晚期大肠癌时间化疗研究

1、晚期大肠癌时间化疗研究生物周期节律（circadian rythms）24hday-night rhythm）也称为休息活动周期（rest-activity circadian）具有内生性（endogenicity）恒定性周期基因（circadian genes）调控性功能的周期调控性：日常的生命活动，如睡眠、活动、激素分泌、细胞的增殖和代谢等时间治疗学（chronotherapeutics）：根据细胞生物学周期节律应用治疗药物，以便获得最佳效果的新兴学科时间化疗（chronochemotherapy）： 时间药理学（Chronopharmaclogy)： 时间毒理学(chronotoxico

2、logy) 时间药效学(chronopharmacodynamics) 时间药代动力学(chronopharmacokinetics) 靶组织细胞增殖的周期性 与药物代谢以及细胞周期调控相关酶的节律变化转移性结直肠癌（metastatic colorectal cancer, mCRC）药物时间WBCMSTNVB7h586 d26mg/kg19h3436 dNHL VS 健康人骨髓DNA合成周期的差异Smaaland R, et al. DNA Synthesis and Ploidy in Non-Hodgkins Lymphomas Demonstrate Intrapatient Var

3、iation Depending on Circadian Stage of Cell Sampling. Cancer Research, 1993,53:3129-3138. （N26）（N16）细胞毒药物的时间药理学研究 时间药理学研究：小鼠为动物模型。节律周期：“光照 黑暗”(lightness-darkness)即“休息活动”(rest-activity)昼夜时间单位采用光照后时间（hours after light onset, HALO）来表示由黑暗期向光照期的过渡预示小鼠休息期的开始，大 约相当于人类的2124点氟尿嘧啶（5-fluorouracil, 5-FU） Harris

4、 BE, et al. Relationship between Dihydropyrimidine Dehydrogenase Activity and Plasma 5-FluorouraciI Levels with Evidence for Orcadian Variation of Enzyme Activity and Plasma Drug Levels in Cancer Patients Receiving 5-Fluorouracil by Protracted Continuous Infusion1. Cancer Res.1990,50:197-201. 7例,5-F

5、U 300mg/m2/d /14days civ D1:9am,12am, 6pm, 12pmD2,3: 3am,6am,3pm, 9pmDPD酶5-FU峰谷差值DPD1am1pm2倍5-FU11am11pm5倍采用Cosinor分析奥沙利铂（Oxaliplatin, L-OHP） 常规治疗剂量：在250500ml 5GS中，室温条件稳定24h如果浓度更高（例如3000mg/L）或在蒸馏水中，120h三种形式：总铂（total platinum）、超滤铂或称游离铂(ultrafilterable or “free” platinum)、红细胞铂（erythrocyte platinum)超滤铂

6、是唯一具有生物活性的铂化合物形式。 Levi F, et al. Oxaliplatin Pharmacokinetics and Chronopharmacological Aspects. Clin Pharmacokinet ,2000;38 (1):1-21.18例转移结直肠癌 X4days采血时间：首次在高峰输注时，之后在第1、4天每6h采血1次。总铂超滤铂超滤铂总铂L-OHP chrono + 5-FU civ药代动力学意大利学者的研究 ：13例mCRC治疗方案：5-FU200mg/m2/day, d1-14，x 6L-OHP 正弦10am-10pm，peak time:4pm，d

7、1-4,q14days x 6L-OHP剂量组: 25、30、35 mg/m2/d 每例收集血样15份(在第1、3、6周期 )采血时间：第1,2,3,4天10am, 5pm, 10pm；第5,10,15天10amCattel L, et al. Pharmacokinetic study of oxaliplatin iv chronomodulated infusion combined with 5-fluorouracil iv continuous infusion in the treatment of advanced colorectal cancer. Il Farmaco,2

8、003,58:1333-1338 5-FU的血浆浓度在不同患者、不同周期及不同L-OHP剂量间无显著统计学差异 伊立替康（irinotecan, CPT-11）Granda TG, DAttino RM, Filipski E, et al. circadian optimization of irinotecan and oxaliplatin efficacy in mice with Glasgow osteosarcoma. Br J Cancer. 2002;86:999-1005. 种植Glasgow骨肉瘤细胞小鼠，种植后第天研究CPT-11和L-OHP联合给药时序：均在15 HA

9、LO给药（间隔1分钟）CPT-11：7 HALO；L-OHP：15 HALOCPT-11：15 HALO；L-OHP：7HALO给药时间7HALO19 HALO23 HALO死亡率(给药后2天）0%30%55.5%MST（d)216给药时间3HALO15HALO19 HALO死亡率(给药后2天）22.2%12.5%11.1%MST（d)2330对照组：接种后11-19天全部死亡第1治疗组(CPT-11)第治疗组(L-OHP)单药CPT-11在6个时间点用药的肿瘤抑制情况 单药L-OHP在6个时间点用药的肿瘤抑制情况 CPT-11联合L-OHP最佳时序相对人类， CPT-11高峰浓度：5am；

