1、前列腺癌争议话题讨论,1.游离PSA/总PSA比值的意义2.寡转移前列腺癌是否可行前列腺根治术3.前列腺癌间歇内分泌是否可行,前列腺癌的间歇性内分泌治疗是否可行？SWOG9346结果解读,北京大学第一医院泌尿外科北京大学泌尿外科研究所何志嵩,为什么开展间歇性内分泌治疗？,1941年以后内分泌治疗成为晚期前列腺癌的标准治疗内分泌治疗可以改善生存质量内分泌治疗是否可以延长生存期？内分泌治疗有不良反应内分泌治疗应早期开始还是延缓进行？动物试验研究发现中等程度地降低激素水平可以减慢激素依赖性肿瘤细胞的生长并延缓其转变为自主细胞（autonomy）去势可以加速细胞向激素非依赖性自主细胞的转化是否可以周期
2、性进行？,间歇性内分泌治疗的历史,1985年Vahlensieck et al报告比较间歇性与连续性应用雌醇氮芥治疗前列腺癌的结果Urol Res 19851986年Klotz et al报告间歇性应用乙烯雌酚治疗20例前列腺癌患者Cancer 19861995年Goldenberg et al报告间歇性应用CAB治疗43例患者Urology 1995,间歇性内分泌治疗的目的,延长内分泌治疗的时间，进而达到延长生存期的目的减少内分泌治疗的副作用减少治疗费用,间歇性内分泌治疗的理论基础,克隆选择学说适应学说突变学说多肽生长因子及其受体的作用,延长内分泌治疗时间？,延长内分泌治疗时间？,Akaku
3、ra K, et al. Cancer 1993，21: 2782.,延长内分泌治疗时间？,LNCap肿瘤发展到AI的时间，IHT组用77天，而CHT组用27天去势后，IHT组的血清PSA水平在70天时只有75%高于去势前，而CHT组则在28天时均高于去势前Sato N,et al.Steroid Biochem Molec Biol 1996, 58: 139.,68例患者 前瞻性随机化期临床研究 3年疾病进展率间歇组显著低于持续组 (P 0.01). 6.7 (4.6)% 37.5 (10.8)% 在20例明显骨转移患者两组3年疾病进展率上无差异 (P=0.3).,Waltregny D,
4、 Boca P, Nicolas H et al. Urol 2002; 168 (Suppl): A701,欧洲43个研究中心，193名患者随机分组 : IHT (n=97) or CHT (n=96)T2-4N1-3M0(n=37), T2-4N0-3M1(n=156)平均随访66个月 总生存期相近,J.F. Langenhuijsen, et al: European Urology Supplements, 2008; 7(3) : 205,延长内分泌治疗时间？,尚无临床试验研究证实期待SWOG研究结果,减少内分泌治疗的副作用？,内分泌治疗的副作用,潮热乏力性欲下降体重增加肌肉无力贫血
5、骨质疏松,减少内分泌治疗的副作用？,21例IAT，停药3个月后100%潮热消失93%性欲提高90%恢复勃起功能80%感到有精神13%体重恢复Higano et al Urology 1996,改善性功能,Calais et al. reported a phase III study on 636 patients with T34M0 and M1 disease, showing an improvement in sexual activity on the intermittent arm.,Calais F, Bono A, Whelan P et al：. Eur Urol 200
6、2; 41 ；(Suppl): A531,减少骨质疏松,IHT组平均骨密度显著高于CHT组(0.920g/cm2 vs. 0.84g/cm2, p0.05) After 9 months, the mean BMD in these patients had decreased by 4.5% at the lumbar spine (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 lumb
7、ar spine and hip relative to the post-AS values was 1.5% (P=0.06) and 0.01% (P=0.09), respectively.,Y. Takezawa, et al: Urology, Volume 70, Issue 3, Supplement 1, September 2007, Page 306,改善生活质量,49 患者 (26 with T3N0M0, 8 with T2-T3N1M0, 2 with T4N0M0, and 13 with T2-T3N0M1)平均随访136.5周compared with tho
8、se in the on-treatment period. QOL 评分中的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,降低费用？,是的！？,是否与药物去势的方法有关？,单纯药物去势LHRH-A抗雄激素制剂？雌激素最大雄激素阻断,适应症是什么？,标准内分泌治疗的适应症新辅助治疗？辅助治疗？,如何进行？,停止治疗的指征,PSA0.2ng/mlPSA4ng/mlPSA升至10-20ng/mlPSA升至20n
9、g/mlPSA升至治疗前的1/2对于PSA下降80%而未达到正常值者,当PSA上升了最低值的20,间歇内分泌治疗 (IHT)推荐：适应症：局限不适应手术；T3-T4；切缘阳性；根治术或放疗后复发 IHT的治疗模式：多用MAB，也可单用LHRHa停药标准：PSA 0.2ng/ml，维持3-6月重新开始治疗的标准：PSA4ng/ml,CUA前列腺癌诊断治疗指南2011,IAD is based on intermittent castration. Thus, only drugs leading to castration should be considered for use in IAD.
