Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer:: The European Organisation for Research and Treatment of Cancer Chronotherapy group
Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer:: The European Organisation for Research and Treatment of Cancer Chronotherapy group
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DOI：
10.1200/jco.2006.06.1440
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发表时间：
2006-08-01
影响因子：
45.3
通讯作者：
Levi, Francis
中科院分区：
文献类型：
--
作者：
Giacchetti, Sylvie;Bjarnason, Georg;Levi, Francis
目的 在之前的两项随机试验中，与 5 天内恒定速率输注相比，转移性结直肠癌患者根据昼夜节律调整化疗输送可提高耐受性和抗癌活性。 患者和方法 在这项多中心随机试验中，假设氟尿嘧啶、亚叶酸和奥沙利铂的时序调节输注 4 天 (chronoFLO4) 与传统输注相比，可将生存率提高 10%相同药物的 2 天给药 (FOLFOX2)。患者每两周接受一次患者内剂量递增治疗。结果 564 名患者（10 个国家、36 个机构）的双臂基线特征相似。 chronoFLO4 的中位生存期为 19.6 个月（95% 置信限 [CL] 18.2, 21.2），FOLFOX2 的中位生存期为 18.7 个月（95% CL = 17.7, 21.0；P = 0.55）。主要的剂量限制性毒性是 chronoFLO4 的腹泻和 FOLFOX2 的中性粒细胞减少。生存预测因素分析表明，性别是最重要的单一因素 (P = .001)。在女性中，与 FOLFOX2 相比，使用 chronoFLO4 的早期死亡风险增加了 38%，中位生存时间分别为 16.3 个月和 19.1 个月 (P = .03)。在男性中，与 FOLFOX2 相比，chronoFLO4 的死亡风险降低了 25%，中位生存时间分别为 21.4 个月和 18.3 个月 (P = 0.02)。 结论 两种方案均实现了相似的中位生存时间（超过 18 个月），且毒性可接受。对于男性来说，时间调节时间表比 FOLFOX 具有生存优势。氟尿嘧啶、亚叶酸和奥沙利铂的最佳给药方案具有强烈的性别依赖性，因此需要对与患者分子钟相关的决定因素进行转化研究。
Purpose In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer.Patients and Methods For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation.Results Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively.Conclusion Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.