Di Maio Massimo, Gridelli Cesare, Gallo Ciro, Shepherd Frances, Piantedosi Franco Vito, Cigolari Silvio, Manzione Luigi, Illiano Alfonso, Barbera Santi, Robbiati Sergio Federico, Frontini Luciano, Piazza Elena, Ianniello Giovanni Pietro, Veltri Enzo, Castiglione Federico, Rosetti Francesco, Gebbia Vittorio, Seymour Lesley, Chiodini Paolo, Perrone Francesco
National Cancer Institute, Naples, Italy.
Lancet Oncol. 2005 Sep;6(9):669-77. doi: 10.1016/S1470-2045(05)70255-2.
Chemotherapy is the standard treatment for advanced non-small-cell lung cancer, and myelosuppression is a common side-effect. We aimed to assess whether haematological toxic effects could be a biological measure of drug activity and a marker of efficacy.
We analysed data for 1265 patients who received chemotherapy (vinorelbine, gemcitabine, gemcitabine and vinorelbine, cisplatin and vinorelbine, or cisplatin and gemcitabine) within three randomised trials. Primary landmark analyses were restricted to 436 patients who received all six planned chemotherapy cycles and who were alive 180 days after randomisation. Neutropenia was categorised on the basis of worst WHO grade during chemotherapy: absent (grade 0), mild (grade 1-2), or severe (grade 3-4). All statistical analyses were stratified by treatment allocation. Analyses were repeated in the out-of-landmark group (829 patients), stratifying by treatment allocation and number of chemotherapy cycles. The primary endpoint was overall survival.
In the landmark group, hazard ratios of death were 0.65 (0.46-0.93) for patients with severe neutropenia and 0.74 (0.56-0.98) for those with mild neutropenia. Median survival after the landmark time of 180 days was 31.4 weeks (95% CI 25.7-39.6) for patients without neutropenia compared with 42.0 weeks (32.7-59.7) for patients with severe neutropenia, and with 43.7 weeks (36.6-66.0) for those with mild neutropenia (severe vs mild vs no neutropenia p=0.0118). Findings were much the same for the out-of-landmark group.
Neutropenia during chemotherapy is associated with increased survival of patients with advanced non-small-cell lung cancer, and its absence might be a result of underdosing. Prospective trials are needed to assess whether drug dosing guided by the occurrence of toxic effects could improve efficacy of standard regimens.
化疗是晚期非小细胞肺癌的标准治疗方法，骨髓抑制是常见的副作用。我们旨在评估血液学毒性效应是否可能是药物活性的生物学指标和疗效标志物。
我们分析了三项随机试验中1265例接受化疗（长春瑞滨、吉西他滨、吉西他滨与长春瑞滨、顺铂与长春瑞滨或顺铂与吉西他滨）患者的数据。主要标志性分析仅限于436例接受了所有六个计划化疗周期且随机分组后存活180天的患者。中性粒细胞减少症根据化疗期间最差的世界卫生组织分级进行分类：无（0级）、轻度（1 - 2级）或重度（3 - 4级）。所有统计分析均按治疗分配进行分层。在非标志性组（829例患者）中重复分析，按治疗分配和化疗周期数进行分层。主要终点是总生存期。
在标志性组中，重度中性粒细胞减少症患者的死亡风险比为0.65（0.46 - 0.93），轻度中性粒细胞减少症患者为0.74（0.56 - 0.98）。在180天的标志性时间后，无中性粒细胞减少症患者的中位生存期为31.4周（95%CI 25.7 - 39.6），重度中性粒细胞减少症患者为42.0周（32.7 - 59.7），轻度中性粒细胞减少症患者为43.7周（36.6 - 66.0）（重度 vs 轻度 vs 无中性粒细胞减少症，p = 0.0118）。非标志性组的结果大致相同。
化疗期间的中性粒细胞减少症与晚期非小细胞肺癌患者生存率的提高相关，而无中性粒细胞减少症可能是给药不足的结果。需要进行前瞻性试验来评估以毒性效应的发生为指导的药物给药是否能提高标准方案的疗效。
