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课件

Treatment strategies for metastatic prostate cancer,Oliver Hakenberg Department of Urology, Rostock University,prostate cancer is hormone-dependent,LHRH = luteinising hormone releasing hormone LH = luteinising hormone ACTH = adrenocorticotropal hormone,testosterone,pineal gland,cortisole,adrenal androgens,Prostata,testes,prolactine,adrenal glands,hypothalamus,LH,ACTH,LHRH,estrogens,orchidectomy,antiandrogens,LHRH analogues,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,permanent advanced metastatic disease M+ locally advanced, if androgen ablation is the only treatment option adjuvant/temporary radical 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/delayed randomized n= 98,Overall survival,Cancer-specific survival,androgen ablation, gonadal testosterone 10-30% 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 testosterone castration-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 mitoxantrone arbiraterone hormonal principle in CPRC,Kantoff et al, N Engl J Med 2010 De Bono et al, Lancet 2010,Arbiraterone inhibition of testosterone biosynthesis,arbiraterone acetate inhibits C17,20 lyase 17 hydroxylase Inhibition selective & irreversible adrenals, testes, prostate cancer cells arbiraterone acetate: prodrug good oral bioavailability Development of resistance,Sonpavde et al, Eur Urol 2011,Attard et al, Cancer Res 2009,Study data: arbiraterone in CRPC,phase I chemotherapy-naive CRPC patients phase-II NCT 00474383 progression after docetaxel phase-III NCT 00638690 progression after docetaxel phase III NCT 00887198 asymptomatic, low metastatic load in chemotherapy-naive patients,phase I,n=21 chemo-naive, CRPC 12/21 with PSA50% and 3 months of which in 6/12 PSA 90% PR (RESIST) in 5/8 patients and analgesic medication no grade grade 3/4 toxicity,Attard et al, J Clin Oncol 2008,phase II a,chemotherapy-naive CRPC patients PSA 50% in 70-80% of patients RESIST response 37.5% median time to PSA-rise 225 days dexamethasone at progression with arbiraterone: further PSA50% in 33%,Attard et al, J Clin Oncol 2009,phase II b,n= 47 docetaxele-pretreated CRPC PSA 50% in 51% of patients 35 with RESIST PR 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 CRPC better efficacy without ketoconazole pretreatment 53% vs 33% PSA-response without/with 31% vs 4% PSA90% without/with ketoconazole median 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 CRPC arbiraterone vs placebo 2:1 randomisation stratification ECOG 0-1 vs 2 prior chemotherapy schedules 1 vs 2 pain score type of progression: PSA vs XR,OS 14.8 vs 10.4 months TTP 10.2 vs 6.6 months rPFS 5.6 vs 3.6 months PSA RR 29.1% vs 5.5% toxicity hyperhydration 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 resistant 2:1 randomisation arbiraterone 1000 mg + 5 mg prednisone vs placebo + 5 mg prednisone overall survival arbiraterone 14.8 months placebo 10.9 months,de Bono et al, N Engl J Med 2011,treatment options for metastatic prostate cancer,hormonal androgen ablation orchidectomy LHRH-antagonists or agonists androgen blockers androgen conversion blocker arbiraterone chemotherapy docetaxel cabazitaxel bisphosphonates pain treatment nuclear medical tretament: samarium, strontium best 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 months 5 year survival rate with M+oss 20%,androgen antagonists,steroidal cyproterone acetate non-steroidal bicalutamide flutamide nilutamide,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,hormone sensitive,hormone dependent,hormone withdrawal,hormone naive,hormone independent,definition of castration-resistant prostate hormone-refractory prostate cancer (HRPC),serume testosteron at castration level secondary hormonal treatment without effect ketoconazole estrogens rising 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 rates 1985: (17 Studien) 6,5 % M. Eisenberger, J Clin Oncol 1985 1992: (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 results improvement in pain improvement in quality of life duration of response 5-7 months no influence on survival,chemotherapy for prostate cancer mitoxantrone for HRPC?,Tannock et al. 1996 Kantoff et al. 1999,mitoxantrone approved by FDA as standard chemotherapy in HRPC,docetaxel,TAX 327 SWOG 9916 both studies showed overall survival advantage for docetaxel,Petrylak, N Engl J Med 2004 Tannock, 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 = 0.01 med. F/U: 1 J,docetaxel chemotherapy overall survival SWOG 9916,no (n) died,Petrylak et al, N Engl J Med 2004,SWOG 99-16,Petrylak J NCI 2006,Survival in subgroups docetaxel 3 weekly vs mitoxantrone,0.2,0.4,0.6,0.8,1,1.2,1.4,Intent to Treat,age 65,age 65,age 75,pain no,pain yes,KPS 80,KPS 70,hazard ratio in favour of,docetaxel mitoxantrone,Tannock et al, N Engl J Med 2004,Cochrane Review chemotherapy of HRPC,n=6929 patients; 47 studies investigated substances: EMP docetaxel 5-FU cyclophosphamide doxorubicine mitoxantrone vinorelbine,Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006,Cochrane Review,PSA response (50%): EMP 48% docetaxel 52% 5-FU 20% cyclophosphamide n.d. doxorubicine 50% (CAVE: only 1 study!) mitoxantrone 33% vinorelbine n.d.,Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006,only DOC = overall survival ( Mit + Pred quality 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?,for benefit established for other entities (breast cancer, colorectal cancer) lower tumour mass treatment prolongs survival against toxicity vs unreliable response early induction of chemotherapy-refractory state outcome is not influenced since no difference in survival between symptomatic vs asymptomatic patients (TAX327),forms of HRPC indications for starting with chemotherapy,only rising PSA asymptomatic, low metastatic load asymptomatic, large metastatic load symptomatic metastases, no indication PSA doubling time?, individual decision inclusion in study?, yes, yes,Estimating the prognosis in CPRC PSA doubling time,gnstig TAX 327: PSA-DT 55 Tage Oudard et al: PSA-DT 45 Tage,Armstrong et al, Clin Cancer Res 2007 Oudard et al, Ann Oncol 2007,Armstrong, A. J. et al. Clin Cancer Res 2007;13:6396-6403,nomographic estimation,rising PSA under chemotherapy,often initiial PSA flare-up no negative influence on survival, unless there are signs of clinical progression = minimum of 8 weeks treatment before deciding to discontinue !,Olbert Anticancer Drugs 2006,Copyright restrictions may apply.,Thuret et al, Ann Oncol 2008,PSA-Flare with chemotherapy in patients with subsequent PSA response or stable disease,PSA values normalized to a starting point of 100 ng/ml,Chemotherapy until,best number of cycles unknown TAX 327: mean of 8 cycles but: chronic toxicity increases with no of cycles intermittend chemotherapy?,When to discontinue chemotherapy?,definite worsening of physical state PSA doubling time 3 Monate slow PSA increase: - discontinue if clinically progressive,Miller et al. Akt Urol 2006,First line chemotherapy