去勢(shì)抵抗性前列腺癌的治療進(jìn)展

1、會(huì)計(jì)學(xué)1去勢(shì)抵抗性前列腺癌的治療進(jìn)展去勢(shì)抵抗性前列腺癌的治療進(jìn)展Source:American Cancer Society,Cancer Facts and Figures 2007.Atlanta,GA;American Cancer Society:2007.2009，USA:192,28027.360摘自：復(fù)旦大學(xué)腫瘤醫(yī)院泌尿外科 葉定偉ClinicallyLocalizedHormoneRefractoryLocal treatmentLocal treatmentEndocrineChemotherapyRelapsedandNewly diagnosed M+EORTG22863

2、.,EORTG22961-SADT vs LADT.2010,4505ADT vs RT+ADTIntergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633). J Clin Oncol (Meeting Abstracts) 2010 28: CRA4504. C

3、linicallyLocalizedHormoneRefractoryLocal treatmentLocal treatmentEndocrineChemotherapyRelapsedandNewly diagnosed M+Safety results of a phase III trial evaluating ADT+ docetaxel versus ADT alone in hormone-nave metastatic prostate cancer patients (GETUG-AFU 15/0403). J Clin Oncol 28:15s, 2010 (suppl;

4、 abstr 4681) 前列腺癌的內(nèi)分泌治療前列腺癌的內(nèi)分泌治療0 4 8 122436480248101214161820平均血清睪酮濃度平均血清睪酮濃度(nmol/L)戈舍瑞林戈舍瑞林 3.6 mg (n=148)睪丸切除術(shù)睪丸切除術(shù) (n=144)時(shí)間時(shí)間 (周周)注射 戈舍瑞林 3.6 mg 或睪丸切除術(shù)后平均血清睪酮濃度腫瘤治療-內(nèi)分泌療法 內(nèi)分泌治療和化學(xué)藥物治療一樣最終出現(xiàn)耐藥現(xiàn)象，即激素治療抵抗（Resistance to hormone therapy），激素受體基因突變是腫瘤獲得性激素抵抗表型的分子機(jī)制。 正是由于激素受體基因突變，一部分患者存在激素治療撤退反應(yīng)（Horm

5、one therapy withdrawal response），如前列腺癌患者抗雄激素藥物治療失敗后，停藥可使約30%的病人腫瘤緩解或PSA水平下降，并且骨掃描、癌性貧血以及其他相關(guān)癥狀改善，中位緩解時(shí)間3.5-5月，個(gè)別患者超過2年，停藥反應(yīng)動(dòng)力學(xué)因不同制劑而異。 內(nèi)分泌治療另一種現(xiàn)象就是激素治療點(diǎn)火現(xiàn)象（Hormone therapy flare），即激素治療初期臨床癥狀、腫瘤指標(biāo)、核素掃描甚至PET掃描有病變加重的現(xiàn)象，但這種現(xiàn)象常預(yù)示進(jìn)一步激素治療有效。如AA治療CRPC約半數(shù)病人出現(xiàn)骨掃描閃爍現(xiàn)象。雄激素依賴性前列腺癌雄激素依賴性前列腺癌（Androgen-dependent Pr

6、ostate Cancer, ADPC）雄激素非依賴性前列腺癌（androgen-independent prostate cancer,AIPC）激素難治性前列腺癌（hormone-refractory prostate cancer,HRPC） 去勢(shì)抵抗性前列腺癌去勢(shì)抵抗性前列腺癌（Castration resistant prostate cancer，CRPC ) J Clin Oncol 28:15s, 2010 (suppl; abstr 4653)J Clin Oncol 28:15s, 2010 (suppl; abstr 4653) PSA-P（prostate-specif

