前列腺癌爭(zhēng)議話(huà)題討論

1、前列腺癌爭(zhēng)議話(huà)題討論,,,1.游離PSA/總PSA比值的意義2.寡轉(zhuǎn)移前列腺癌是否可行前列腺根治術(shù)3.前列腺癌間歇內(nèi)分泌是否可行,前列腺癌的間歇性?xún)?nèi)分泌治療是否可行？——SWOG9346結(jié)果解讀,北京大學(xué)第一醫(yī)院泌尿外科北京大學(xué)泌尿外科研究所何志嵩,為什么開(kāi)展間歇性?xún)?nèi)分泌治療？,1941年以后內(nèi)分泌治療成為晚期前列腺癌的標(biāo)準(zhǔn)治療內(nèi)分泌治療可以改善生存質(zhì)量?jī)?nèi)分泌治療是否可以延長(zhǎng)生存期？?jī)?nèi)分泌治療有不良反應(yīng)內(nèi)分泌治療應(yīng)早期

2、開(kāi)始還是延緩進(jìn)行？動(dòng)物試驗(yàn)研究發(fā)現(xiàn)中等程度地降低激素水平可以減慢激素依賴(lài)性腫瘤細(xì)胞的生長(zhǎng)并延緩其轉(zhuǎn)變?yōu)樽灾骷?xì)胞（autonomy）去勢(shì)可以加速細(xì)胞向激素非依賴(lài)性自主細(xì)胞的轉(zhuǎn)化是否可以周期性進(jìn)行？,間歇性?xún)?nèi)分泌治療的歷史,1985年Vahlensieck et al報(bào)告比較間歇性與連續(xù)性應(yīng)用雌醇氮芥治療前列腺癌的結(jié)果Urol Res 19851986年Klotz et al報(bào)告間歇性應(yīng)用乙烯雌酚治療20例前列腺癌患者Canc

3、er 19861995年Goldenberg et al報(bào)告間歇性應(yīng)用CAB治療43例患者Urology 1995,間歇性?xún)?nèi)分泌治療的目的,延長(zhǎng)內(nèi)分泌治療的時(shí)間，進(jìn)而達(dá)到延長(zhǎng)生存期的目的減少內(nèi)分泌治療的副作用減少治療費(fèi)用,間歇性?xún)?nèi)分泌治療的理論基礎(chǔ),克隆選擇學(xué)說(shuō)適應(yīng)學(xué)說(shuō)突變學(xué)說(shuō)多肽生長(zhǎng)因子及其受體的作用,,延長(zhǎng)內(nèi)分泌治療時(shí)間？,,延長(zhǎng)內(nèi)分泌治療時(shí)間？,,Akakura K, et al. Cancer 1993，21: 2

4、782.,延長(zhǎng)內(nèi)分泌治療時(shí)間？,LNCap腫瘤發(fā)展到AI的時(shí)間，IHT組用77天，而CHT組用27天去勢(shì)后，IHT組的血清PSA水平在70天時(shí)只有75%高于去勢(shì)前，而CHT組則在28天時(shí)均高于去勢(shì)前Sato N,et al.Steroid Biochem Molec Biol 1996, 58: 139.,68例患者 前瞻性隨機(jī)化期臨床研究 —3年疾病進(jìn)展率間歇組顯著低于持續(xù)組 (P < 0.01).

5、 6.7 (4.6)% 37.5 (10.8)% —在20例明顯骨轉(zhuǎn)移患者兩組3年疾病進(jìn)展率上無(wú)差異 (P=0.3).,Waltregny D, Boca P, Nicolas H et al. Urol 2002; 168 (Suppl): A701,歐洲43個(gè)研究中心，193名患者隨機(jī)分組 : IHT (n=97) or CHT (n=96)T2-4N1-3M0(n=37), T2-4N0

6、-3M1(n=156)平均隨訪(fǎng)66個(gè)月 總生存期相近,J.F. Langenhuijsen, et al: European Urology Supplements, 2008; 7(3) : 205,延長(zhǎng)內(nèi)分泌治療時(shí)間？,尚無(wú)臨床試驗(yàn)研究證實(shí)期待SWOG研究結(jié)果,減少內(nèi)分泌治療的副作用？,,內(nèi)分泌治療的副作用,潮熱乏力性欲下降體重增加肌肉無(wú)力貧血骨質(zhì)疏松,減少內(nèi)分泌治療的副作用？,21例IAT，停藥3個(gè)月后100%

7、潮熱消失93%性欲提高90%恢復(fù)勃起功能80%感到有精神13%體重恢復(fù)Higano et al Urology 1996,改善性功能,Calais et al. reported a phase III study on 636 patients with T3–4M0 and M1 disease, showing an improvement in sexual activity on the intermittent a