10、L-OHP ：4pm晚期大肠癌时间化疗的临床研究 晚期大肠癌治疗的基础方案Myao Clinic 方案 5-FU 425mg/m2，CF 20mg/m2,IV d1-d5,q4wRosewell Park 5-FU 500mg/m2，CF 500mg/m2,IV qw6w,休2周De Gramont 5-FU 400mg/m2，IV d1.2 5-FU 1200mg/m2，CIV 46h,CF 200mg/m2,2h d1.2 q2wAIO 5-FU 1500-2000mg/m2， CIV 24h,CF 500mg/m2,IV qw6w,休2周Cure, H. et al. J Clin On

11、col; 20:1175-1181 2002时间化疗对5-FU剂量与疗效的影响？5-FU第1周期：900mg/m2/d第2周期：10 00mg/m2/d第3周期：1100mg/m2/d，连续4天如果出现3度的毒性，则每天剂量降低100mg/m2/dCure, H. et al. J Clin Oncol; 20:1175-1181 2002Fig 2. Median dose-intensity of 5-FU over three, six, or nine courses2000 mg/m2/wk1846 mg/m2/wk1711mg/m2/wkCure, H. et al. J Clin

12、 Oncol; 20:1175-1181 2002Progression-free survival (PFS) overall survival curves of the 100 eligible patientsmPFS ：7mon；MST：17mon(有效者22mon,无效者15mon p=0.015)2,3年生存率分别为28和19Terzoli E, et al.High-dose chronomodulated infusion of 5-fluorouracil (5-FU) and folinic acid (FA) (FF516) in advanced colorectal

13、 cancer patients. J Cancer Res Clin Oncol,2004,130:445452. 5-FU剂量强度与疗效的关系Garufi C,et al. Overcoming resistance to chronomodulated 5-fluorouracil and folinic acid by the addition of chronomodulated oxaliplatin in advanced colorectal cancer patients. Anticancer Drugs, 2000:11:495501Cure H, et al. Phas

14、e II trial of chronomodulated infusion of 5-fluorouracil and folinic acid in metastatic colorectal cancer. Anticancer Res, 2000: 20:46494654Cure H, et al. Phase II trial of chronomodulated infusion of high dose 5-fluorouracil and lfolinic acid in previously untreated patients with metastatic colorec

15、tal cancer.J Clin Oncol, 2002,20:11751181Terzoli E, et al.High-dose chronomodulated infusion of 5-fluorouracil (5-FU) and folinic acid (FA) (FF516) in advanced colorectal cancer patients. J Cancer Res Clin Oncol,2004,130:445452 卡培他滨联合奥沙利铂的时间调节方案 Santini D, Vincenzi B, Schiavon G, et al. Chronomodula

16、ted administration of oxaliplatin plus capecitabine (XELOX) as frst line chemotherapy in advanced colorectal cancer patients: phase II study. Cancer Chemother Pharmacol, 2007; 59:613620. L-OHP：70mg/m2,8am-8pm civ,d1,8卡培他滨: 1750 mg/m2/d8am,6pm,给 1/4 剂量；11pm给1/2 剂量，连续14天, q21daysQvortrup(2008)：卡培他滨时间用

17、药方案联合L-OHP作为二线化疗，对71例CPT-115-FU治疗失败者进行了II期临床研究。有效率为18，PFS 5.1个月，MST 10.2个月不良反应: 23度外周神经毒性分别为25和2.3度腹泻12。 Qvortrup C, Yilmaz M, Ogreid D,et al.Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal

18、 cancer after failure to irinotecan and 5-flourouracilJ. Ann Oncol,2008,9(6):1154-1159. L-OHP 130 mg/m2，d1，下午13时卡培他滨 2000 mg/m2/d总剂量的20%在上午79时、80% 在下午68时应用以奥沙利铂为基础的研究 1997，II chronoFLO4方案 vs FOLFOX2方案 Giacchetti S et al. Phase III Trial Comparing 4-Day Chronomodulated Therapy Versus 2-Day Convention

19、al 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. Clin Oncol,2006,24(22):3562-3569. 10个国家36中心，564例 CPT-11为基础的方案 Garufi C, et al. Randomised phase II study of standard versus chronomodulated CPT-11 plus chronomodulated 5-fluorouracil and folinic acid in advanced colorectal cancer patients. Eur J Cancer. 2006 Mar;42(5):608-16） 68例挽救治疗 有效率 PFS MST标准治疗组 18.2 6个月 18个月时间治疗组 25.7 8个月 28个月1hN=33N=352006年 Gholam的研究 Gholam D, et al. chronomodulated Irino