7、ic antigen progression ,PSA-P）作為疾病進(jìn)展的指標(biāo)近來用于研究的終點(diǎn)。 99共識(shí)把PSA-P定義為PSA較基礎(chǔ)值或最低值增加50%，并且PSA5ng/ml（07共識(shí)2ng/ml），一周后應(yīng)確認(rèn)。 以99共識(shí)對(duì)S9346研究進(jìn)行分析（激素敏感性前列腺癌），發(fā)現(xiàn)在7個(gè)月時(shí)達(dá)PSA-P的患者總生存為10月，而7個(gè)月時(shí)未達(dá)到PSA-P者總生存為43月；對(duì)S9916研究進(jìn)行分析（HRPC），以PSA-P為3個(gè)月，則總生存分別為10月和18月。* 這說明不論P(yáng)SA是否達(dá)到最低值，PSA-P定義為PSA較基礎(chǔ)值或最低值增加50%，并且PSA25ng/ml，對(duì)激素敏感性或激素難治性

8、前列腺癌均能很好的反應(yīng)總生存。Hussain MH,et al.ASCO 2008,5015aPSAPSA進(jìn)展進(jìn)展FactorHazard Ratio95% CIPBiochemical progression using the definition of PSAWG1, yes v no1.441.28 to 1.62 .0001Biochemical progression using the definition of PSAWG2, yes v no1.431.27 to 1.61 .0001Multivariable Proportional Hazards Model of Bi

9、ochemical PFS at 3 Months as Time-Dependent Covariate Predicting Overall Survival Stratified on Study（1296pts)Halabi, S. et al. J Clin Oncol; 27:2766-2771 2009Copyright American Society of Clinical OncologyHalabi, S. et al. J Clin Oncol; 27:2766-2771 2009Kaplan-Meier survival curves by biochemical p

10、rogression using Prostate-Specific Antigen Working Group 1999 Criteria (PSAWG1) at 3 monthsCopyright American Society of Clinical OncologyHalabi, S. et al. J Clin Oncol; 27:2766-2771 2009Kaplan-Meier survival curves by progression-free survival (PFS) at 3 months6個(gè)月的PFSHR 1.9,P50%Estramustine-based C

11、hemotherapy雌二醇氮芥加化療治療雌二醇氮芥加化療治療CRPCCRPC薈萃分析薈萃分析Fizazi K,et al. Lancet Oncol,2007,8:994-1000.以泰素蒂為基礎(chǔ)的化療與米托蒽醌加波尼以泰素蒂為基礎(chǔ)的化療與米托蒽醌加波尼松兩項(xiàng)松兩項(xiàng)IIIIII期臨床試驗(yàn)的比較期臨床試驗(yàn)的比較 SWOG9916 TAX327泰素蒂治療組PSA有效率（%） 50 45.4米托蒽醌治療組PSA有效率（%） 27 32泰素蒂治療組總生存（月） 18 18.9與米托蒽醌治療組比較生存期改善（月） 2 2.5與米托蒽醌治療組比較風(fēng)險(xiǎn)比（P值） 0.8(0.01) 0.76(0.009)

12、Docetaxel (D) plus high-dose calcitriol versus D plus prednisone (P) for patients (Pts) with progressive castration-resistant prostate cancer (CRPC): Results from the phase III ASCENT2 trial D（weekly)+C:477D(3 weeks):467疾病死亡(%)142（29.8%)108(22.7%)其它(%)32（6.7%)30(6.3%)中位總生存（月）16.819.9HR1.33,P=0.019J

13、Clin Oncol 2010 28, No 15_suppl: 4509 Sartor AO, et al. ASCO GU 2010. Abstract 9.Cabazitaxel 25 mg/m2 q3w + Prednisone* PO 10 mg/day(n = 378)Mitoxantrone 12 mg/m2 q3w + Prednisone* PO 10 mg/day(n = 377)Patients with mCRPC who progressed during/after docetaxel-based treatment (N = 755)Stratified by E

14、COG PS (0-1 vs 2) and measurable vs nonmeasurable disease10 cycles*Prednisone/prednisolone.Sartor AO, et al. ASCO GU 2010. Abstract 9.Cabazitaxel/prednisone 15.1 mosMitoxantrone/prednisone 12.7 mosMedian OS100806040200Proportion of OS (%)0 Mos6 Mos12 Mos18 Mos24 Mos30 Mos37730018867113783212319028MP

