Lévi F, Giacchetti S, Adam R, Zidani R, Metzger G, Misset J L
Centre de Chronothérapie, Villejuif, France.
Eur J Cancer. 1995 Jul-Aug;31A(7-8):1264-70. doi: 10.1016/0959-8049(95)00242-b.
Toxic effects of 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), two active drugs against metastatic colorectal cancer, varied by 50% or more according to circadian dosing time in mice or rats. Adaptation of chemotherapy delivery to circadian rhythms (chronotherapy) was assessed in fully ambulatory outpatients, using multichannel programmable pumps. These devices allowed us to reliably test the clinical relevance of such a chronotherapy principle. First, single agent 5-day chronomodulated schedules were devised and assessed in Phase I and II trials with 5-fluorouracil (5-FU, peak delivery at 4:00 h) or oxaliplatin (L-OHP, peak at 16:00 h). Both schedules were then combined, folinic acid (FA) being added, synchronous with 5-FU infusion. This three-drug chronomodulated regimen (chrono-FFL) produced a 58% response rate (95% C.I.: 48-68%) in 93 patients with metastatic colorectal cancer, 46 of whom had previously received chemotherapy. In the first European randomised trial in 92 previously untreated patients, chronomodulated three-drug delivery achieved 53% response, as compared to 32% in those patients receiving flat infusion (P = 0.038). These respective figures were confirmed in a subsequent multicentre randomised trial involving 186 additional patients. Since the most active schedule was also the least toxic one by 2- to 10-fold, chrono-FFL was further intensified in three consecutive Phase II trials involving a total of 200 additional patients. Results suggest that both response rate and quality were further improved with such treatment intensification. Thus, chrono-FFL more than doubled the activity of chemotherapy against metastatic colorectal cancer in a multicentre European setting.(ABSTRACT TRUNCATED AT 250 WORDS)
5-氟尿嘧啶（5-FU）和奥沙利铂（L-OHP）是两种治疗转移性结直肠癌的活性药物，在小鼠或大鼠中，根据昼夜给药时间的不同，其毒性作用相差50%或更多。在完全可自由活动的门诊患者中，使用多通道可编程泵评估了化疗给药与昼夜节律的适配性（时间疗法）。这些装置使我们能够可靠地测试这种时间疗法原则的临床相关性。首先，在I期和II期试验中设计并评估了单药5天时间调制方案，使用5-氟尿嘧啶（5-FU，给药高峰在4:00）或奥沙利铂（L-OHP，高峰在16:00）。然后将这两种方案联合起来，同时加入亚叶酸（FA），与5-FU输注同步。这种三药时间调制方案（chrono-FFL）在93例转移性结直肠癌患者中产生了58%的缓解率（95%置信区间：48-68%），其中46例患者此前接受过化疗。在第一项针对92例未接受过治疗患者的欧洲随机试验中，时间调制的三药给药方案的缓解率为53%，而接受固定输注的患者为32%（P = 0.038）。在随后一项纳入186例额外患者的多中心随机试验中，这些数据得到了证实。由于最有效的方案毒性也是最低的，毒性相差2至10倍，因此在三项连续的II期试验中对chrono-FFL进行了进一步强化，共纳入200例额外患者。结果表明，这种治疗强化进一步提高了缓解率和治疗质量。因此，在欧洲多中心环境中，chrono-FFL使化疗对转移性结直肠癌的活性提高了一倍多。（摘要截选至250字）