10、It 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 (induction) cycle must last between 6 and 9 months, otherwise testosterone recovery i
11、s unlikely.,In conclusion, IAD is currently widely offered to patients with PCa in various clinical settings, and its status should no longer be regarded as investigational (LE: 2).,存在什么问题？,是否回加速疾病进展？PSA是否是合适的判断指标？缺乏大样本的随机对照研究,间歇性内分泌治疗临床研究,Overall, eight randomised trials are underway, only some of
12、which have published findings. Most of the trials included 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 than 1,300 patients, with
13、one trial focused only on metastatic patients (SWOG 9346) and the other on relapsing patients after radiotherapy (SWOG JPR7),间歇雄激素去除与持续雄激素去除治疗激素敏感性转移性前列腺癌: 国际III期临床研究SWOG 9346 (INT-0162)结果,Hussain M, Tangen CM, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Akdas A, Small EJ, Dawson NA, Donne
14、lly BJ, Venner P, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Vogelzang NJ, Thompson Jr, IM Univ. 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
15、 Wisconsin Carbone Cancer Center, 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 Center, Washington, DC; Prostate Cancer Institute, C
16、algary, Alberta, Canada, Calgary, AB; Cross Cancer Institute, Edmonton, AB; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Urology of Virginia, Norfolk, VA; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Levine Cancer Institute, Carolinas Heal
17、thCare System, Charlotte NC; US Oncology Research, LLC, McKesson Specialty Health, The Woodlands, 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; Cl
18、inicalTrials.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 Group (SWOG).Patients were enrolled by the SWOG, the Eastern Cooperative On
19、cology Group (ECOG), the Cancer and Leukemia Group B (CALGB), the National Cancer Institute of CanadaClinical Trials Group (NCIC-CTG), and the EORTC.Patients who had received prior neoadjuvant or adjuvant androgen-deprivation therapy were eligible if they had received the therapy for 4 months or les
20、s. Patients who had received prior finasteride therapy for prostate 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,主要间歇性内分泌治疗的生存期 is Not Inferior to 持续性内分泌治疗 生活质量*: 比较三项治疗特异性症状（勃起功能、性欲、体能）次要-More general QOL mea
21、sures-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,主要入选标准,新诊断的转移性前列腺癌. 开始内分泌治疗前PSA 5 ng/ml Prior neoadjuvant or adjuvant hormone therapy or prior finasteride was allowed with
22、 some restrictions. SWOG performance status of 0-2. Signed IRB approved informed consent.,2012 ASCO,亚组分层:,体质状态评分: 0 - 1 vs. 2 疾病严重程度: 轻微: 脊柱、骨盆 &/or 淋巴结转移vs.严重: 肋骨、长骨 &/or 内脏 (肝、肺)既往内分泌治疗: 新辅助内分泌治疗 vs. 非那雄胺 vs. 无既往内分泌治疗,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,PRESENTED BY: Maha Hussain, MD, F
23、ACP,研究设计,Induction Registration新诊断的转移性前列腺癌 & a PSA 5 ng/mL,如果在治疗的第6和第7月时PSA 4 ng/mL,步骤 2随机化,持续内分泌治疗（CAD）,间歇性内分泌治疗（IAD）,步骤 1,内分泌治疗 = Goserelin + Bicalutamide X 7 months,停止内分泌治疗，每月检测PSA，当PSA达到标准时恢复内分泌治疗,2012 ASCO,The South West Oncology Group (SWOG) trial 9346 randomised 1,134 men with stage D2 PCa to