15、CBZPPts at Risk, n14Outcome, MosCabazitaxel/Prednisone(n = 378)Mitoxantrone/Prednisone(n = 377)Median PFS2.81.4Median TTPTumor assessment8.85.4PSA assessment6.43.1Pain assessment11.1Not reachedCabazitaxel/prednisoneMitoxantrone/prednisoneHR: 0.74 (95% CI: 0.64-0.86;P .0001)100806040200Proportion of

16、OS (%)031218213771159423781681500MPCBZPPts at Risk, n15646529092752MosSartor AO, et al. ASCO GU 2010. Abstract 9.AE, %Cabazitaxel/Prednisone (n = 371)Mitoxantrone/Prednisone (n = 371)All GradeGrade 3All GradeGrade 3Anemia97.310.581.44.9Leukopenia95.768.292.542.3Neutropenia93.581.787.658.0Thrombocyto

17、penia47.44.043.11.6Diarrhea46.66.210.50.3Fatigue36.74.927.53Nausea34.21.922.90.3Vomiting22.61.910.20Asthenia20.54.612.42.4Hematuria16.71.93.80.5Back pain16.23.812.13Abdominal pain11.61.93.50Febrile neutropenia7.57.51.31.3Sartor AO, et al. ASCO GU 2010. Abstract 9.PopulationPopulation N (%)N (%)Media

18、nMedianOS (mos)OS (mos)N (%)N (%)MedianMedianOS (mos)OS (mos)HR (95%CI)HR (95%CI)ITTITT377 (100)12.7378 (100)15.10.70 (0.59-0.83)PD while on DPD while on D103 (27)12.0113 (30)14.20.65 (0.47-0.90)PD after last D PD after last D dosedose 3 mos3 mos180 (48)10.3158 (42)13.90.70 (0.54-0.90) 3 mos3 mos91

19、(24)17.7103 (27)17.50.78 (0.53-1.14) MP CbzP CbzP vs. MPDeBono JS,et al.J Clin Oncol 28:7s, 2010 (suppl; abstr 4508) J Clin Oncol 28:7s, 2010 (suppl; abstr 4682) Petrylak D,et al.ASCO 2007 5019aSartor AO,et al. ASCO, 2008,5003aCopyright American Society of Clinical OncologySternberg, C. N. et al. J

20、Clin Oncol; 27:5431-5438 2009 (A) Progression-free survival (intent-to-treat population) and (B) overall survival (intent-to-treat population)Ning YM,et al.ASCO 2008,5000aNing YM et al.J Clin Oncology, 2010;28 (12) : 2070-2076 There was also a strong inverse correlation between relative change in PS

21、A over 6 weeks and the absolute difference in CAECs (r = 0.82; P .001). circulating apoptotic endothelial cells (CAECs) EndpointEndpointDP+BDP+B(N=524)(N=524)DPDP(N=526)(N=526)HRHR(95% CI)(95% CI)p valuep valueMedian OS (months)Median OS (months) (95% CI)(95% CI)22.622.6 (21.1-24.5)(21.1-24.5)21.521

22、.5 (20.0-23.0)(20.0-23.0)0.910.91 (0.78-1.05)(0.78-1.05)0.1810.181* *Median PFS Median PFS (months)(months) (95% CI)(95% CI)9.99.9 (9.1-10.6)(9.1-10.6)7.57.5 (6.7-8.0)(6.7-8.0)0.770.77 (0.68-0.88)(0.68-0.88)0.00010.0001* * 50% decline in 50% decline in PSAPSA (95% CI)(95% CI)69.5%69.5% (65.2-73.5)(6

23、5.2-73.5)57.9%57.9% (53.3-62.3)(53.3-62.3)N/AN/A0.00020.0002Objective responseObjective response (95% CI)(95% CI) (#pts with (#pts with measurable disease)measurable disease)53.2%53.2% (46.8-59.6)(46.8-59.6) (248)(248)42.1%42.1% (36.2-48.2)(36.2-48.2) (273)(273)N/AN/A0.01130.0113Grade 3 or higher Gr

