Meisel Alexander, von Felten Stefanie, Vogt Deborah R, Liewen Heike, de Wit Ronald, de Bono Johann, Sartor Oliver, Stenner-Liewen Frank
Department of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland; Department of Internal Medicine, Stadtspital Waid, Tièchestrasse 99, 8037 Zurich, Switzerland.
Clinical Trial Unit, CTU, University Hospital of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland.
Eur J Cancer. 2016 Mar;56:93-100. doi: 10.1016/j.ejca.2015.12.009. Epub 2016 Jan 30.
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.
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.
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 as compared with 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.
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.
卡巴他赛可显著改善多西他赛治疗期间或之后疾病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≥3级中性粒细胞减少症发生率高于多西他赛相关。因此，我们研究了卡巴他赛诱导的≥3级中性粒细胞减少症、基线中性粒细胞与淋巴细胞比值（NLR）和治疗结果之间的关系。
分析了TROPIC 3期试验实验组的数据，该试验将mCRPC男性患者随机分为每3周接受卡巴他赛或米托蒽醌治疗，两者均联合每日服用泼尼松。使用Cox回归模型研究卡巴他赛治疗期间至少发生一次≥3级中性粒细胞减少症对OS（主要终点）和无进展生存期（PFS）的影响，并对基线疼痛进行校正。还分析了卡巴他赛治疗期间与前列腺特异性抗原（PSA）反应及基线NLR的关系。
与未发生≥3级中性粒细胞减少症的患者相比，卡巴他赛治疗期间发生≥3级中性粒细胞减少症与OS延长（中位时间16.3个月对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（中位时间5.3个月对2.6个月，HR = 0.56[0.40 - 0.79]，p = 0.001）及确认的PSA反应≥50%的比例更高（49.8%对24.4%，p = 0.005）相关。与基线NLR≥3相比，基线NLR<3时≥3级中性粒细胞减少症更常见（88.8%对75.3%，p = 0.002）。基线NLR低且治疗期间发生≥3级中性粒细胞减少症与最长OS（中位时间19.2个月）相关，而基线NLR高且未发生≥3级中性粒细胞减少症与较差的OS（中位时间12.9个月，HR 0.46[0.28 - 0.76]，p = 0.002）相关。在中性粒细胞减少症患者亚组中，接受粒细胞集落刺激因子（G - CSF）治疗的患者中位OS为19.7个月，未接受G - CSF支持的患者为16个月。
TROPIC的这项事后分析表明，卡巴他赛导致的≥3级中性粒细胞减少症的发生与OS和PFS改善相关。基线NLR低的患者在卡巴他赛治疗期间更有可能发生≥3级中性粒细胞减少症，且OS最长。基线NLR高且治疗期间未发生≥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反应的影响有限。预防性使用G - CSF（一级或二级预防）对结局无不良影响。如果能前瞻性地得到证实，这些结果将证明尽可能维持卡巴他赛25mg/m²的目标剂量是合理的。