8、rm.,Calais F, Bono A, Whelan P et al：. Eur Urol 2002; 41 ；(Suppl): A531,減少骨質(zhì)疏松,IHT組平均骨密度顯著高于CHT組(0.920g/cm2 vs. 0.84g/cm2, p<0.05) After 9 months, the mean BMD in these patients had decreased by 4.5% at the lumbar s

9、pine (P=0.0007) and by 2.5% at the hip (P=0.00013). After a median off-treatment period of 7.9 months, the mean change in BMD of the lumbar spine and hip relative to the post-AS values was 1.5% (P=0.06) and 0.01% (P=0.

10、09), respectively.,Y. Takezawa, et al: Urology, Volume 70, Issue 3, Supplement 1, September 2007, Page 306,改善生活質(zhì)量,49 患者 (26 with T3N0M0, 8 with T2-T3N1M0, 2 with T4N0M0, and 13 with T2-T3N0M1)平均隨訪(fǎng)136.5周compared with th

11、ose in the on-treatment period. QOL 評(píng)分中的potency(11.4 versus 2.4) social/family well-being (20.3 versus 16.1),NAOHIDE SATO,et al: UROLOGY 64 (2), 2004: 341-45,降低費(fèi)用？,是的?。?是否與藥物去勢(shì)的方法有關(guān)？,單純藥物去勢(shì)LHRH-A抗雄激素制劑？雌激素最大雄激素阻斷,適

12、應(yīng)癥是什么？,標(biāo)準(zhǔn)內(nèi)分泌治療的適應(yīng)癥新輔助治療？輔助治療？,如何進(jìn)行？,,停止治療的指征,PSA<0.2ng/mlPSA<4.0ng/mlPSA下降至治療前的90%在最低點(diǎn)維持3~6個(gè)月各家報(bào)道極不統(tǒng)一,停止治療的指征,The median PSA nadir was 0.1, 1.1, 0.8, 2.0 and 3.3 ng/mL after the first, second, third, fourth,

13、and fifth cycles, respectively (Fig. 1).,(Am J Clin Oncol 2003;26: e119–e123),恢復(fù)治療的指征,PSA>4ng/mlPSA升至10-20ng/mlPSA升至20ng/mlPSA升至治療前的1/2對(duì)于PSA下降80%而未達(dá)到正常值者,當(dāng)PSA上升了最低值的20％,,間歇內(nèi)分泌治療 (IHT)推薦：適應(yīng)癥：局限不適應(yīng)手術(shù)；T3-T4；切緣陽(yáng)性；根治

14、術(shù)或放療后復(fù)發(fā) IHT的治療模式：多用MAB，也可單用LHRHa停藥標(biāo)準(zhǔn)：PSA ≤0.2ng/ml，維持3-6月重新開(kāi)始治療的標(biāo)準(zhǔn)：PSA＞4ng/ml,CUA前列腺癌診斷治療指南2011,,IAD is based on intermittent castration. Thus, only drugs leading to castration should be considered for use in IAD.It

15、 is unclear if an LHRH agonist may be used alone, as published experiences are based on CAB. An LHRH antagonist might be a valid alternative, provided clear results are obtained from randomised trials.The initial (indu

16、ction) cycle must last between 6 and 9 months, otherwise testosterone recovery is unlikely.,,,,,In conclusion, IAD is currently widely offered to patients with PCa in various clinical settings, and its status should no l

17、onger be regarded as investigational (LE: 2).,存在什么問(wèn)題？,是否回加速疾病進(jìn)展？PSA是否是合適的判斷指標(biāo)？缺乏大樣本的隨機(jī)對(duì)照研究,間歇性?xún)?nèi)分泌治療臨床研究,Overall, eight randomised trials are underway, only some of which have published findings. Most of the trials incl

18、uded a mixed patient population, i.e. both locally advanced and metastatic disease. Only three trials included only metastatic patients, and two trials only relapsing patients. The two largest trials each contained more

19、than 1,300 patients, with one trial focused only on metastatic patients (SWOG 9346) and the other on relapsing patients after radiotherapy (SWOG JPR7),間歇雄激素去除與持續(xù)雄激素去除治療激素敏感性轉(zhuǎn)移性前列腺癌: 國(guó)際III期臨床研究SWOG 9346 (INT-0162)結(jié)果,Huss

20、ain M, Tangen CM, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Akdas A, Small EJ, Dawson NA, Donnelly BJ, Venner P, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Vogelzang NJ, Thompson Jr, IM Univ.

