Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
复制标题
DOI：
10.1016/s1470-2045(16)30532-0
复制
发表时间：
2016-12
期刊：
影响因子：
51.1
通讯作者：
Heymach, John V.
中科院分区：
文献类型：
--
作者：
Gomez, Daniel R.;Blumenschein, George R., Jr.;Lee, J. Jack;Hernandez, Mike;Ye, Rong;Camidge, D. Ross;Doebele, Robert C.;Skoulidis, Ferdinandos;Gaspar, Laurie E.;Gibbons, Don L.;Karam, Jose A.;Kavanagh, Brian D.;Tang, Chad;Komaki, Ritsuko;Louie, Alexander V.;Palma, David A.;Tsao, Anne S.;Sepesi, Boris;William, William N.;Zhang, Jianjun;Shi, Qiuling;Wang, Xin Shelley;Swisher, Stephen G.;Heymach, John V.
回顾性证据表明，转移性非小细胞肺癌（NSCLC）一线化疗后的疾病进展最常发生在基线时已知存在的疾病部位。然而，侵袭性局部巩固治疗（LCT）对寡转移性NSCLC患者的无进展生存期（PFS）的潜在获益尚不清楚。我们进行了一项多中心随机研究（NCT 01725165;目前正在进行但未招募参与者），以评估LCT对无进展生存期（PFS）的影响。符合条件的患者包括：（1）组织学确诊为IV期NSCLC，（2）全身治疗后≤3个病变部位，（3）随机分组前无疾病进展。对于EGFR突变或ALK重排患者，一线治疗为≥4个周期的铂双药治疗或≥3个月的表皮生长因子受体（EGFR）或间变性淋巴瘤激酶（ALK）抑制剂。患者随机接受LCT（[化疗]放疗或切除所有病变）+/−维持治疗与仅维持治疗/观察。根据批准的治疗方案列表推荐维持治疗，观察定义为密切监测，无细胞毒性治疗。随机化不设盲，并根据5个因素进行动态平衡：转移瘤数量、初始治疗缓解、中枢神经系统转移、胸内淋巴结状态和EGFR/ALK状态。主要终点是PFS，使用意向治疗分析，有把握度检测从4个月增加至7个月（风险比[HR]=0.57）。计划研究94例随机患者，对44例事件进行中期分析。采用对数秩检验比较两组的PFS、总生存期（OS）和至发生新病变的时间。49例患者治疗后提前终止研究（LCT组25例，对照组24例），当PFS的中位随访时间为18.7个月时，LCT组的中位PFS时间为11.9个月（90%置信区间[CI] 5.72，20.90）与维持组3.9个月（90% CI 2.30，6.64）（HR=0.35，90% CI 0.18，0.66，对数秩p=0.005）。两组之间的毒性相似，没有4-5级事件。维持治疗组的3级或以上不良事件为疲乏（n=1）和贫血（n=1）。在LCT组中，3级事件为：食管炎（n=2）、贫血（n=1）、气胸（n=1）和腹痛（n=1）。总体生存数据尚不成熟，仅记录了14例死亡。对于初始全身治疗后未进展的NSCLC转移≤3例的患者，LCT +/−维持治疗相对于单独维持治疗可改善PFS。这些发现意味着，积极的局部治疗应进一步探讨在III期临床试验作为标准的治疗方案在这种情况下。
Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.