Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial
Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial
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DOI：
10.1016/j.ejca.2015.12.009
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发表时间：
2016-03-01
影响因子：
8.4
通讯作者：
Stenner-Liewen, Frank
中科院分区：
文献类型：
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作者：
Meisel, Alexander;von Felten, Stefanie;Stenner-Liewen, Frank
背景资料：卡巴他赛显著改善多西他赛治疗期间或治疗后进展的转移性去势抵抗性前列腺癌（mCRPC）男性患者的总生存期（OS），但与多西他赛相比，卡巴他赛与≥ 3级中性粒细胞减少症的发生率较高相关。因此，我们研究卡巴他赛诱导的≥ 3级中性粒细胞减少症，基线嗜中性粒细胞-淋巴细胞比率（NLR）和治疗outcomes.Methods：从TROPIC 3期试验的实验臂的数据，随机分配男性mCRPC卡巴他赛或米托蒽醌每3周，都结合每日泼尼松，进行了分析。使用考克斯回归模型研究卡巴他赛治疗期间至少一次≥ 3级中性粒细胞减少症发作对OS（主要终点）和无进展生存期（PFS）的影响，校正基线疼痛。还分析了卡巴他赛治疗期间前列腺特异性抗原（PSA）应答与基线NLR的关系。卡巴他赛治疗期间≥ 3级中性粒细胞减少症的发生与OS延长相关（中位16.3 vs 14.0个月，风险比（HR）[95%置信区间] = 0.65 [0.43-0.97]，p = 0.035），PFS延长两倍（中位数5.3 vs 2.6个月，HR = 0.56 [0.40-0.79]，p = 0.001）和较高的确认PSA应答≥ 50%（49.8% vs 24.4%，p = 0.005），与未发生≥ 3级中性粒细胞减少的患者相比。在基线NLR = 3的情况下，≥ 3级中性粒细胞减少症更常见（88.8% vs 75.3%，p = 0.002）。基线时低NLR和治疗期间≥ 3级中性粒细胞减少与最长OS（中位数19.2个月）相关，而基线时高NLR和无≥ 3级中性粒细胞减少与较差OS相关（中位数12.9个月，HR 0.46 [0.28-0.76]，p = 0.002）。在血小板减少症患者亚组中，用粒细胞集落刺激因子（G-CSF）治疗的患者的中位OS为19.7个月，而不用G-CSF支持的患者的中位OS为16个月。基线NLR低的患者在卡巴他赛治疗期间更可能发生≥ 3级中性粒细胞减少症，并显示最长的OS。基线NLR高且治疗期间无≥ 3级中性粒细胞减少症与不良结局相关，这可能表明药物暴露不足或对肿瘤相关免疫应答的影响有限。一级或二级预防性使用G-CSF对结局无不良影响。如果得到前瞻性证实，这些结果将证明在可能的情况下维持卡巴他赛25 mg/m2的预期剂量是合理的。(C)2015爱思唯尔有限公司版权所有。
Background: Cabazitaxel significantly improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel, but is associated with a higher rate of grade >= 3 neutropenia compared with docetaxel. We thus examined the relationship between cabazitaxel-induced grade >= 3 neutropenia, baseline neutrophil-lymphocyte ratio (NLR) and treatment outcomes.Methods: Data from the experimental arm of the TROPIC phase 3 trial which randomly assigned men with mCRPC to cabazitaxel or mitoxantrone every 3 weeks, both combined with daily prednisone, were analysed. The influence on OS (primary end-point) and progression-free survival (PFS) of at least one episode of grade >= 3 neutropenia during cabazitaxel therapy was investigated using Cox regression models, adjusted for pain at baseline. The relationships with prostate-specific antigen (PSA) responses during cabazitaxel therapy and baseline NLR were also analysed.Findings: The occurrence of grade >= 3 neutropenia during cabazitaxel therapy was associated with a prolonged OS (median 16.3 versus 14.0 months, hazard ratio (HR) [95% confidence interval] = 0.65 [0.43-0.97], p = 0.035), a twice longer PFS (median 5.3 versus 2.6 months, HR = 0.56 [0.40-0.79], p = 0.001) and a higher confirmed PSA response >= 50% (49.8% versus 24.4%, p = 0.005), as compared with patients who did not develop grade >= 3 neutropenia. Grade >= 3 neutropenia was more common in case of NLR = 3 at baseline (88.8% versus 75.3%, p = 0.002). Combining low NLR at baseline and grade >= 3 neutropenia during therapy was associated with the longest OS (median 19.2 months) while high NLR at baseline and no grade >= 3 neutropenia was associated with a poor OS (median 12.9 months, HR 0.46 [0.28-0.76], p = 0.002). In the subgroup of neutropenic patients the median OS was 19.7 months in those treated with granulocyte colony-stimulating factor (G-CSF) and 16 months on those without G-CSF support.Interpretation: This post-hoc analysis of TROPIC suggests that the occurrence of grade >= 3 neutropenia with cabazitaxel is associated with improved OS and PFS. Patients with a low NLR at baseline were more likely to develop grade >= 3 neutropenia during cabazitaxel therapy and showed the longest OS. High NLR at baseline and no grade >= 3 neutropenia during therapy was associated with poor outcomes which may suggest insufficient drug exposure or a limited impact on the tumour-associated immune response. Primary or secondary prophylactic use of G-CSF had no adverse impact for outcome. If prospectively confirmed, these results would justify maintaining the intended cabazitaxel dose of 25 mg/m(2) whenever possible. (C) 2015 Elsevier Ltd. All rights reserved.