胃癌的內(nèi)科治療現(xiàn)狀概要

1、胃癌的內(nèi)科治療現(xiàn)狀湘雅醫(yī)院腫瘤科 鐘美佐,一例特發(fā)性脊柱側(cè)彎患者的護理 脊柱外科一病室,,化療放療手術(shù)分子靶向藥物生物免疫BSC…,,化療現(xiàn)狀,主要藥物與常用的化療方案,氟脲嘧啶類：5-FU；希羅達；S-1…..鉑類;順鉑;奧沙利鉑等紫杉類:紫杉醇;多西他賽;紫杉醇脂質(zhì)體;白 蛋白紫杉醇等蒽環(huán)類:表阿酶素;吡喃阿酶素等CP-11,常用的化療方案,

2、PF; EOF; EOX; DCF; TCF; FOLFOX系列; FOLFIRI; 單藥; 聯(lián)合分子靶向藥物…,,上述方案中氟脲類是基礎藥物,全身化療,模擬靜脈輸注,組織細胞靶向,Approve in 1968,1957年,替加氟 Tegafur,,優(yōu)福定 UFT,,Approve in 2007 (Gastric ca.),Capecitabine,,,替吉奧 S-1,提高5-FU靶向性降低毒性,氟尿嘧啶藥物

3、：經(jīng)歷了三代分子的發(fā)展90年代后期進入靶向口服時代,5-FU,,,第三代：靶向口服：高效、低毒,第二代：全身性口服：模擬靜脈給藥提效、增毒低毒則低效,第一代：全身靜脈：有效、高毒,改進用藥方式iv、bolus、CIV……,1967年,1976年,1991年,1998年,,5-FU,傳統(tǒng)藥物在全身形成濃度基本一致的5-FU池成為發(fā)揮療效和產(chǎn)生毒性的基礎,Ishikawa T et al., Biochem Pharm

4、acol, 55: 1091-1097 (1998),,,,,5-FU,19.5 mg/kg (MTD),,,,,,,0,,1,,2,,3,,2,,1,,0,Muscle,,,,,,16,,14,,12,,10,,8,,6,,4,,2,,0,,0,,2,,4,,6,8,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,,1,,2,,3,,2,,1,,0,,,,

5、,,,,,,,,,,,,,,,,,,,,,,,,,Plasma,Tumor,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

6、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,16,,14,,12,,10,,8,,6,,4,,2,,0,,0,,2,,4,,6,,,血漿組織5-Fu池,,,骨髓及其他,抗腫瘤與毒副作用,,降解與排泄,,,腫瘤,胃腸道,卡培他濱的腫瘤靶向機制不會形成高濃度的血漿5FU池,抗腫瘤活性,毒性低,,,卡培他濱,,卡培他濱5‘DFCR5’DFUR,,Rei

7、gner B, et al. Clin pharmacokinet 2001;40:85,,口服,TP酶,,希羅達也不依賴肝臟活化成為5-FU減少了肝臟毒性的風險,說明書指出中度以下肝損傷患者使用希羅達無需調(diào)整劑量依賴肝臟P450酶的替加氟制劑（替吉奧等）則被國家藥監(jiān)局要求在說明書予以黑框提示：,,優(yōu)效性研究證實：接受希羅達為基礎化療方案的胃癌患者，OS優(yōu)于接受CIV 5-FU為基礎化療方案者，總體死亡風險下降13％,Okines,

8、 et al.Annals of oncology. 2009 May,100806040200,0,1,2,3,4,5,6,5-FUXeloda,,,664,220,42,8,2,654,243,55,12,3,1,Survival (%),Number at risk5-FUCape,Time since randomisation (years),9.4 months (95% CI: 265­305 d

