Effect of Concurrent Chemoradiation With Celecoxib vs Concurrent Chemoradiation Alone on Survival Among Patients With Non-Small Cell Lung Cancer With and Without Cyclooxygenase 2 Genetic Variants A Phase 2 Randomized Clinical Trial
Effect of Concurrent Chemoradiation With Celecoxib vs Concurrent Chemoradiation Alone on Survival Among Patients With Non-Small Cell Lung Cancer With and Without Cyclooxygenase 2 Genetic Variants A Phase 2 Randomized Clinical Trial
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DOI：
10.1001/jamanetworkopen.2019.18070
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发表时间：
2019-12-01
影响因子：
13.8
通讯作者：
Wang, Luhua
中科院分区：
文献类型：
--
作者：
Bi, Nan;Liang, Jun;Wang, Luhua
局部晚期非小细胞肺癌(NSCLC)的重要治疗仍然具有挑战性。环氧合酶-2(COX-2)抑制剂联合同步放化疗(CCRT)的基本原理是基于临床前研究和前瞻性临床研究的结果；然而，没有随机临床试验提供证据来直接与单纯CCRT进行比较。目的确定选择性COX-2抑制与标准CCRT联合应用对不能切除的III期NSCLC患者生存的影响。参与者登记时间为2011年11月至2015年8月。对2018年2月至10月的数据进行分析。干预患者随机接受胸部放射治疗，60Gy6周，同时接受依托泊苷和顺铂，或相同方案的CCRT联合200 mg塞来昔布，每日两次。主要结局和衡量标准是总生存期。次要终点是COX-2基因携带者和非COX-2基因携带者中出现治疗相关毒性反应、无进展生存期和总生存期的患者比例。排除4个异常值后，96名参与者(96.0%)被分析(51名随机接受CCRT，45名随机接受CCRT加塞来昔布；平均[SD]年龄60.0[8.3]岁；73.0[76.0%]男性)。接受CCRT联合塞来昔布治疗的中位生存期为32.8(95%CI，17.0~48.5)个月，而单纯接受CCRT的中位生存期为35.5(95%CI，25.8~45.2)个月(P=0.88)。塞来昔布联合CCRT的耐受性良好；接受CCRT和单纯CCRT组的症状性放射性肺炎发生率分别为6.6%(95%CI，1.4%-18.0%)和11.8%(95%CI，4.4%-23.9%)(P=0.49)。在高危基因型的患者中，塞来昔布联合CCRT与单纯CCRT相比，无进展生存率(风险比，0.36；95%CI，0.13-1.04；P=0.05)或总生存率(风险比，0.50；95%CI，0.15-1.72；P=.26)并不相关。结论：在不能切除的III期NSCLC中，在同步放化疗的同时添加塞来昔布并不能提高生存率。与单纯CCRT组相比，CCRT加塞来昔布组患者发生症状性放射性肺炎的比例较小，在统计学上没有显著意义。在高危基因型的患者中，在CCRT中加入塞来昔布并不能改善总体或无进展生存率。
IMPORTANCE Treatment of locally advanced non-small cell lung cancer (NSCLC) remains challenging. The rationale of combining a cyclooxygenase 2 (COX-2) inhibitor with concurrent chemoradiation (CCRT) was based on results of preclinical research and prospective clinical studies; however, no randomized clinical trial has provided evidence of a direct comparison with CCRT alone.OBJECTIVE To determine the effect of combined selective COX-2 inhibition with standard CCRT on survival among patients with unresectable stage III NSCLC.DESIGN, SETTING, AND PARTICIPANTS A single-center, open-label, randomized phase 2 clinical trial was performed among 96 patients who had histologically and cytologically confirmed unresectable stage III NSCLC. Participants were enrolled from November 2011 to August 2015. Data were analyzed from February to October 2018.INTERVENTION Patients were randomized to receive thoracic radiation, 60 Gy, for 6 weeks concurrent with etoposide and cisplatin or the same regimen of CCRT combined with 200 mg of celecoxib, taken twice daily.MAIN OUTCOMES AND MEASURES The primary end point was overall survival. The secondary end points were the proportion of patients with treatment-related toxic effects, progression-free survival, and overall survival in subgroups with and without the COX-2 genotype.RESULTS A total of 100 patients were randomized. Following the exclusion of 4 outliers, 96 participants (96.0%) were analyzed (51 randomized to CCRT alone and 45 randomized to CCRT with celecoxib; mean [SD] age, 60.0 [8.3] years; 73.0 [76.0%] male). The median overall survival time was 32.8 (95% CI, 17.0-48.5) months in the group that received CCRT with celecoxib and 35.5 (95% CI, 25.8-45.2) months in the group that received CCRT alone (P = .88). Celecoxib with CCRT was well tolerated; the incidence of symptomatic radiation pneumonitis was 6.6% (95% CI, 1.4%-18.0%) in the group that received CCRT with celecoxib and 11.8% (95% CI, 4.4%-23.9%) in the group that received CCRT alone (P = .49). Among patients with the high-risk genotype, celecoxib plus CCRT was not associated with higher progression-free survival (hazard ratio, 0.36; 95% CI, 0.13-1.04; P = .05) or overall survival (hazard ratio, 0.50; 95% CI, 0.15-1.72; P = .26) compared with CCRT alone.CONCLUSIONS AND RELEVANCE In unresectable stage III NSCLC, adding celecoxib to concurrent chemoradiation did not improve survival. A smaller, not statistically significant proportion of patients in the CCRT with celecoxib group compared with the CCRT alone group developed symptomatic radiation pneumonitis. Among patients with the high-risk genotype, adding celecoxib to CCRT did not improve overall or progression-free survival.