limits of tumorectomy in clinical localized renal cell cancer：在临床局限性肾细胞癌的肿瘤切除术的限制

Treatment strategies for metastatic prostate cancer,Oliver HakenbergDepartment of Urology, Rostock University,prostate cancer is hormone-dependent,LHRH = luteinising hormone releasing hormoneLH = luteinising hormoneACTH = adrenocorticotropal hormone,testosterone,pineal gland,cortisole,adrenalandrogens,Prostata,testes,prolactine,adrenal glands,hypothalamus,LH,ACTH,LHRH,estrogens,orchidectomy,antiandrogens,LHRHanalogues,antiandrogens,0,1,2,3,4,5,6,7,8,9,0,10,20,30,40,50,Pathologic fractures after orchidektomy,n=235,Daniell et al, J Urol 1997,orchidectomy,no orchidectomy,years,% cumulative incidence of osteoporotic fractures,Immediate androgen ablation,permanentadvanced metastatic disease M+locally advanced, if androgen ablation is the only treatment optionadjuvant/temporaryradical prostatectomy with positive nodes (pN+)adjuvant with radiotherapy in intermediate and high risk disease,Early or delayed androgen ablation?,Messing et al, Lancet Oncology 2006,RPE pN+early vs observation/delayedrandomizedn= 98,Overall survival,Cancer-specific survival,androgen ablation, gonadal testosterone10-30% serum androgens from other sources Adrenal cortex: DHEA + androstendione transformed to testosterone in periphery (including prostate)progression after xx months hormone resistant,hormone resistance?,de novo intratumoral androgen synthesis in progressive CRPC maintenance of intracellular andogen levels androgen receptor (AR) stimulation despite low serume testosteronecastration-resistant prostate cancer“ = CRPC,Locke et al, Cancer Res 2008,3 new developments,autologous vaccine sipuleucel-T (IMPACT)mCRPC docetaxel-naive (85%)improved OS vs placebo cabazitaxel (TROPIC)mCRPC doxetaxel-refractory improved OS vs mitoxantronearbirateronehormonal principle in CPRC,Kantoff et al, N Engl J Med 2010De Bono et al, Lancet 2010,Arbirateroneinhibition of testosterone biosynthesis,arbiraterone acetate inhibitsC17,20 lyase17 hydroxylaseInhibition selective & irreversibleadrenals, testes, prostate cancer cells arbiraterone acetate: prodruggood oral bioavailabilityDevelopment of resistance,Sonpavde et al, Eur Urol 2011,Attard et al, Cancer Res 2009,Study data: arbiraterone in CRPC,phase Ichemotherapy-naive CRPC patientsphase-II NCT 00474383progression after docetaxelphase-III NCT 00638690progression after docetaxelphase III NCT 00887198asymptomatic, low metastatic load in chemotherapy-naive patients,phase I,n=21chemo-naive, CRPC12/21 with PSA50% and 3 monthsof which in 6/12 PSA 90%PR (RESIST) in 5/8 patients and analgesic medicationno grade grade 3/4 toxicity,Attard et al, J Clin Oncol 2008,phase II a,chemotherapy-naive CRPC patientsPSA 50% in 70-80% of patientsRESIST response 37.5%median time to PSA-rise 225 daysdexamethasone at progression with arbiraterone: further PSA50% in 33%,Attard et al, J Clin Oncol 2009,phase II b,n= 47 docetaxele-pretreated CRPCPSA 50% in 51% of patients35 with RESISTPR 17%SD 66%23% ECOG improvement,Reid et al, J Clin Oncol 2009,Reid et al, J Clin Oncol 2009,Reid et al, J Clin Oncol 2009,Phase II c,docetaxele-pretreated CRPCbetter efficacy without ketoconazole pretreatment53% vs 33% PSA-response without/with31% vs 4% PSA90% without/with ketoconazolemedian time to progression 198 vs 99 days with/without ketoconazole,Danila et al, J Clin Oncol 2009,phase III (COU-AA-301),n=1195 docetaxel-refractory CRPCarbiraterone vs placebo 2:1 randomisationstratificationECOG 0-1 vs 2prior chemotherapy schedules 1 vs 2pain score type of progression: PSA vs XR,OS 14.8 vs 10.4 monthsTTP 10.2 vs 6.6 monthsrPFS 5.6 vs 3.6 monthsPSA RR 29.1% vs 5.5%toxicityhyperhydration 2.3% vs 1.0%hypokalaemia 3.8% vs 0.8%hypertension 1.3% vs 0.3%cardiopulmonary 4.1% vs 2.3%,phase III (COU-AA-301) 1.interim analysis 2010,De Bono et al, ESMO 2010,arbiraterone,n=1195 docetaxel resistant2:1 randomisationarbiraterone 1000 mg + 5 mg prednisonevsplacebo + 5 mg prednisoneoverall survivalarbiraterone 14.8 monthsplacebo 10.9 months,de Bono et al, N Engl J Med 2011,treatment options for metastatic prostate cancer,hormonal androgen ablationorchidectomyLHRH-antagonists or agonistsandrogen blockersandrogen conversion blockerarbirateronechemotherapydocetaxelcabazitaxelbisphosphonatespain treatmentnuclear