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完全切除的非小细胞肺癌且伴有确证性纵隔 N2 转移患者的术后放疗与无术后放疗(LungART):一项开放标签、随机、3 期临床试验。

Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.

机构信息

Department of Radiation Oncology, Gustave Roussy, Villejuif, France.

Radiation Oncology, Institut Sainte Catherine, Avignon, France.

出版信息

Lancet Oncol. 2022 Jan;23(1):104-114. doi: 10.1016/S1470-2045(21)00606-9. Epub 2021 Dec 15.


DOI:10.1016/S1470-2045(21)00606-9
PMID:34919827
Abstract

BACKGROUND: In patients with non-small-cell lung cancer (NSCLC), the use of postoperative radiotherapy (PORT) has been controversial since 1998, because of one meta-analysis showing a deleterious effect on survival in patients with pN0 and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many changes have occurred in the management of patients with NSCLC, the role of three-dimensional (3D) conformal PORT warrants further investigation in patients with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT should be part of their standard treatment. METHODS: Lung ART is an open-label, randomised, phase 3, superiority trial comparing mediastinal PORT to no PORT in patients with NSCLC with complete resection, nodal exploration, and cytologically or histologically proven N2 involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients aged 18 years or older, with an WHO performance status of 0-2, were recruited from 64 hospitals and cancer centres in five countries (France, UK, Germany, Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the PORT or no PORT (control) groups via a web randomisation system, and minimisation factors were the institution, administration of chemotherapy, number of mediastinal lymph node stations involved, histology, and use of pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30 daily fractions, on five consecutive days a week. Three dimensional conformal radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted in centres with expertise. The primary endpoint was disease-free survival, analysed by intention to treat at 3 years; patients from the PORT group who did not receive radiotherapy and patients from the control group with no follow-up were excluded from the safety analyses. This trial is now closed. This trial is registered with ClinicalTrials.gov number, NCT00410683. FINDINGS: Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly staged with F-fluorodeoxyglucose (F-FDG) PET (456 [91%]; 232 (92%) in the PORT group and 224 (90%) in the control group), were enrolled and randomly assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9-7·0). 3-year disease-free survival was 47% (95% CI 40-54) with PORT versus 44% (37-51) without PORT, and the median disease-free survival was 30·5 months (95% CI 24-49) in the PORT group and 22·8 months (17-37) in the control group (hazard ratio 0·86; 95% CI 0·68-1·08; p=0·18). The most common grade 3-4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3-4 cardiopulmonary toxicity was reported in 26 patients (11%) in the PORT group versus 12 (5%) in the control group. Two patients died from pneumonitis, partly related to radiotherapy and infection, and one patient died due to chemotherapy toxicity (sepsis) that was deemed to be treatment-related, all of whom were in the PORT group. INTERPRETATION: Lung ART evaluated 3D conformal PORT after complete resection in patients who predominantly had been staged using (F-FDG PET-CT and received neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher than expected in both groups, but PORT was not associated with an increased disease-free survival compared with no PORT. Conformal PORT cannot be recommended as the standard of care in patients with stage IIIAN2 NSCLC. FUNDING: French National Cancer Institute, Programme Hospitalier de Recherche Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK, Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer Research Foundation, Swiss Cancer League.

摘要

背景:自 1998 年以来,对于非小细胞肺癌(NSCLC)患者,术后放疗(PORT)的使用一直存在争议,因为一项荟萃分析显示,对于 pN0 和 pN1 的患者,PORT 对生存有不利影响,但对 pN2 NSCLC 的患者影响不明确。由于 NSCLC 患者的治疗管理发生了许多变化,因此需要进一步研究三维(3D)适形 PORT 在 IIIAN2 NSCLC 患者中的作用。本研究旨在确定 PORT 是否应该作为其标准治疗的一部分。

方法:Lung ART 是一项开放性、随机、III 期、优效性临床试验,比较了纵隔 PORT 与无 PORT 在完全切除、淋巴结探查、经细胞学或组织学证实 N2 受累的 NSCLC 患者中的疗效。允许患者接受新辅助或辅助化疗。年龄在 18 岁或以上,世界卫生组织表现状态为 0-2 分的患者,从五个国家(法国、英国、德国、瑞士和比利时)的 64 家医院和癌症中心招募。患者通过网络随机系统以 1:1 的比例随机分配到 PORT 组或无 PORT(对照组),最小化因素为机构、化疗的使用、纵隔淋巴结站受累的数量、组织学和治疗前 PET 扫描的使用。PORT 组患者接受 54 Gy 的剂量,在每周 5 天连续 27 或 30 个每日剂量。强制性采用三维适形放疗,有专业知识的中心可以使用调强放疗。主要终点是无病生存期,3 年时进行意向治疗分析;PORT 组未接受放疗的患者和对照组无随访的患者被排除在安全性分析之外。本试验现已关闭。本试验在 ClinicalTrials.gov 注册号为 NCT00410683。

结果:2007 年 8 月 7 日至 2018 年 7 月 17 日,共招募了 501 例患者,主要采用 F-氟脱氧葡萄糖(F-FDG)PET(456 例[91%];PORT 组 232 例[92%],对照组 224 例[90%])分期,随机分配接受 PORT(252 例)或无 PORT(249 例)。在 2019 年 5 月 31 日的截止日期,中位随访时间为 4.8 年(IQR 2.9-7.0)。PORT 组 3 年无病生存率为 47%(95%CI 40-54),无 PORT 组为 44%(37-51),PORT 组的中位无病生存期为 30.5 个月(95%CI 24-49),对照组为 22.8 个月(17-37)(风险比 0.86;95%CI 0.68-1.08;p=0.18)。最常见的 3-4 级不良事件是肺炎(PORT 组 241 例中有 13 例[5%],对照组 246 例中有 1 例[<1%])、淋巴细胞减少症(9 例[4%])和疲劳(6 例[3%])。PORT 组有 26 例(11%)患者报告了晚期 3-4 级心肺毒性,对照组有 12 例(5%)患者报告了晚期 3-4 级心肺毒性。两名患者因肺炎部分与放疗和感染有关而死亡,一名患者因与化疗毒性(败血症)有关而死亡,这些患者均在 PORT 组。

结论:Lung ART 在主要使用(F-FDG PET-CT 分期并接受新辅助或辅助化疗的患者中,评估了完全切除后的 3D 适形 PORT。两组的 3 年无病生存率均高于预期,但 PORT 与无 PORT 相比,无病生存率并未增加。适形 PORT 不能作为 IIIAN2 NSCLC 患者的标准治疗方法。

资金来源:法国国家癌症研究所、法国卫生部的临床研究计划、古斯塔夫·鲁西癌症研究所、英国癌症研究协会、瑞士联邦教育、研究和创新部、瑞士癌症研究基金会、瑞士癌症联盟。

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