医学表柔比星膀胱内灌注化疗方案的优化.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,表柔比星膀胱内灌注化疗方案的优化,There is no single drug that is superior with regards to efficacy.Mitomycin C,epirubicin and doxorubicin have all shown a beneficial effect(evidence:1b).,2010 EAU,对,NMIBC,的治疗的推荐,TURBT+,即刻单次膀胱内灌注,复发,复发,/,进展,根治性膀胱切除术,化疗,BCG+,维持治疗,单瘤、原发,低分级,Ta,多发、复发,低分级肿瘤,任何,T1,和,/,或,G3,和,/,或原位癌,观察,复发,/,进展,BCG+,维持治疗,低危,中危,高危,TURBT+,单次化疗,TURBT+,单次化疗,表柔比星膀胱内灌注方案的优化,提高疗效（尤其是能否替代,BCG,？）,减少不良反应,增加便利性（减少不必要的灌注次数）,表柔比星膀胱内灌注方案的优化,剂量优化,灌注频率和疗程的优化,联合用药,剂型优化,比较法玛新不同剂量膀胱内灌注给药的研究,50mg/50ml,80mg/50ml,Ali-El-Dein B,et al.The Journal of Urology 1997;158:68-74.,膀胱内灌注在术后,7-14,天开始，每周进行一次，进行,8,周,然后每月进行一次至一年疗程结束,随访时间为,12,月,-48,月,(,平均为,30.1,月,),组1,：,法玛新,50mg/50ml,生理盐水,组2,：,法玛新,80mg/50ml,生理盐水,组3,：,阿霉素,50mg/50ml,生理盐水,组,4：,未接受,任何辅助治疗,浅表性膀胱癌患者,R,手术,基线特征,组,1,组,2,组,3,组,4,合计,(%),分级,pT1/pTa/Tis57/7/4,56/12/8,56/4/-,55/6/-,88.6/11.4/4.7,分期,I/II/III,6/50/8,11/47/10,10/42/8,12/40/9,15.4/70.8/13.8,DNA,双,/,四,/,异倍体,48/8/8,50/14/4,40/12/8,45/13/3,72.3/18.6/19.1,发病数,单发,/,多发,22/42,28/40,19/41,19/42,34.8/65.2,肿瘤大小,0.05,研究结果：不良反应,Ali-El-Dein B,et al.The Journal of Urology 1997;158:68-74.,法玛新,50mg,组n=64),不良反应发生例数,(,个,),研究结论：,法玛新的剂量和疗效正相关,临床推荐,TURBT,术后可常规使用,50mg,法玛新，最高可以用到,80mg,法玛新局部刺激性小，严重不良反应少,比较Ta/T1期移行细胞膀胱癌患者接受TURBT术后两次法玛新膀胱内灌注研究,Saika T,et al.World J Urol 2010.,主要终点：至首次复发时间,N=303,A.TURBT+,法玛新,20 mg/40 ml(N=79),TURBT,术后,1,小时内即刻灌注,1,次，第二天早晨灌注,1,次，术后,24,小时内灌注,2,次,C.,仅,TURBT,(N=,77,),Ta/T1,移行细胞癌,NMIBC,患者,B.TURBT+,法玛新,50 mg/100 ml,(N=84),TURBT,术后,1,小时内即刻灌注,1,次，第二天早晨灌注,1,次，术后,24,小时内灌注,2,次,R,中位随访,44,个月,基线特征,A,B,C,总计,中位年龄,(,岁,),69,69,71,69,性别,(,男性,/,女性,),67/16,80/10,74/10,221/36,原发,/,复发,50/33,51/39,50/34,151/106,单瘤,/,多瘤,38/45,38/52,36/48,112/145,原发单瘤,/,原发多瘤,28/22,28/23,24/26,80/71,复发单瘤,/,复发多瘤,10/23,10/29,12/22,32/74,最大肿瘤直径,1cm,49%,56%,48%,51%,肿瘤分级,(G1/G2/G3),21/49/12,30/42/18,26/44/14,77/135/44,肿瘤分期,(Ta/T1),45/36,54/36,54/30,153/102,总计,83,90,84,257,Saika T,et al.World J Urol 2010.,研究结果：无复发生存,Saika T,et al.World J Urol 2010.,A,B,C,中位,RFS(,月,),24,38,13,时间,(,年,),generalized Wilcoxon tesB vs.C,P=0.04,100,80,60,40,20,0,0.0,1.0,2.0,3.0,4.0,5.0,A,法玛新,20mg,无复发率,(%),B,法玛新,50mg,C,无法玛新,研究结果：不良事件,研究结论：,TURBT,后,24,小时内给予膀胱内灌注两次法玛新,50mg,比两次灌注,20mg,可进一步延长复发时间，且副作用很小。,法玛新,20,法玛新,50,P,1,级膀胱刺激性,(%),22.9,35.6,0.106,1,级外周红细胞减少,(n),2,2,-,1,级血清转氨酶升高,(n),1,3,-,1,级外周白细胞减少,1,-,所有不良反应均可逆,Saika T,et al.World J Urol 2010.,比较高剂量法玛新膀胱内灌注与BCG对中危浅表性膀胱癌患者预防作用的研究,Moutzouris G,et al.Eur Urol Suppl 2007;6(2):171,Abstract 595.,DFS,复发,安全性,N=234,法玛新,80mg/50ml,生理盐水,(N=121),BCG,(N=113),TURBT,术后,原发或复发,Ta G2-3,T1 