晚期大腸癌時(shí)間化療研究

1、晚期大腸癌時(shí)間化療研究生物周期節(jié)律（circadian rythms）24hday-night rhythm）也稱為休息活動(dòng)周期（rest-activity circadian）具有內(nèi)生性（endogenicity）恒定性周期基因（circadian genes）調(diào)控性功能的周期調(diào)控性：日常的生命活動(dòng)，如睡眠、活動(dòng)、激素分泌、細(xì)胞的增殖和代謝等時(shí)間治療學(xué)（chronotherapeutics）：根據(jù)細(xì)胞生物學(xué)周期節(jié)律應(yīng)用治療藥物，以便獲得最佳效果的新興學(xué)科時(shí)間化療（chronochemotherapy）： 時(shí)間藥理學(xué)（Chronopharmaclogy)： 時(shí)間毒理學(xué)(chronotoxico

2、logy) 時(shí)間藥效學(xué)(chronopharmacodynamics) 時(shí)間藥代動(dòng)力學(xué)(chronopharmacokinetics) 靶組織細(xì)胞增殖的周期性 與藥物代謝以及細(xì)胞周期調(diào)控相關(guān)酶的節(jié)律變化轉(zhuǎn)移性結(jié)直腸癌（metastatic colorectal cancer, mCRC）藥物時(shí)間WBCMSTNVB7h586 d26mg/kg19h3436 dNHL VS 健康人骨髓DNA合成周期的差異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）細(xì)胞毒藥物的時(shí)間藥理學(xué)研究 時(shí)間藥理學(xué)研究：小鼠為動(dòng)物模型。節(jié)律周期：“光照 黑暗”(lightness-darkness)即“休息活動(dòng)”(rest-activity)晝夜時(shí)間單位采用光照后時(shí)間（hours after light onset, HALO）來表示由黑暗期向光照期的過渡預(yù)示小鼠休息期的開始，大 約相當(dāng)于人類的2124點(diǎn)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分析奧沙利鉑（Oxaliplatin, L-OHP） 常規(guī)治療劑量：在250500ml 5GS中，室溫條件穩(wěn)定24h如果濃度更高（例如3000mg/L）或在蒸餾水中，120h三種形式：總鉑（total platinum）、超濾鉑或稱游離鉑(ultrafilterable or “free” platinum)、紅細(xì)胞鉑（erythrocyte platinum)超濾鉑

6、是唯一具有生物活性的鉑化合物形式。 Levi F, et al. Oxaliplatin Pharmacokinetics and Chronopharmacological Aspects. Clin Pharmacokinet ,2000;38 (1):1-21.18例轉(zhuǎn)移結(jié)直腸癌 X4days采血時(shí)間：首次在高峰輸注時(shí)，之后在第1、4天每6h采血1次?？傘K超濾鉑超濾鉑總鉑L-OHP chrono + 5-FU civ藥代動(dòng)力學(xué)意大利學(xué)者的研究 ：13例mCRC治療方案：5-FU200mg/m2/day, d1-14，x 6L-OHP 正弦10am-10pm，peak time:4pm，d

7、1-4,q14days x 6L-OHP劑量組: 25、30、35 mg/m2/d 每例收集血樣15份(在第1、3、6周期 )采血時(shí)間：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的血漿濃度在不同患者、不同周期及不同L-OHP劑量間無顯著統(tǒng)計(jì)學(xué)差異 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. 種植Glasgow骨肉瘤細(xì)胞小鼠，種植后第天研究CPT-11和L-OHP聯(lián)合給藥時(shí)序：均在15 HA

9、LO給藥（間隔1分鐘）CPT-11：7 HALO；L-OHP：15 HALOCPT-11：15 HALO；L-OHP：7HALO給藥時(shí)間7HALO19 HALO23 HALO死亡率(給藥后2天）0%30%55.5%MST（d)216給藥時(shí)間3HALO15HALO19 HALO死亡率(給藥后2天）22.2%12.5%11.1%MST（d)2330對(duì)照組：接種后11-19天全部死亡第1治療組(CPT-11)第治療組(L-OHP)單藥CPT-11在6個(gè)時(shí)間點(diǎn)用藥的腫瘤抑制情況 單藥L-OHP在6個(gè)時(shí)間點(diǎn)用藥的腫瘤抑制情況 CPT-11聯(lián)合L-OHP最佳時(shí)序相對(duì)人類， CPT-11高峰濃度：5am；

10、L-OHP ：4pm晚期大腸癌時(shí)間化療的臨床研究 晚期大腸癌治療的基礎(chǔ)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時(shí)間化療對(duì)5-FU劑量與療效的影響？5-FU第1周期：900mg/m2/d第2周期：10 00mg/m2/d第3周期：1100mg/m2/d，連續(xù)4天如果出現(xiàn)3度的毒性，則每天劑量降低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,無效者15mon p=0.015)2,3年生存率分別為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劑量強(qiáng)度與療效的關(guān)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 卡培他濱聯(lián)合奧沙利鉑的時(shí)間調(diào)節(jié)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卡培他濱: 1750 mg/m2/d8am,6pm,給 1/4 劑量；11pm給1/2 劑量，連續(xù)14天, q21daysQvortrup(2008)：卡培他濱時(shí)間用

17、藥方案聯(lián)合L-OHP作為二線化療，對(duì)71例CPT-115-FU治療失敗者進(jìn)行了II期臨床研究。有效率為18，PFS 5.1個(gè)月，MST 10.2個(gè)月不良反應(yīng): 23度外周神經(jīng)毒性分別為25和2.3度腹瀉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時(shí)卡培他濱 2000 mg/m2/d總劑量的20%在上午79時(shí)、80% 在下午68時(shí)應(yīng)用以奧沙利鉑為基礎(chǔ)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個(gè)國家36中心，564例 CPT-11為基礎(chǔ)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例挽救治療 有效率 PFS MST標(biāo)準(zhǔn)治療組 18.2 6個(gè)月 18個(gè)月時(shí)間治療組 25.7 8個(gè)月 28個(gè)月1hN=33N=352006年 Gholam的研究 Gholam D, et al. chronomodulated Irino