24、 intermittent and continuous ADT after 7 months induction ADT with PSA reduction 4 ng/mL was identified as a significant prognostic factor with regard to survival, achieving 13 months, 44 months and 75 months, respectively.,J Clin Oncol 2006 Aug;24(24):3984-90,IAD 组: 治疗流程,当PSA上升至 20 ng/ml (如初始治疗时PSA
25、 20 ng/ml，则当PSA上升至初始治疗水平) or 出现症状时：恢复内分泌治疗 如果恢复内分泌治疗7个月后的PSA水平再次满足正常标准，患者开始进入另一个间歇期.如果在在第6和第7月时PSA均大于 4 ng/ml，则患者转为接受出现内分泌治疗.,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,PRESENTED BY: Maha Hussain, MD, FACP,统计学方法,主要目的: 随机后生存期假设: “IAD is NOT inferior to CAD” Design specifications:Survival with IAD
26、 is not inferior if the 95% confidence interval for the hazard ratio (IAD vs. CAD) excludes 1.2, =0.05, power=90%, adjusting for stratification factors in proportional hazards model. 假设: 随机后中位生存期 CAD = 3 years:样本量: 1500 eligible, randomized patients计划: 6.25 yrs. + 2 additional yrs. of follow-up.,201
27、2 ASCO,SWOG9346,启动: 5/15/1995 结束: 9/1/2008,CAD765 eligible patients,PRESENTED BY: Maha 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,随机时（步骤二）患者特征,2012 ASCO,Adverse Events with a Grade 4 Reported*,*
28、 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 267 47 Continuous 301 53,Overall Survival: Intermittent Therapy is Inferior Compared to Continuous Therapy,
29、PRESENTED BY: 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*,Extensive disease,Minimal disease,Bone pain,No bone pain,PSA at Randomizatio
30、n 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, 1.16),7 YearSurvival,33%,33%,At riskIntermittent 119 11 Continuous 106 22,Overall Survival for Patients with Extensive Disease by Treatment Arm,PRESENTED BY: Maha Hussai
31、n, MD, FACP,2012 ASCO,7 yr. Survival,HR: 1.23, 95% CI (1.02, 1.49) p=0.034,50%42%,At riskIntermittent 143 35 Continuous 194 30,Overall Survival for Patients with Minimal Disease by Treatment Arm,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,结论,根据SWOG9346研究预设的标准，IAD的生存期 was inferior to CAD HR: 1.09,
32、 95% CI (0.95, 1.24). 因此 CAD仍应为标准治疗.In a secondary analysis: 对于转移程度严重的患者，IAD was not-inferior to CAD HR: 0.96 95% CI (0.80, 1.16). 对于转移程度轻微的患者，IAD was inferior ，统计学有显著性差异 HR: 1.23, 95% CI (1.02, 1.49), p=0.034. These observations suggest inherent biological differences and warrant further mechanisti
33、c evaluation.,PRESENTED BY: Maha Hussain, MD, FACP,2012 ASCO,关于SWOG9346研究的疑问,停止及恢复内分泌治疗的标准分层的标准预期生存远低于实际生活质量评估,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,HR1.10; 90%
34、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,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,Late Effects: Cumulative Incidence,Presented
35、By Dawn Hershman at 2015 ASCO Annual Meeting,Late Effects: Cumulative Incidence,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,Multivariable Regression Results,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,ADT治疗的早期是CVD发生的危险时期,Summary,Presented By Dawn Hershman at 2015 ASCO Annual Meeting,谢 谢,
