前列腺癌PPT課件

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前列腺癌 ASCO,,1,1. 多西他賽：E3805 (CHAARTED)與STAMPEDE 2.生化復(fù)發(fā)的挽救治療：GETUG-AFU16 3.轉(zhuǎn)移性前列腺癌間斷或持續(xù)雄激素剝奪治療的長期結(jié)果 4. PAS升高前列腺癌ADT干預(yù)時機：2個Ⅲ期隨機臨床試驗聯(lián)合分析,主要內(nèi)容,2,1. 多西他賽：E3805 (CHAARTED)與STAMPEDE 2.生化復(fù)發(fā)的挽救治療：GETUG-AFU16 3.轉(zhuǎn)移性前列腺癌間斷或持續(xù)雄激素剝奪治療的長期結(jié)果 4. PAS升高前列腺癌ADT干預(yù)時機：2個Ⅲ期隨機臨床試驗聯(lián)合分析,主要內(nèi)容,3,E3805 (CHAARTED)：研究設(shè)計,Sweeney C, et al. 2014 ASCO Abstract LBA2.,4,E3805 (CHAARTED)：主要入組標準,轉(zhuǎn)移性前列腺癌 既往抗雄治療，限于： 隨機前12天或輔助治療<24個月或完成后12個月內(nèi)無進展 ECOG PS 0-2 足夠肝腎、骨髓、心臟、肺與神經(jīng)功能 適合接受多西他賽 既往未接受多西他賽治療,Sweeney C, et al. 2014 ASCO Abstract LBA2.,5,E3805 (CHAARTED)：OS (主要終點),,,延長13.6個月 降低死亡風(fēng)險39%,Sweeney C, et al. 2014 ASCO Abstract LBA2.,6,E3805 (CHAARTED)：開始治療時不同轉(zhuǎn)移性疾病程度的OS,,,延長17個月 降低死亡風(fēng)險40%,Sweeney C, et al. 2014 ASCO Abstract LBA2.,高腫瘤負荷：內(nèi)臟轉(zhuǎn)移，和/或?4個骨轉(zhuǎn)移(至少1個越過盆腔和脊柱),7,8,E3805 (CHAARTED)：去勢治療聯(lián)合多西他賽在所有亞組中均獲益,Sweeney C, et al. 2014 ASCO Abstract LBA2.,Slide 1,Presented By Nicholas James at 2015 ASCO Annual Meeting,9,Rationale for study agents,Presented By Nicholas James at 2015 ASCO Annual Meeting,研究藥物選擇依據(jù)： 多系紫杉醇： 可以延長去勢抵抗轉(zhuǎn)移性前列腺癌生存期； 老年人也有較好的耐受性 唑來膦酸： 降低去勢抵抗轉(zhuǎn)移性前列腺癌骨相關(guān)事件的發(fā)生 系列研究把唑來膦酸作為預(yù)防轉(zhuǎn)移的藥物 聯(lián)合治療： 體外有證據(jù)支持二者有協(xié)調(diào)作用 預(yù)期二者聯(lián)合耐受性良好,10,Inclusion criteria,Presented By Nicholas James at 2015 ASCO Annual Meeting,未經(jīng) ADT 治療的新診斷轉(zhuǎn)移性前列腺癌患者,11,Outcome measures,Presented By Nicholas James at 2015 ASCO Annual Meeting,主要終點： OS 次要終點： FFS(Failure-free survival） 毒性、生活質(zhì)量、骨相關(guān)事件、經(jīng)濟影響 FFS：PSA失敗、局部失敗、淋巴結(jié)失敗、遠處轉(zhuǎn)移、前列腺癌死亡 PSA失?。篜AS下降小于50%；如PSA下降大于50%：24周內(nèi)最低值+50%和大于4ng/ml,12,Docetaxel & ZA comparisons: patients,Presented By Nicholas James at 2015 ASCO Annual Meeting,13,Accrual,Presented By Nicholas James at 2015 ASCO Annual Meeting,按 2：1：1：1 分成 4 個治療組： 標準治療（≥ 3 年 ADT±局部放療） 標準治療 + 多西他賽（6 周期） 標準治療 + 唑來膦酸（2 年） 標準治療 + 多西他賽 + 唑來膦酸 多西他賽給藥方案是 3 周一次 75 mg/m2+ 強的松每日 10 mg 為一個周期，持續(xù) 6 個周期。 唑來膦酸的給藥方案是每 3 周一次 4 mg，6 周期后每 4 周一次，持續(xù) 2 年。,14,Zoledronic acid: Failure-free survival,Presented By Nicholas James at 2015 ASCO Annual Meeting,15,Zoledronic acid: Survival,Presented By Nicholas James at 2015 ASCO Annual Meeting,唑來膦酸組生存差異不具統(tǒng)計學(xué)意義,16,Docetaxel: Failure-free survival,Presented By Nicholas James at 2015 ASCO Annual Meeting,17,Docetaxel: Survival,Presented By Nicholas James at 2015 ASCO Annual Meeting,多西他賽組總生存延長 10 