21、of Michigan, Ann Arbor, MI; SWOG Statistical Center, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Colorado Health Science Center, Aurora, CO; University of Wisconsin Carbone Cancer Cent

22、er, Madison, WI; St. James University Hopsital, Leeds, UK; Marmara University, Istanbul, Turkey; University of California, San Francisco, San Francisco, CA; Georgetown University Hospital Lombardi Comprehensive Cancer Ce

23、nter, Washington, DC; Prostate Cancer Institute, Calgary, Alberta, Canada, Calgary, AB; Cross Cancer Institute, Edmonton, AB; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Urology of Virginia, Norfolk,

24、VA; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Levine Cancer Institute, Carolinas HealthCare System, Charlotte NC; US Oncology Research, LLC, McKesson Specialty Health, The Woo

25、dlands, TX, and Comprehensive Cancer Centers of Nevada, Las Vegas, NV; University of Texas Health Science Center at San Antonio, San Antonio, TX,2012 ASCO,,,(Funded by the National Cancer Institute and others; ClinicalTr

26、ials.gov number, NCT00002651.),N Engl J Med 2013;368:1314-25.,,The study was designed in 1993 by the first author and by the leaders of the genitourinary cancer and quality-of-life committees of the Southwest Oncology Gr

27、oup (SWOG).Patients were enrolled by the SWOG, the Eastern Cooperative Oncology Group (ECOG), the Cancer and Leukemia Group B (CALGB), the National Cancer Institute of Canada–Clinical Trials Group (NCIC-CTG), and the E

28、ORTC.Patients who had received prior neoadjuvant or adjuvant androgen-deprivation therapy were eligible if they had received the therapy for 4 months or less. Patients who had received prior finasteride therapy for pro

29、state cancer were eligible if they had received the drug for 9 months or less.,PRESENTED BY: Maha Hussain, MD, FACP,SWOG9346 (INT-0162): 研究目的,主要間歇性?xún)?nèi)分泌治療的生存期 is Not Inferior to 持續(xù)性?xún)?nèi)分泌治療 生活質(zhì)量*: 比較三項(xiàng)治療特異性癥狀（勃起功能、性欲、體能）

30、次要-More general QOL measures-PSA dynamics between arms, and correlations with other endpoints,*Moinpour et-al, Abstract # 4571 describes results for QOL,2012 ASCO,PRESENTED BY: Maha Hussain, MD, FACP,主要入選標(biāo)準(zhǔn),新診斷的轉(zhuǎn)移性前

31、列腺癌. 開(kāi)始內(nèi)分泌治療前PSA ? 5 ng/ml Prior neoadjuvant or adjuvant hormone therapy or prior finasteride was allowed with some restrictions. SWOG performance status of 0-2. Signed IRB approved informed consent.,2012 ASCO,

32、亞組分層:,體質(zhì)狀態(tài)評(píng)分: 0 - 1 vs. 2 疾病嚴(yán)重程度: 輕微: 脊柱、骨盆 &/or 淋巴結(jié)轉(zhuǎn)移vs.嚴(yán)重: 肋骨、長(zhǎng)骨 &/or 內(nèi)臟 (肝、肺)既往內(nèi)分泌治療: 新輔助內(nèi)分泌治療 vs. 非那雄胺 vs. 無(wú)既往內(nèi)分泌治療,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,PRESENTED BY: Maha Hussain, MD, FACP,研

33、究設(shè)計(jì),Induction Registration新診斷的轉(zhuǎn)移性前列腺癌 & a PSA ? 5 ng/mL,,如果在治療的第6和第7月時(shí)PSA ? 4 ng/mL,步驟 2隨機(jī)化,,持續(xù)內(nèi)分泌治療（CAD）,間歇性?xún)?nèi)分泌治療（IAD）,步驟 1,,內(nèi)分泌治療 = Goserelin + Bicalutamide X 7 months,停止內(nèi)分泌治療，每月檢測(cè)PSA，當(dāng)PSA達(dá)到標(biāo)準(zhǔn)時(shí)恢復(fù)內(nèi)分泌治療,,,2012 ASC

34、O,,The South West Oncology Group (SWOG) trial 9346 randomised 1,134 men with stage D2 PCa to intermittent and continuous ADT after 7 months’ induction ADT with PSA reduction 4 ng/mL was identified as a significant progn

35、ostic factor with regard to survival, achieving 13 months, 44 months and 75 months, respectively.,J Clin Oncol 2006 Aug;24(24):3984-90,IAD 組: 治療流程,當(dāng)PSA上升至 20 ng/ml (如初始治療時(shí)PSA < 20 ng/ml，則當(dāng)PSA上升至初始治療水平) or 出現(xiàn)癥狀時(shí)：恢復(fù)內(nèi)分泌治

