Ychou Marc, Duffour Jacqueline, Kramar Andrew, Debrigode Charles, Gourgou Sophie, Bressolle Françoise, Pinguet Frédéric
Digestive Oncology Unit, CRLC Val d'Aurelle, Parc Euromédecine, 34298 Montpellier Cedex 5, France.
Cancer Chemother Pharmacol. 2003 Oct;52(4):282-90. doi: 10.1007/s00280-003-0658-0. Epub 2003 Jun 19.
The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers.
A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m2 per day followed by a 5-FU bolus 400 mg/m2 per day and a 22-h 5-FU continuous infusion 600 mg/m2 per day for two consecutive days every 2 weeks), and the AUC in mg.h/l.m2 was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC < or =5, by 100% for AUC >5-10, by 50% for AUC >10-15, and by 25% for AUC >15-20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program.
Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5-1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23-50%) in the intention-to-treat population and 47% (95% CI 29-65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient).
This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.
本II期研究旨在确定每两个月一次、药代动力学强化的LV5FU2方案治疗转移性结直肠癌的疗效和耐受性。
共有53例患者（23%为二线治疗；25例男性/28例女性；平均年龄67岁；38例患者世界卫生组织体能状态为0，10例为1，5例为2）在第1周期接受标准LV5FU2方案治疗（亚叶酸钙200mg/m²/天，随后5-氟尿嘧啶推注400mg/m²/天，22小时持续输注600mg/m²/天，每2周连续2天），并计算mg.h/l.m²的曲线下面积（AUC）。对于第2周期，根据预先定义的时间表，取决于第1周期的AUC值，在无3级毒性的情况下，当AUC≤5时，5-氟尿嘧啶输注剂量增加150%；当AUC＞5至10时，增加100%；当AUC＞10至15时，增加50%；当AUC＞15至20时，增加25%。使用高效液相色谱法测定5-氟尿嘧啶血浆浓度。使用NONMEM计算机程序，采用贝叶斯方法评估个体药代动力学参数。
在53例符合条件的患者中，87%（符合方案人群）在第2周期接受了增加剂量，72%接受了相同剂量。与未调整的理论总5-氟尿嘧啶剂量相比，相对剂量强度中位数为1.28（范围0.5 - 1.54）。意向性分析人群的客观缓解率为37%（95%可信区间23 - 50%），一线符合方案人群为47%（95%可信区间29 - 65%）。缓解持续时间中位数为10.4个月。无进展生存期（PFS）和总生存期（OS）中位数分别为7个月和18.6个月。一线符合方案患者的PFS和OS分别为9.2个月和20个月。尽管给予了高剂量的5-氟尿嘧啶，但无死亡归因于其毒性。53例患者中，19%出现胃肠道毒性，30%出现血液学3/4级毒性。手足综合征常见但程度较轻（1例患者为3级）。
该策略可在III期试验中与标准LV5FU2方案进行比较。