9、ays),10.6 months (95% CI 300­343 days),,,HR＝0.87，95％CI 0.77-0.98，P＝0.02,希羅達在保證療效的基礎上更容易耐受,近期口服氟尿嘧啶治療晚期胃癌的國際III期臨床安全性組間比較(3/4 度不良事件),,,希羅達初步實現(xiàn)高效低毒,國內(nèi)組織進行兩個多中心研究間的比較,,希羅達替代靜脈5-FU也使胃癌化療的整體花費變得更少,XELOX比FOLFOX在總醫(yī)療費用上更節(jié)?。?/p>

10、進口奧沙利鉑）,陳 文等，卡培他濱聯(lián)合奧沙利鉑方案與FOLFOX方案治療轉(zhuǎn)移性胃癌的經(jīng)濟學評價 2010 亞太藥物經(jīng)濟學年會 No.2188,創(chuàng)新藥物均以含希羅達聯(lián)合化療作為胃癌化療的基礎化療,,皆為國際多中心三期臨床，屬于全球胃癌領域最重要也是最嚴謹?shù)囊活惻R床研究：,87% 選擇 XP,希羅達成為胃癌治療的基石藥物,,希羅達®,,鉑類,紫杉類,奧沙利鉑（XO、XEO）,順鉑（XP、XEC）,多西紫杉醇（XD）,紫杉醇

11、（XT）,分子靶向,,,,Herceptin（ToGA）,Avastin（AVAGAST）,Cetuximab（EXPAND）,Lapatini（LOGic）,Panitumumab（REAL-3）,……,小 結(jié),提高藥物靶向性是抗腫瘤藥物的發(fā)展方向，全身性給藥不能區(qū)分腫瘤與正常組織決定了唯有更高的靶向性才能真正實現(xiàn)減毒增效卡培他濱先進的腫瘤靶向機制突破了先前口服氟尿嘧啶模擬靜脈給藥的機制，血漿組織內(nèi)5FU濃度降低。初步實

12、現(xiàn)了高效基礎上安全性的提升在此基礎上，希羅達較傳統(tǒng)靜脈5FU具有藥物經(jīng)濟學優(yōu)勢；且獲得國際國內(nèi)各種權(quán)威指南的推薦分子靶向藥物的III期臨床多以希羅達作為化療的基礎藥物, 顯示出希羅達是胃癌化療的新標準,,S-1,隨機 III期臨床研究比較 S-1 單藥、S-1 + 順鉑治療晚期胃癌 (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the tre

13、atment of stomach cancer,H. Narahara1, W. Koizumi2, T. Hara3, A. Takagane4, T. Akiya5, M. Takagi6, K. Miyashita7, T. Nishizaki8, O. Kobayashi9, S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group;,1Osaka Medical Cen

14、ter for Cancer and CV Diseases, Osaka, JAPAN, 2Kitasato University East Hospital, Kanagawa, JAPAN, 3Kouseiren Takaoka Hospital, Toyama, JAPAN, 4Iwate Medical University, Iwate, JAPAN, 5Gunma Prefectural Cancer Center, Gu

15、nma, JAPAN, 6Shizuoka General Hospital, Shizuoka, JAPAN, 7National Hospital Organization Nagasaki Medical Center, Nagasaki, JAPAN, 8Matsuyama Red Cross Hospital,Ehime, JAPAN, 9Kanagawa Cancer Center, Kanagawa, JAPAN.,SP

16、IRITS,ASCO 2007: #4514,背景-1,替吉奧—— 口服的氟嘧啶類藥物，在日本已經(jīng)廣泛用于晚期胃癌. 兩個單獨的II期臨床研究表明，單藥有效率 44-49 %， MST 207-250 天 1,2,1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7,AS

17、CO 2007: #4514,背景-2,JCOG92051),1): A. Ohtsu et al. J Clin Oncol 2003; 21:54-59,FP 組比 5FU 組明顯更長的 PFS. (P<0.001) 兩組的OS無顯著差異,,In Japan, recommended regimen for AGC was 5-FU alone,ASCO 2007: #4514,背景-3,JCOG9912,5-FU,,,

