Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Celecoxib in Addition to Standard Chemotherapy for Advanced Non-Small-Cell Lung Cancer With Cyclooxygenase-2 Overexpression: CALGB 30801 (Alliance)
Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Celecoxib in Addition to Standard Chemotherapy for Advanced Non-Small-Cell Lung Cancer With Cyclooxygenase-2 Overexpression: CALGB 30801 (Alliance)
复制标题
DOI：
10.1200/jco.2016.71.3743
复制
发表时间：
2017-07-01
影响因子：
45.3
通讯作者：
Vokes, Everett E.
中科院分区：
文献类型：
--
作者：
Edelman, Martin J.;Wang, Xiaofei;Vokes, Everett E.
目的环氧化酶-2 （COX-2）肿瘤过表达与非小细胞肺癌（NSCLC）预后较差相关。在癌症和白血病B组（CALGB） 30203中，我们发现选择性COX-2抑制剂塞来昔布在晚期非小细胞肺癌的化疗之外，通过免疫组织化学（IHC）改善了中度至高COX-2表达患者的无进展和总生存期。CALGB 30801（联盟）旨在前瞻性地证实这一发现。患者和方法非小细胞肺癌患者（IIIB期合并胸腔积液或根据美国癌症联合委员会[第六版]标准的IV期）预先登记，活检标本通过免疫组化分析COX-2。COX-2表达>= 2，运动状态0 ~ 2，器官功能正常的患者入选。化疗由组织学决定：卡铂加培美曲塞治疗非鳞状NSCLC，卡铂加吉西他滨治疗鳞状组织学。患者被随机分配到塞来昔布组（400毫克，每天两次；A组）或安慰剂组（B组）。主要目的是证明COX-2指数>= 4的患者无进展生存期的改善，风险比为0.645，双侧显著性水平为0.05，功率约为85%。结果在计划的322例COX-2指数>= 2的患者中有312例被随机分配后，研究因无效而终止。两组间差异无统计学意义（COX-2 bb0 = 4的风险比为1.046）。评估组织学、化疗方案和增加COX-2表达的亚组分析没有显示COX-2抑制的任何优势。前列腺素E2基线尿代谢物升高，表明COX-2通路激活，是一个负面预后因素。高于第三个四分位数的值可能是一个预测因素。结论免疫组化法检测COX-2表达并不能筛选出选择性抑制COX-2的患者。前列腺素E2的尿代谢物可能能够识别可能受益于COX-2抑制的患者。(C) 2017年由美国临床肿瘤学会出版
PurposeTumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non-small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding.Patients and MethodsPatients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression >= 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index >= 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05.ResultsThe study was halted for futility after 312 of the planned 322 patients with COX-2 index >= 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 >= 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor.ConclusionCOX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition. (C) 2017 by American Society of Clinical Oncology