24、ade 3 or higher treatmenttreatment related AErelated AE74.8%74.8%55.3%55.3%N/AN/A0.001 10 bone metastases, %42.842.7Bisphosphonate use, %48.148.0Prior docetaxel, %15.512.3Serum PSA, ng/mL51.747.2Alkaline phosphatase, g/dL99.0109.0LDH, u/L194.0193.0Kantoff P, et al. ASCO GU 2010. Abstract 8.Kantoff P

25、, et al. ASCO GU 2010. Abstract 8.Sipuleucel-T Placebo HR: 0.759 (95% CI: 0.606-0.951)P = .017 (Cox model)Median OS25.8 mos21.7 mos36-Month OS32.1%23.0%Sipuleucel-T was approved by the FDA on April 30, 2010, for the treatment of metastatic prostate cancer100806040200Survival (%)012Time From Randomiz

26、ation (Mos)243648607234127414256183171123592252Sipuleucel-TPlaceboPts at Risk, nAE,* %Sipuleucel-TPlaceboChills54.112.5Pyrexia29.313.7Headache16.04.8Influenzalike illness9.83.6Myalgia9.84.8Hypertension7.43.0Hyperhidrosis5.30.6Groin pain5.02.4*Occurring in 5% of patients receiving sipuleucel-T with 2

27、-fold increase in incidence relative to placebo.Kantoff P, et al. ASCO GU 2010. Abstract 8.Predictors of outcome and subgroup results from the integrated analysis of sipuleucel-T trials in metastatic castration-resistant prostate cancer J Clin Oncol 28:7s, 2010 (suppl; abstr 4550) Methods: OS for 3

28、randomized, double blind, placebo controlled trials was analyzed using a Cox regression model with treatment, adjusted for baseline PSA (ln) and LDH (ln), stratified by study. Results: The integrated analysis included 737 randomized patients (488 sipuleucel-T: 249 placebo) with median follow-up of 3

29、6 months. There was a significant sipuleucel-T treatment effect (HR=0.735, 95% CI:0.613, 0.882, P 0.001), which was found to be homogeneous across the 3 trials (study by treatment interaction P=0.66). A positive treatment effect (HR 20nmol/mmol Cr 和uNTx 20nmol/mmol Cr的患者中位總生存分別為12月和25月。Rajpar S ，et

30、al.ASCO 2008,5138a隨隨機(jī)機(jī)化化安慰劑 ，1次/3周+口服維生素D 400 IU和鈣500 mg/天唑來膦酸 4 mg，1次/3周 + 口服維生素D 400 IU和鈣500 mg/天015 月核心分析24 月最終分析n = 214n = 208根據(jù)診斷前列腺癌時(shí)是否出現(xiàn)遠(yuǎn)處轉(zhuǎn)移對(duì)患者進(jìn)行分層唑來膦酸 8 mg，1次/3周 +口服維生素D 400 IU和鈣500 mg/天n = 221唑來膦酸用于晚期前列腺癌唑來膦酸用于晚期前列腺癌-039研究前列腺癌前列腺癌療效總結(jié)療效總結(jié) 產(chǎn)生SRE的 產(chǎn)生SRE的 平均骨并發(fā)癥多事件分析 患者比例, % 中位時(shí)間, 天 發(fā)病率危險(xiǎn)比唑來膦酸

31、4 mg 38488 0.77 0.640 n = 214安慰劑493211.47n = 208P 值 .028.009.005.002唑來膦酸可以顯著減少前列腺癌骨轉(zhuǎn)移患者的骨并發(fā)癥前列腺癌前列腺癌生存分析生存分析 0204060801000120240360480600720840960天天*生存患者比例，生存患者比例，中位數(shù)中位數(shù), 天天P 值值唑來膦酸唑來膦酸 4 mg 546 .103安慰劑安慰劑469*開始研究藥物治療后的時(shí)間開始研究藥物治療后的時(shí)間.唑來膦酸唑來膦酸 4 mg214 1621135610 安慰劑安慰劑 20814894405前列腺癌患者的骨折與生存情況呈負(fù)相關(guān)前列

