Lévi F, Zidani R, Misset J L
Hôpital Paul Brousse, Villejuif, France.
Lancet. 1997 Sep 6;350(9079):681-6. doi: 10.1016/s0140-6736(97)03358-8.
The efficacy of chemotherapy may be affected by circadian rhythms. Therefore, we tested chronomodulated infusion (administered to coincide with relevant circadian rhythms) of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method. The combination of three drugs was delivered for 5-day courses with 16-day intervals.
We expected chronotherapy to increase objective response rate by 20% compared with constant-rate infusion. We tested this effect in a randomised multicentre trial involving patients with previously untreated metastases from colorectal cancer who were enrolled at nine institutions in three countries. 93 patients were assigned chronotherapy and 93 were assigned constant-rate infusion via multichannel programmable ambulatory pumps. The trial was interrupted when a significant difference in main outcome was reached. All data were analysed by intention to treat.
On enrollment, we found significant imbalances in two characteristics-abdominal gland or bone metastases (constant-rate infusion two patients, chronotherapy ten patients) and relapse from surgically treated metastases (constant-rate infusion seven patients, chronotherapy 22 patients). An objective response was obtained in 47 (51%) of the chronotherapy group, and in 27 (29%) of the constant-rate group (difference 21.5% [95% CI 13.7-31.2], p = 0.003). Chronotherapy reduced five-fold the rate of severe mucosal toxicity (14% vs 76%, p < 0.0001) and halved that of functional impairment from peripheral sensitive neuropathy (16% vs 31%, difference 15.0% [9.5-25.7], p < 0.01). Median time to treatment failure was 6.4 months on chronotherapy and 4.9 months on constant-rate infusion (p = 0.006), and 24% of the patients from the constant-rate infusion group received chronotherapy after failure. With a minimum follow-up of 3 years, median survival times and 3-year survival were similar in both groups (15.9 vs 16.9 months and 22% vs 21%, respectively).
Chronotherapy was significantly less toxic and more effective than constant-rate infusion. The results support the concept of temporal selectivity of cancer chemotherapy.
化疗疗效可能受昼夜节律影响。因此，我们对奥沙利铂、氟尿嘧啶和亚叶酸钙的时辰调制输注（与相关昼夜节律同步给药）与恒速输注方法进行了比较。三种药物联合给药，疗程为5天，间隔16天。
我们预期时辰疗法相比恒速输注可使客观缓解率提高20%。我们在一项随机多中心试验中对这一效果进行了测试，该试验纳入了来自三个国家九个机构的既往未接受过治疗的结直肠癌转移患者。93例患者被分配接受时辰疗法，93例患者被分配通过多通道可编程便携式泵进行恒速输注。当主要结局出现显著差异时，试验中断。所有数据均按意向性分析。
入组时，我们发现两组在两个特征上存在显著失衡——腹部淋巴结或骨转移（恒速输注组2例患者，时辰疗法组10例患者）以及手术治疗后转移灶复发（恒速输注组7例患者，时辰疗法组22例患者）。时辰疗法组47例（51%）患者获得客观缓解，恒速输注组27例（29%）患者获得客观缓解（差异21.5%[95%CI 13.7 - 31.2]，p = 0.003）。时辰疗法使严重黏膜毒性发生率降低了五倍（14%对76%，p < 0.0001），使外周感觉神经病变导致的功能障碍发生率减半（16%对31%，差异15.0%[9.5 - 25.7]，p < 0.01）。时辰疗法组的中位治疗失败时间为6.4个月，恒速输注组为4.9个月（p = 0.006），恒速输注组24%的患者在治疗失败后接受了时辰疗法。在至少3年的随访中，两组的中位生存时间和3年生存率相似（分别为15.9个月对16.9个月以及22%对21%）。
时辰疗法的毒性显著低于恒速输注且疗效更佳。这些结果支持了癌症化疗的时间选择性概念。