36、療 如果恢復(fù)內(nèi)分泌治療7個(gè)月后的PSA水平再次滿(mǎn)足正常標(biāo)準(zhǔn)，患者開(kāi)始進(jìn)入另一個(gè)間歇期.如果在在第6和第7月時(shí)PSA均大于 4 ng/ml，則患者轉(zhuǎn)為接受出現(xiàn)內(nèi)分泌治療.,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,PRESENTED BY: Maha Hussain, MD, FACP,統(tǒng)計(jì)學(xué)方法,主要目的: 隨機(jī)后生存期假設(shè): “IAD is NOT inferior to

37、 CAD” Design specifications:Survival with IAD is not inferior if the 95% confidence interval for the hazard ratio (IAD vs. CAD) excludes 1.2, α=0.05, power=90%, adjusting for stratification factors in proportional haz

38、ards model. 假設(shè): 隨機(jī)后中位生存期 CAD = 3 years:樣本量: 1500 eligible, randomized patients計(jì)劃: 6.25 yrs. + 2 additional yrs. of follow-up.,2012 ASCO,SWOG9346,啟動(dòng): 5/15/1995 結(jié)束: 9/1/2008,,CAD765 eligible patients,PRESENTED BY: M

39、aha Hussain, MD, FACP,2012 ASCO,S9346 Study Information N=3040,PRESENTED BY: Maha Hussain, MD, FACP,Black,2012 ASCO,PRESENTED BY: Maha Hussain, MD, FACP,隨機(jī)時(shí)（步驟二）患者特征,2012 ASCO,Adverse Events with a Grade 4 Reported*

40、,* Treatment attribution: possible, probable, or definite, No Grade 5 reported,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,HR: 1.09 95% CI (0.95, 1.24),7 yrSurvival,42%38%,At riskIntermittent

41、 267 47 Continuous 301 53,,Overall Survival: Intermittent Therapy is Inferior Compared to Continuous Therapy,PRESENTED BY:

42、 Maha Hussain, MD, FACP,2012 ASCO,PRESENTED BY: Maha Hussain, MD, FACP,Evaluating Homogeneity of Treatment Effect Across Subsets of Patients,favors favors intermittent continuous,1.0,1.2,,,,p=0.08*,p=0.26*,p=0.94

43、*,Extensive disease,Minimal disease,Bone pain,No bone pain,PSA at Randomization ≤ 0.2 ng/ml,PSA at Randomization 0.3 - 4.0 ng/ml,Overall,* test of factor x treatment interaction,2012 ASCO,,HR: 0.96 95% CI (0.80,

44、1.16),7 YearSurvival,33%,33%,At riskIntermittent 119 11 Continuous 106 22,Overall Survival for Patien

45、ts with Extensive Disease by Treatment Arm,,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,7 yr. Survival,HR: 1.23, 95% CI (1.02, 1.49) p=0.034,,50%42%,At riskIntermittent 143

46、 35 Continuous 194 30,,Overall Survival for Patients with Minimal Disease by Treatment Arm,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,結(jié)論,根據(jù)

47、SWOG9346研究預(yù)設(shè)的標(biāo)準(zhǔn)，IAD的生存期 was inferior to CAD [HR: 1.09, 95% CI (0.95, 1.24)]. 因此 CAD仍應(yīng)為標(biāo)準(zhǔn)治療.In a secondary analysis: 對(duì)于轉(zhuǎn)移程度嚴(yán)重的患者，IAD was not-inferior to CAD [HR: 0.96 95% CI (0.80, 1.16)]. 對(duì)于轉(zhuǎn)移程度輕微的患者，IAD was inferior

48、 ，統(tǒng)計(jì)學(xué)有顯著性差異 [HR: 1.23, 95% CI (1.02, 1.49), p=0.034]. These observations suggest inherent biological differences and warrant further mechanistic evaluation.,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,關(guān)于SWOG9346研究的疑問(wèn)

49、,停止及恢復(fù)內(nèi)分泌治療的標(biāo)準(zhǔn)分層的標(biāo)準(zhǔn)預(yù)期生存遠(yuǎn)低于實(shí)際生活質(zhì)量評(píng)估,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,,,,

50、,,,HR1.10; 90%CI, 0.99 to 1.23,,,Study Objectives / Hypothesis,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,,Slide 8,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,,Late Effects: Cumulative Incidence,P

51、resented By Dawn Hershman at 2015 ASCO Annual Meeting,Late Effects: Cumulative Incidence,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,Late Effects: Cumulative Incidence,Presented By Dawn Hershman at 2015 ASCO A