32、腺癌患者的骨折與生存情況呈負(fù)相關(guān)Oefelein M, et al. J Urol. 2002;168:1005-1007.1.00.90.80.70.60.50.40.30.20.1+ + + +有骨折史有骨折史24 .04無骨折史無骨折史171020406080100120140160180200時(shí)間時(shí)間, 月月累積生存患者比例P 值值nJ Clin Oncol 28:18s, 2010 (suppl; abstr LBA4507) 1. Smith MR, et al N Engl J Med. 2009;361:745-755. 2. Smith MR, et al. ASCO GU

33、2010. Abstract 25. Denosumab 60 mg SQ q6m(n = 734)Placebo(n = 734)Men age 70 yrs (or 70 yrs with low BMD or history of fracture) undergoing ADT for nonmetastatic prostate cancer(N = 1468)Smith MR, et al. ASCO GU 2010. Abstract 25.On-Study Mortality, %PVFNo PVFUnadjusted HRP ValueAdjusted* HRP ValueA

34、ll patients7.65.11.57.0621.55.070Placebo arm9.24.62.14.0192.13.021Denosumab arm5.85.61.09.811.08.84*Adjusted for age and ADT duration.Nilsson S, et al. ASCO GU 2010. Abstract 106.Nilsson S, et al. ASCO GU 2010. Abstract 106.外照射外照射已廣泛用于晚期前列腺癌孤立的痛性病灶的的姑息已廣泛用于晚期前列腺癌孤立的痛性病灶的的姑息治療，尤其是骨轉(zhuǎn)移性疼痛；治療，尤其是骨轉(zhuǎn)移性疼痛；

35、放射性同位素放射性同位素（8989Sr,Sr,153153Sm)Sm)有同時(shí)治療所有骨轉(zhuǎn)移灶的潛力有同時(shí)治療所有骨轉(zhuǎn)移灶的潛力；二磷酸鹽二磷酸鹽能明顯減輕能明顯減輕CRPCCRPC患者的疼痛，明顯減少止痛藥物患者的疼痛，明顯減少止痛藥物的用量，部分患者可以完全無痛，并改善病人的生活質(zhì)量的用量，部分患者可以完全無痛，并改善病人的生活質(zhì)量；Denosumab-RANKLDenosumab-RANKL單抗單抗，RANKLRANKLRANKRANK信號(hào)在破骨細(xì)胞的形信號(hào)在破骨細(xì)胞的形成、分化、存活及骨的改建中發(fā)揮著不可缺少的重要作用成、分化、存活及骨的改建中發(fā)揮著不可缺少的重要作用。 藥物止痛藥物止痛

36、。骨質(zhì)疏松（骨質(zhì)疏松（osteoporosisosteoporosis）性功能障礙（性功能障礙（sexual dysfunctionsexual dysfunction） 熱潮紅（熱潮紅（hot flasheshot flashes）男子女性型乳房（男子女性型乳房（gynecomastiagynecomastia） J Natl Cancer Inst 2010,102(1):39實(shí)現(xiàn)實(shí)現(xiàn)IADIAD的兩個(gè)條件的兩個(gè)條件雄激素剝奪制劑（LHRH類似物） 的可逆性血清PSA作為一個(gè)敏感的腫瘤標(biāo)志 物能監(jiān)測(cè)腫瘤緩解和進(jìn)展的時(shí)間 Gulati R ，et al.ASCO 2008,5134aKaplan-Meier survival curves for years to (A, B) castration-resistant prostate cancer and (C, D) death stratified by (A, C) on-treatment prostate-specific antigen (PSA) nadir or more than 0.1 ng/mL and (B, D) off-treatment (1O