比，改善了总生存（风险比[HR] 0.65 [95% 置信区间 0.54-0.77]），而同时使用替莫唑胺与未同时使用替莫唑胺相比，并未改善总生存（HR 0.91 [0.76-1.08]）。

In univariable analysis of the participants with an IDHmt tumour, concurrent temozolomide had no statistically significant effect on overall survival(median 9·7 years [8·2-12·5] vs 7·2 years [6·2-9·4]; HR 0·81 [0·63-1·04]), but median overall survivalwas 12·5 years (95% CI 9·4-15·0) with adjuvant temozolomide compared with 6·0 years (5·1-7·2) with no adjuvant temozolomide (HR 0·54 [0·42-0·69]).

在对IDHmt肿瘤患者进行的单变量分析中，同时使用替莫唑胺对总生存没有统计学上的显著影响（中位生存期9.7年[8.2-12.5]对比7.2年[6.2-9.4]；风险比HR 0.81 [0.63-1.04]），但辅助使用替莫唑胺的中位总生存期为12.5年（95%置信区间9.4-15.0），而未使用辅助替莫唑胺的中位总生存期为6.0年（5.1-7.2）（HR 0.54 [0.42-0.69]）。

No benefit of temozolomide, neither concurrent nor adjuvant, was observed in participants with IDH wild-type tumours.

在IDH野生型肿瘤患者中，无论是同时使用还是辅助使用替莫唑胺，均未观察到其带来的益处。

Methylation-based subtyping and several DNA alterations (eg, amplification of PDGFRA and CDK4, homozygous deletion of CDKN2A, and total copy number variation) were associated with worse outcome, none of which was predictive for benefit to temozolomide.

基于甲基化的亚型分型以及几种DNA改变（例如PDGFRA和CDK4的扩增，CDKN2A的纯合性缺失，以及总的拷贝数变异）与较差的预后相关，但这些均不能预测对替莫唑胺的益处。

interpretation

Long-term follow-up confirms that radiotherapy followed by 12 cycles of adjuvant temozolomide without concurrent temozolomide during radiotherapy improves survival for individuals with aggressive IDHmt astrocytoma.

长期随访证实，对于具有侵袭性IDHmt星形细胞瘤的个体，放疗后接受12个周期的辅助性替莫唑胺治疗，而不进行放疗期间的同步替莫唑胺治疗，可以改善生存。

funding

MSD.

MSD