18、,S-1,CPT-11+CDDP,,Non-inferiority,Boku et al. ASCO2007 abstract#: LBA4513,ASCO 2007: #4514,背景-4,S-1+CDDP Phase I/II Study1),S-1 40-60mg BID for 3wks,Day 1,Day 8,Day 15,Day 22,Day 29,Day 36,,CDDP 60mg/m2 on Day 8,S-1,,,,1

19、: W Koizumi et al. Br J Cancer 2003; 89:2207-2212,S-1 給藥劑量是依據(jù)患者的體表面積 (BSA) BSA < 1.25 : 40 mg BID 1.25 - < 1.50 : 50 mg BID 1.50 - < BSA : 60 mg BID,ASCO 2007: #4514,研究設計,AGCNo priorChemo.,R

20、,S-1 aloneS-1: 40-60 mg BID for 28 days q6wks,S-1 + CDDPS-1: 40-60 mg BID for 21 days q5wksCDDP: 60 mg/m2 iv on day 8,,,Central Randomization (dynamic balancing)Adjustment Factors: Institute PS Unresectable vs

21、Recurrent,ASCO 2007: #4514,Primary Endpoint,,Overall SurvivalEstimated OS (S-1/S-1+CDDP) : 8/12 months N=142 in each arm for 90% power to establish superiority in OS(Two-sidedlog-rank a=0.05).Follow up: 2 years

22、142 pts in each arm,,Secondary Endpoints,,Progression Free SurvivalTime to Treatment FailureOverall ResponseSafety,研究終點,入組標準,組織學證實的胃腺癌 (unresectable/recurrent gastric cancer) 以前沒有化療 PS (ECOG scale) 0-2 Age 20

23、-74 預期生存 > 3 months Adequate organ function (bone marrow, liver, renal function) 知情同意,ASCO 2007: #4514,患者一般狀況 -1,ASCO 2007: #4514,,,Randomized : 305 pts (S-1/S-1+CDDP : 152/153) between Mar/2002 and Nov/2004

24、,,FAS : 298 pts (S-1/S-1+CDDP : 150/148),患者一般狀況 -2,ASCO 2007: #4514,Months,Estimated probability (%),,,11.0,13.0,總生存期,Log-rank p-value: 0.0366HR: 0.774 [ 95% CI: 0.608 – 0.985]Median follow-up time (M): 34.6,,ASCO 2007

25、: #4514,無進展生存期,Log-rank p-value: <0.0001HR: 0.567 [ 95% CI: 0.437 – 0.734],Estimated probability (%),Months,,,,6.0,4.0,ASCO 2007: #4514,到治療失敗的時間,Log-rank p-value: 0.0089HR: 0.699 [ 95% CI: 0.536 – 0.912],Estimated p

26、robability (%),Months,,,,4.8,3.9,ASCO 2007: #4514,療 效,Criteria : RECIST (Extramural Review),Fisher’s Exact Test p-value: 0.0018,ASCO 2007: #4514,藥物的副作用-1,Criteria : NCI-CTC ver. 2.0,ASCO 2007: #4514,藥物的副作用-2,No treatmen

27、t-related death was observed,Criteria : NCI-CTC ver. 2.0,ASCO 2007: #4514,AGC的III期臨床研究,*TTP,3) Proc ASCO 2006; Vol 24, No. 18S: LBA4018,1) J Clin Oncol 2006; 24: 4991 – 49972) Proc ASCO 2006; Vol 24, No. 18S: LBA4017,AS

28、CO 2007: #4514,結(jié) 論,S-1+CDDP 的生存期長于 S-1 單藥 S-1 中位生存 11.0 M, S-1+CDDP 13.0 M S-1+CDDP 耐受性好，無治療相關(guān)的死亡 S-1+CDDP 方案可以當作 AGC 的一線治療方案,ASCO 2007: #4514,,化療聯(lián)合分子靶向治療,總 結(jié),1.如何選擇胃癌的化療方案取決于許多因素 患者的狀況；腫瘤的生物學特