個月,18,Zoledronic acid + docetaxel: Failure-free survival,Presented By Nicholas James at 2015 ASCO Annual Meeting,19,Zoledronic acid + docetaxel: Survival,Presented By Nicholas James at 2015 ASCO Annual Meeting,多西他賽 + 唑來膦酸組生存改善與多西他賽組相似,20,Treatment effect by metastatic status: FFS,Presented By Nicholas James at 2015 ASCO Annual Meeting,M1亞組分析,21,Treatment effect by metastatic status: Overall survival,Presented By Nicholas James at 2015 ASCO Annual Meeting,M1亞組分析,22,Docetaxel: Survival – M1 Patients,Presented By Nicholas James at 2015 ASCO Annual Meeting,轉(zhuǎn)移的亞組延長 22 個月,M1亞組分析,23,Grade 3+ adverse events ever reported,Presented By Nicholas James at 2015 ASCO Annual Meeting,毒副反應(yīng),24,Grade 3+ adverse events ever reported,Presented By Nicholas James at 2015 ASCO Annual Meeting,毒副反應(yīng),25,Grade 3+ adverse events at 1 year,Presented By Nicholas James at 2015 ASCO Annual Meeting,毒副反應(yīng),26,Conclusions,Presented By Nicholas James at 2015 ASCO Annual Meeting,結(jié)論 多西他賽可以改善未用過激素治療的前列腺癌病人的生存 唑來膦酸不能改善生存 兩藥聯(lián)合改善生存，但未超過單獨加用多西他賽 多臂、多階段臨床試驗是有實踐意義的 多西他賽 可以考慮用于新診斷轉(zhuǎn)移性前列腺癌的常規(guī)治療 可以考慮用于高危非轉(zhuǎn)移性前列腺癌（是基于亞組分析：可以延長無失敗生存時間FFS）,27,1. 多西他賽：E3805 (CHAARTED)與STAMPEDE 2.生化復(fù)發(fā)的挽救治療：GETUG-AFU16 3.轉(zhuǎn)移性前列腺癌間斷或持續(xù)雄激素剝奪治療的長期結(jié)果 4. PAS升高前列腺癌ADT干預(yù)時機：2個Ⅲ期隨機臨床試驗聯(lián)合分析,主要內(nèi)容,28,GETUG-AFU 16 Interest of short androgen deprivation therapy (ADT) combined with radiotherapy (RT) as salvage treatment for biological relapse (BR) after radical prostatectomy (RP) Results of the GETUG-AFU 16 phase III randomized trial,Presented By Christian Carrie at 2015 ASCO Annual Meeting,短期去勢聯(lián)合放療作為挽救治療根治術(shù)后生化復(fù)發(fā)前列腺癌的療效影響：GETUG-AFU16 Ⅲ期隨機臨床試驗,29,Background and objective,Presented By Christian Carrie at 2015 ASCO Annual Meeting,背景： 約1/3的前列腺癌根治術(shù)后8年內(nèi)會出現(xiàn)復(fù)發(fā)：表現(xiàn)PSA升高，但無臨床或影像學(xué)證據(jù)，最終出現(xiàn)遠處轉(zhuǎn)移 挽救性放療是僅有生化復(fù)發(fā)（PSA）病人的標準治療，可使35%的病人5年內(nèi)不會再出現(xiàn)生化復(fù)發(fā)并且推遲長期雄激素抑制時間 回顧性資料也提示：短期去勢聯(lián)合放療可以改善高危復(fù)發(fā)病人的預(yù)后 研究目的： 觀察去勢聯(lián)合放療與單純放療對前列腺癌根治術(shù)后生化復(fù)發(fā)5年P(guān)FS的療效,30,Study endpoints,Presented By Christian Carrie at 2015 ASCO Annual Meeting,研究終點 主要終點：PFS：從隨機化開始到生化或臨床進展，或死亡 次要終點： OS 急性和最終毒性（TTCAE V3.0） 生活質(zhì)量,31,Study design,Presented By Christian Carrie at 2015 ASCO Annual Meeting,32,Main inclusion criteria,Presented By Christian Carrie at 2015 ASCO Annual Meeting,主要入組標準 前列腺腺癌，分期：pT2、T3、T4（膀胱頸受侵），根治性前列腺切除術(shù)后（RP） pN0/pNX RP術(shù)后至少6個月PSA正常 