medical tretament: samarium, strontiumbest supportive care,Prognosis of metastatic prostate cancer,initial response to androgen ablation 80%progression in 50-60% of patients within 2 years after that median survival 23-37 months5 year survival rate with M+oss 20%,androgen antagonists,steroidalcyproterone acetatenon-steroidalbicalutamideflutamidenilutamide,proportion without event,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,6,12,18,24,30,36,42,48,60,time (months),bicalutamide 150 mg + standard care,Placebo + standard care,54,reduction of the risk of PSA progression by 59 %Kaplan-Meier curve of time to PSA progression,HR 0.41; 95% CI 0.38, 0.45; p0.0001,Early Prostate Cancer Program,natural course of prostate cancer after radical prostatectomy and PSA recurrence (n= 311),15,0,5,10,years,PSA recurrence,distant,metastases,death of prostate cancer,Pound et al., JAMA 1999,Hormone-independent prostate cancer,hormone independent,hormonesensitive,hormone dependent,hormone withdrawal,hormone naive,hormone independent,definition of castration-resistant prostate hormone-refractory prostate cancer (HRPC),serume testosteron at castration levelsecondary hormonal treatment without effectketoconazoleestrogensrising PSA at 3 consecutive measurements at intervals of 1 week at leastt with continued LHRH blockade and after witrhdrawal of androgen blocker lowest PSA limit: 0.4 ng/ml,Chemotherapy for prostate cancer?,Reviews response rates1985: (17 Studien)6,5 % M. Eisenberger, J Clin Oncol 19851992: (26 Studien)8,7 % Yagoda & Petrylak, Cancer 1993,P.Walsh 1995:This is going to be an extremely short discussion. Not only does it fail to cure the cancer, it doesnt even prolong survival to any significant degree, and its side effects only add to the unpleasantness of having prostate cancer.“,phase III: mitoxantrone (12mg/m) + prednisone (10mg/d) vs. prednisone (10mg/d)161 patients. (80 M+P; 81 P)phase III: mitoxantrone (14mg/m) + hydrocortisone (40mg/d) vs. hydrocortisone (40mg/d) 242 patients resultsimprovement in painimprovement in quality of lifeduration of response 5-7 monthsno influence on survival,chemotherapy for prostate cancer mitoxantrone for HRPC?,Tannock et al. 1996Kantoff et al. 1999,mitoxantrone approved by FDA as standard chemotherapy in HRPC,docetaxel,TAX 327SWOG 9916both studies showed overall survival advantage for docetaxel,Petrylak, N Engl J Med 2004Tannock, N Engl J Med 2004,20%,40%,60%,80%,100%,0,12,24,36,48,months,D + E,M + P,no. at Risk,338,336,217,235,median survival(months),18,16,HR: 0.80 (95% CI 0.67, 0.97), p = 0.01med. F/U: 1 J,docetaxel chemotherapyoverall survival SWOG 9916,no (n)died,Petrylak et al, N Engl J Med 2004,SWOG 99-16,Petrylak J NCI 2006,Survival in subgroupsdocetaxel 3 weekly vs mitoxantrone,0.2,0.4,0.6,0.8,1,1.2,1.4,Intent to Treat,age 50%):EMP48%docetaxel52%5-FU20%cyclophosphamiden.d.doxorubicine50% (CAVE: only 1 study!)mitoxantrone 33%vinorelbinen.d.,Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006,only DOC = overall survival ( Mit + Predquality of life DOC Mit + Pred,results,authors conclusion:At the present time this* probably represents the best chemotherapeutic regime available for men with HRPC“*- docetaxel q3w,Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006,secondary hormone manipulation or chemotherapy?,Bellmunt, Eur Urol Suppl 2009,open questions,when to start with chemotherapy?should asymptomatic M+ patients be treated?how long to continue treatment?secondary treatment?intermittent chemotherapy?re-exposition?,Early vs late chemotherapy?,forbenefit established for other entities (breast cancer, colorectal cancer)lower tumour masstreatment prolongs survivalagainsttoxicity vs unreliable responseearly induction of chemotherapy-refractory stateoutcome is not influenced since no difference in survival between symptomatic vs asymptomatic patients (TAX327),forms of HRPCindications for starting with chemotherapy,only rising PSAasymptomatic, low metastatic loadasymptomatic, large metastatic loadsymptomatic metastases, no indication PSA doubling time?, individual decisioninclusion in study?, yes, yes,Estimating the prognosis in CPRCPSA doubling time,gnstigTAX 327:PSA-DT 55 Tage Oudard et al:PSA-DT 45 Tage,Armstrong et al, Clin Cancer Res 2007Oudard et al, Ann Oncol 2007,Armstrong, A. J. et