G1-2,TCC,患者,R,每周膀胱内灌注，共六周；后续第,3/6/12/18/24/30/36,个月给予,3,次每周膀胱内灌注,中位随访,21,个月,前瞻性随机对照研究,研究结果,研究结论,高剂量膀胱内灌注法玛新作为延长治疗方案耐受性良好,对于中危,NMIBC,患者,TURBT,术后复发的预防疗效与,BCG,相同,可评估患者,法玛新,(N=109),BCG(N=103),P,肿瘤复发,(%),31.2,20.4,0.1016,中位,DFS(,月,),23.24,23.26,0.0778,化学性膀胱炎,(G1-G3),，,%,47.93,54.87,0.1213,因膀胱炎停药，,%,5.79,9.73,-,Moutzouris G,et al.Eur Urol Suppl 2007;6(2):171,Abstract 595.,表柔比星膀胱内灌注方案的优化,剂量优化,灌注频率和疗程的优化,联合用药,剂型优化,Hendricksen K,Witjes WP,Idema JG,et al.,Eur Urol,，,2008,，,53(5),：,984-991.,Patients with,intermediate-and high-risk,urothelial cell carcinoma of the bladder,except carcinoma in situ,were randomised for adjuvant intravesical instillations with 50 mg epirubicin/50 ml NaCl for 1 h.,Group 1 received 4 weekly and 5 monthly instillations(standard schedule).,group 2 received the same schedule as group 1,but with,an additional instillation 48 h after TURBT,.,group 3 received the same scheme as group 1,but with,additional instillations at 9 and 12 mo,(maintenance schedule).,group 1,group 2,group 3,5-yr recurrence free,44.4%,42.7%,45.0%,5-yr,progression free,90.0%,87.7%,88.2%,Trkeri L,Tandr Y,al,et al.Urol Int,2010,85(3):261-5.,Comparison of the efficacy of single or double intravesical epirubicin instillation in the early postoperative period to prevent recurrences in non-muscle-invasive urothelial carcinoma of the bladder:prospective,randomized multicenter study.,primary and solitary or multiple(3 or less)Ta(grade 2-3)or T1(grade 1-2)tumors,were enrolled.,A total of 299 patients from 24 institutions were randomized to receive either a single dose of,100 mg epirubicin instillation within 6 h,or,a second 100 mg epirubicin instillation during the 12th-18th hours,after a complete TUR-BT.,RESULTS:,The follow-up and disease-free survival periods were 16.9 months and 16 months,respectively.,CONCLUSIONS:,A second intravesical epirubicin instillation did not provide any significant benefit.,比较Ta/T1膀胱癌TUR术后长疗程与短疗程法玛新膀胱内灌注的研究,Koga H,et al.J Urol 2004;171(1):153-157.,N=150,复发率,安全性,1,年：法玛新,30mg/30ml,生理盐水,19(N=77),3,个月：法玛新,30mg/30ml,生理盐水,9(N=73),TUR,术后,Ta/T1,膀胱癌患者,R,膀胱内灌注次数,1,年组,3,个月组,1,TUR,后,5,5,10,：每,2,周,5,9,：每,2,周,11,19,：每月,1,年组,3,个月组,5,年,RFS(,),85.2,63.9,Koga H,et al.J Urol 2004;171(1):153-157.,研究结果：复发率,术后时间,(,月,),P=0.005,无肿瘤复发患者比例,(%),100,80,60,40,20,0,0,12,24,36,48,60,72,1,年组,3,个月组,研究结果：不良反应,研究结论：,与短疗程法玛新膀胱内灌注相比，长疗程（,1,年）法玛新明显降低复发率，且不增加严重不良反应。