無臨床或影像學(xué)進展證據(jù) PSA≥0.2ng/ml或PSA≤2ng/ml必須從最低點起間隔2個月以上連續(xù)檢測2次，可認為是生化復(fù)發(fā) PS≤2分 之前未行ADT治療,33,Recruitment and follow-up,Presented By Christian Carrie at 2015 ASCO Annual Meeting,入組與隨訪,34,Baseline characteristics,Presented By Christian Carrie at 2015 ASCO Annual Meeting,35,Results – Treatment administration,Presented By Christian Carrie at 2015 ASCO Annual Meeting,結(jié)果：治療情況 放療 738病人接受了放療 705（96%）3D RT 33（4%）IMRT 前列腺床的中位劑量66Gy/7周 15%病人接受盆腔淋巴結(jié)放療 ADT（戈舍瑞林：10.8mg） 3個病人未接受第一次注射（1人拒絕、2人遺漏） 15個病人（4%）未接受第二次注射 10人拒絕、2人遺漏、2人因為毒性、1人原因不清楚,36,Acute toxicities (CTC-AE v3),Presented By Christian Carrie at 2015 ASCO Annual Meeting,潮紅和出汗(大于3度),37,Late toxicities (CTC-AE v3),Presented By Christian Carrie at 2015 ASCO Annual Meeting,38,Progression-Free Survival,Presented By Christian Carrie at 2015 ASCO Annual Meeting,39,Subgroups analysis,Presented By Christian Carrie at 2015 ASCO Annual Meeting,40,Overall Survival,Presented By Christian Carrie at 2015 ASCO Annual Meeting,41,Description of deaths,Presented By Christian Carrie at 2015 ASCO Annual Meeting,42,Quality of life : QLQ-C30,Presented By Christian Carrie at 2015 ASCO Annual Meeting,43,Conclusions,Presented By Christian Carrie at 2015 ASCO Annual Meeting,與單獨挽救性放療相比，聯(lián)合短期去勢改善5年P(guān)FS率（79.6%VS62.1%） 而且在所有亞組均可見到 OS沒有區(qū)別，是由于隨訪時間短，5年時將進一步更新結(jié)果 毒副反應(yīng)低、生活質(zhì)量兩組間無差異,44,1. 多西他賽：E3805 (CHAARTED)與STAMPEDE 2.生化復(fù)發(fā)的挽救治療：GETUG-AFU16 3.轉(zhuǎn)移性前列腺癌間斷或持續(xù)雄激素剝奪治療的長期結(jié)果 4. PAS升高前列腺癌ADT干預(yù)時機：2個Ⅲ期隨機臨床試驗聯(lián)合分析,主要內(nèi)容,45,Long Term Consequences of Intermittent and Continuous Androgen Deprivation in Men with Metastatic Prostate Cancer on S9346,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,轉(zhuǎn)移性前列腺癌間斷或持續(xù)雄激素剝奪治療的長期結(jié)果,46,Androgen Deprivation Therapy,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,背景 ADT是轉(zhuǎn)移性前列腺癌的標準治療 觀察性研究顯示ADT通常會引起： 性功能障礙 骨質(zhì)疏松或骨折 心血管疾病 代謝綜合征或糖尿病 認知功能改變,47,Study Objectives / Hypothesis,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,研究目的與假設(shè) 評估間斷與持續(xù)ADT治療對轉(zhuǎn)移性前列腺癌最終影響 假設(shè)：間斷ADT治療的心血管和內(nèi)分泌副作用低于持續(xù)ADT,48,Slide 6,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,比卡魯胺,49,Intermittent ADT Criteria,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,間斷ADT標準 當PSA升高到20ng/ml、或至基線水平、或出現(xiàn)癥狀時，重新開始ADT 如果7個月后PSA≤4ng/ml，病人進入停止ADT觀察模式 如果在6、7個月誘導(dǎo)過程中PSA＞ng/ml，病人接受持續(xù)直到進展,50,Slide 8,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,51,Study Population,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,52,Late Effects: Cumulative Incidence,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,最終結(jié)果：累及發(fā)生率,缺血和血栓性事件,缺血性事件,53,Late Effects: Cumulative Incidence,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,最終結(jié)果：累及發(fā)生率,癡呆,性功能障礙,54,Late Effects: Cumulative Incidence,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,最終結(jié)果：累及發(fā)生率,抑郁,內(nèi)分泌,55,Multivariable Regression Results,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,多變量回歸分析結(jié)果,56,Sensitivity Analysis 1: Cumulative Incidence of Late Effects prior?to median PFS (812 days),Presented By Dawn Hershman at 2015 ASCO Annual Meeting,57,Why would Ischemic/thrombotic events be lower for patients on Continuous ADT?,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,為什么ADT持續(xù)組的缺血與血栓性事件低？,58,Black Box Warning - 2010,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,黑箱警示-2010 “增加糖尿病和某些心血管疾病” 然而: 血循環(huán)中凝結(jié)物的累積會增加危險 最高危險發(fā)生在ADT誘導(dǎo)的前6個月，所以每個誘導(dǎo)者都增加 間斷ADT伴隨雌激素增，進而導(dǎo)致凝結(jié)物增加 中斷ADT后睪丸激素仍持續(xù)受抑制,59,Why would bone effects be the same?,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,為什么骨相關(guān)事件相當？,60,ADT and Bone Loss,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,ADT與骨丟失 與沒進行ADT相比，ADT病人的骨折發(fā)生率增加40% 所有病人在前7個月都接受了ADT或比卡魯胺—兩組骨相關(guān)事件都較常見 前瞻性間斷ADT對骨密度影響研究顯示：治療接受后骨密度恢復(fù)的差異性較大 試驗病人應(yīng)該隨訪骨密度 骨密度變化的病人應(yīng)該接受二膦酸鹽治療,61,Limitations,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,局限性 可能不是所有病人都被要求記錄并發(fā)癥 醫(yī)療保險缺乏關(guān)于嚴重程度的資料?？赡苓@些并發(fā)癥是中度的、對生命無威脅的 我們沒有對多因素比較進行調(diào)整 臨床試驗中所有病人進行籠統(tǒng)評價，這些結(jié)果沒有被歸納分析 病人的PS評分主要是0-1分。,62,Summary,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,小結(jié) 臨床試驗病人與醫(yī)保政策有關(guān)（受醫(yī)保限制） 這是一項未來大型臨床試驗的典范 我們觀察到間斷ADT病人的缺血與血栓性事件增加 間斷ADT的長期骨相關(guān)事件、內(nèi)分泌事件或認知相關(guān)事件沒有明顯降低 結(jié)合S9346研究的非劣效結(jié)果，臨床醫(yī)生應(yīng)該謹慎使用間斷ADT,63,1. 多西他賽：E3805 (CHAARTED)與STAMPEDE 2.生化復(fù)發(fā)的挽救治療：GETUG-AFU16 3.轉(zhuǎn)移性前列腺癌間斷或持續(xù)雄激素剝奪治療的長期結(jié)果 4. PAS升高前列腺癌ADT干預(yù)時機：2個Ⅲ期隨機臨床試驗聯(lián)合分析,主要內(nèi)容,64,TROG 03.06 and VCOG PR 01-03: the ‘Timing of androgen deprivation therapy in prostate cancer patients with a rising PSA (TOAD)’ collaborative randomised Phase III trial.,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,TROG 03.06和VCOG PR 01-03兩項隨機Ⅲ期臨床試驗合并分析：PAS升高前列腺癌病人ADT干預(yù)時機,65,History,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,歷史 這是2004年開始的一項Ⅲ期臨床研究，由澳大利亞和新西蘭泌尿?qū)W會支持，由Trans Tasman Radiation Oncology Group和Cancer Council Victoria聯(lián)系承擔的 本研究重點關(guān)注PSA時代在管理前列腺癌時未回答的問題：當疾病進展但尚未考慮治愈性治療時，什么時候開始ADT?,66,Asymptomatic men with PSA,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,無癥狀前列腺癌 PSA檢測證實有前列腺癌存在的生化證據(jù)，但病人無相關(guān)癥狀 本研究對象為接受過一種或一種以上治愈性治療的前列腺癌病人；或新診斷的前列腺癌，但由于其他因素影響不適合治愈性治療手段的病人,67,Slide 5,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,我們關(guān)注點： 1. 