疲劳和体重减轻可预测转移性结直肠癌昼夜节律化疗的生存情况。

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.

机构信息

National Institute for Health and Medical Research (INSERM) Unit 776, "Biological Rhythms and Cancers," Villejuif, France.

出版信息

Cancer. 2013 Jul 15;119(14):2564-73. doi: 10.1002/cncr.28072. Epub 2013 Apr 30.

DOI:10.1002/cncr.28072

PMID:23633399

Abstract

BACKGROUND

Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy.

METHODS

Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS).

RESULTS

The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively.

CONCLUSIONS

Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.

摘要

背景

化疗引起的中性粒细胞减少症与生存时间延长有关，这种现象选择性地出现在接受常规方案（联合氟尿嘧啶、亚叶酸钙和奥沙利铂[FOLFOX2]）治疗的患者中，但在接受相同药物的节律调制方案（chronoFLO4）治疗的患者中则没有。作者假设，化疗引起的症状的早期发生与昼夜节律紊乱相关，这种紊乱会选择性地阻碍节律治疗的疗效。

方法

根据先前的数据，疲劳和体重减轻（FWL）被认为与昼夜节律紊乱有关。来自一项国际 3 期试验的转移性结直肠癌患者（n=543），比较了 FOLFOX2 与 chronoFLO4，根据化疗初始 2 个疗程中 FWL 或其他临床相关毒性的发生情况，将患者分为 4 个亚组。使用多变量 Cox 模型评估毒性对无进展生存期（TTP）和总生存期（OS）的作用。

结果

在两个治疗组中，4 个亚组的患者比例相当（P=0.77）。在 FOLFOX2 组中，无毒性与 TTP 或 OS 相关。在 FOLFOX2 组中，根据毒性亚组，中位 OS 范围为 16.4（95%置信区间[CL]，7.2-25.6 个月）至 19.8 个月（95% CL，17.7-22.0 个月）（P=0.45）。相反，FWL 但无其他毒性，独立预测 chronoFLO4 治疗的 TTP（P<0.0001）和 OS（P=0.001）显著缩短。在 chronoFLO4 组中，中位 OS 分别为 13.8 个月（95% CL，10.4-17.2 个月）或 21.1 个月（95% CL，19.0-23.1 个月），分别根据是否存在化疗引起的 FWL。