,Koga H,et al.J Urol 2004;171(1):153-157.,严重局部不良反应发生率,P=NS,表柔比星膀胱内灌注方案的优化,剂量优化,灌注频率和疗程的优化,联合用药,剂型优化,Raitanen MP,Lukkarinen O,Finnish Multicentre Study Group.Br J Urol,1995,76(6):697-701.,A controlled study of intravesical epirubicin with or without alpha 2b-interferon as prophylaxis for recurrent superficial transitional cell carcinoma of the bladder.Finnish Multicentre Study Group.,PATIENTS AND METHODS:,81 patients with superficial(,stage Ta and T1,),well or moderately differentiated(,grades 1 and 2,)TCC were randomized into three groups:,Group 1,：,TUR alone;,Group 2,：,50 mg,epirubicin,;,Group 3,：,50 mg,epirubicin,combined with 10 MU alpha 2b-IFN,intravesically,.,The instillations were started 1 week after TUR and were performed weekly during the first month and then once a month for one year.,RESULTS:,The patients were followed for a mean of 20 months.,Patients receiving,intravesical,chemoimmunotherapy,(Group 3)had the most,favourable,outcome,;they had comparatively lower recurrence and,tumour,rates,fewer patients with recurrences and,most importantly,the longest disease-free interval.Side-effects were mostly mild and transient,and no differences were found among the groups.,Malmstrom P,Wiklund F,Duchek M.et al.,Journal of Urology,2008,179(4-sup1):587,ADJUVANT INTRAVESICAL EPIRUBICIN AND INTERFERON 2b IS COMPARABLE TO BCG FOR TREATMENT OF T1 TUMOURS OF THE URINARY BLADDER,BCG,Epirubicin+Interferon2b,N(T1 bladder cancer),117,118,Recurrence,25%,23%,progression,11%,9%,Worsened urinary symptoms at,6 months follow-up,24%,16%,The first TUR of the,T1 tumour,was followed within 4-6 weeks by a second-look resection including bladder mapping and resection biopsy of the prostatic urethra.,Two weeks later,patients received according to randomisation schedule either BCG(Oncotice)or the combination of epirubicin(Farmorubicin 50mg,）,and Interferon2b(100,000IU),Both regimens given as induction treatment for 6 weeks followed by maintenance therapy for 2 years.,The mean duration of follow-up is presently 3.2(0.1-7.9)years.,Naito S,et al.The Journal of Urology,，,2008,，,179:485-490.,LC,：干酪乳酸菌,多中心、前瞻性、随机对照研究,临床诊断为浅表性膀胱癌患者,TUR,术后,1,周内,膀胱内灌注,(,法玛新,30mg/30ml,生理盐水,),共,2,次,R,法玛新组,(N=102),术后,3,月内附加,6,次法玛新膀胱内灌注,法玛新联合,LC,组,(N=100),术后,3,月内附加,6,次法玛新膀胱内灌注,口服干酪乳杆菌,3mg/,天 持续,1,年,评估复发、疾病进展、预后及药物不良反应,基线特征,Naito S,et al.The Journal of Urology 2008;179:485-490.,单药组,联合组,P,总计,102,100,0.2510,性别,(,男,/,女,),86/16,78/22,年龄,70,岁,55,53,0.8955,70,岁,47,47,吸烟,(,是,/,否,),53/49,55/45,0.6650,肿瘤类型,原发单瘤,40,40,0.9903,原发多瘤,52,50,复发单瘤,10,10,T分类,(Ta/T1),53/49,52/48,0.9955,肿瘤分级,(1/2),21/81,21/79,0.9425,肿瘤大小,50mg20mg,）。,对于中危复发的,NMIBC,患者，高剂量（,80mg,）表柔比星长程灌注对,TURBT,术后肿瘤复发的预防疗效与,BCG,相同。,对中高危复发的,NMIBC,患者，如果,TURBT,术后,6,小时内给予,50mg-100mg,表柔比星膀胱内灌注，则在,24,或,48,小时内给予第二次膀胱内灌注，并不能进一步降低肿瘤的复发率。,对中高危复发的,NMIBC,患者，表柔比星长疗程（至少半年）灌注的疗效优于短疗程；而采用低剂量（,30mg,）灌注，则最好灌注疗程至少,1,年。,小 结,联合,IFN-2b,膀胱内灌注可提高表柔比星的疗效；对,T1,肿瘤，该联合方案的长程（,2,年）灌注对,TURBT,术后肿瘤复发的预防疗效与,BCG,相同。,联合口服免疫调节剂干酪乳杆菌能进一步提高表柔比星膀胱内灌注的疗效。,尚未明确：环丙沙星能提高表柔比星的疗效？表柔比星纳米颗粒剂型膀胱内灌注的疗效优于表柔比星水溶剂？,谢谢！,