是否早期干預(yù)會影響總生存（OS）？ 2. PSA達到多高水平時推薦干預(yù)？ 3. 控制疾病與治療相關(guān)并發(fā)癥的最佳平衡點在哪？ 4. 疾病控制與生活質(zhì)量的最佳平衡點在哪？ 5. 所有無癥狀非治愈性疾病都需要治療嗎？ 6. 哪些因素影響預(yù)后和臨床復(fù)發(fā)或死亡？,68,Trial hypothesis,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,試驗假設(shè)： 與ADT延遲干預(yù)相比，立即ADT干預(yù)可以改善OS并保持可接受的生活質(zhì)量 兩組病人：PAS復(fù)發(fā)僅是指治愈性治療后；無癥狀病人不考慮可治愈性治療,69,Study schema: Group 1- PSA relapse,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,研究簡介：組1-PSA復(fù)發(fā),入組標準 分層,70,Study schema: Group 2 - de novo,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,入組標準 分層,研究簡介：組2-新診斷的,71,Triggers for treatment: Arm A (delayed),Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,治療開始：A組（延遲組） 除非出現(xiàn)下列情況，如果臨床合適，至少推遲2年 研究1：PSA 12月內(nèi)翻倍或大于10μg/L；研究2：PSA大于60μg/L 或：PSA 6月內(nèi)翻倍 或：出現(xiàn)轉(zhuǎn)移（限于復(fù)發(fā)組）或癥狀 基于臨床的影像學(xué)證據(jù),72,Patient demographics Group 1Median follow-up = 5.0 years,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,73,Patient demographics Group 2 -> Combined with Group 1 for analysis,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,74,Primary endpoint: overall survival,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,75,Primary endpoint: overall survival,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,76,Primary endpoint: overall survival,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,77,Cause-specific survival,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,78,Overall survival by ADT schedule,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,79,Other disease endpoints,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,80,Time to first prostate cancer complication,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,出現(xiàn)前列腺癌并發(fā)癥時間,81,ADT-related symptoms,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,ADT相關(guān)癥狀 A組：89人接受了ADT，61人沒接受 34.7%在前2年 16.7%在2-4年間 8.0%在4年后 40.6%在研究期間未開始ADT ADT平均開始時間18.7月 A組：47.3%報告了ADT相關(guān)癥狀，52.7%無 B組：77.9%報告了ADT相關(guān)癥狀，22.1%無,82,Conclusions,Presented By Gillian Duchesne at 2015 ASCO Annual Meeting,結(jié)論 本試驗提供中等證據(jù)：對于初治或非治愈性前列腺癌PSA復(fù)發(fā)立即進行ADT可以改善5年的OS約10% 立即組前列腺癌并發(fā)癥發(fā)生率低且晚 因為這是一種非治愈性手段，因此，獲益必須考慮ADT治療相關(guān)并發(fā)癥的發(fā)生率（立即組80%，延遲組50%）,83,謝謝！,84,