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

1、Treatment strategies for metastatic prostate cancerOliver HakenbergDepartment of Urology, Rostock University prostate cancer is hormone-dependentLHRH = luteinising hormone releasing hormoneLH = luteinising hormoneACTH = adrenocorticotropal hormone testosteronepineal glandcortisoleadrenalandrogensPro

2、statatestesprolactineadrenal glands hypothalamusLHACTHLHRHestrogensorchidectomyantiandrogensLHRHanaloguesantiandrogens012345678901020304050Pathologic fractures after orchidektomy n=235Daniell et al, J Urol 1997orchidectomyno orchidectomyyears% cumulative incidence of osteoporotic fracturesImmediate

3、androgen ablationpermanentadvanced 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 diseaseEarly or delayed androgen ablation?Messing et al

4、, Lancet Oncology 2006RPE pN+early vs observation/delayedrandomizedn= 98Overall survivalCancer-specific survivalandrogen ablation gonadal testosterone10-30% serum androgens from other sources Adrenal cortex: DHEA + androstendione transformed to testosterone in periphery (including prostate)progressi

5、on after xx months hormone resistanthormone 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“ = CRPCLocke et al, Cancer Res 20213 n

6、ew developmentsautologous vaccine sipuleucel-T (IMPACT)mCRPC docetaxel-naive (85%)improved OS vs placebo cabazitaxel (TROPIC)mCRPC doxetaxel-refractory improved OS vs mitoxantronearbirateronehormonal principle in CPRCKantoff et al, N Engl J Med 2021De Bono et al, Lancet 2021Arbirateroneinhibition of

7、 testosterone biosynthesisarbiraterone acetate inhibitsC17,20 lyase17 hydroxylaseInhibition selective & irreversibleadrenals, testes, prostate cancer cells arbiraterone acetate: prodruggood oral bioavailabilityDevelopment of resistanceSonpavde et al, Eur Urol 2021Attard et al, Cancer Res 2021Study d

8、ata: arbiraterone in CRPCphase Ichemotherapy-naive CRPC patientsphase-II NCT 00474383progression after docetaxelphase-III NCT 00638690progression after docetaxelphase III NCT 00887198asymptomatic, low metastatic load in chemotherapy-naive patientsphase In=21chemo-naive, CRPC12/21 with PSA50% and 3 m

9、onthsof which in 6/12 PSA 90%PR (RESIST) in 5/8 patients and analgesic medicationno grade grade 3/4 toxicityAttard et al, J Clin Oncol 2021phase II achemotherapy-naive CRPC patientsPSA 50% in 70-80% of patientsRESIST response 37.5%median time to PSA-rise 225 daysdexamethasone at progression with arb

10、iraterone: further PSA50% in 33%Attard et al, J Clin Oncol 2021phase II bn= 47 docetaxele-pretreated CRPCPSA 50% in 51% of patients35 with RESISTPR 17%SD 66%23% ECOG improvementReid et al, J Clin Oncol 2021Reid et al, J Clin Oncol 2021Reid et al, J Clin Oncol 2021Phase II cdocetaxele-pretreated CRPC

11、better 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 2021phase III (COU-AA-301)n=1195 docetaxel-refractory CRPCarbiraterone vs plac

12、ebo 2:1 randomisationstratificationECOG 0-1 vs 2prior chemotherapy schedules 1 vs 2pain score type of progression: PSA vs XROS 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%cardi

13、opulmonary 4.1% vs 2.3% phase III (COU-AA-301) 1.interim analysis 2021De Bono et al, ESMO 2021arbirateronen=1195 docetaxel resistant2:1 randomisationarbiraterone 1000 mg + 5 mg prednisonevsplacebo + 5 mg prednisoneoverall survivalarbiraterone 14.8 monthsplacebo 10.9 monthsde Bono et al, N Engl J Med

14、 2021treatment options for metastatic prostate cancerhormonal androgen ablationorchidectomyLHRH-antagonists or agonistsandrogen blockersandrogen conversion blockerarbirateronechemotherapydocetaxelcabazitaxelbisphosphonatespain treatmentnuclear medical tretament: samarium, strontiumbest supportive ca

15、rePrognosis of metastatic prostate cancerinitial 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 antagonistssteroidalcyproterone acetatenon-steroidalbicalutamideflutamidenilutamidepro

16、portion without event0.01.0061218243036424860time (months)bicalutamide 150 mg + standard carePlacebo + standard care54reduction of the risk of PSA progression by 59 %Kaplan-Meier curve of time to PSA progressionHR 0.41; 95% CI 0.38, 0.45; p0.0001Early Prostate Cancer Progr

17、amnatural course of prostate cancer after radical prostatectomy and PSA recurrence (n= 311) 150510yearsPSA recurrencedistant metastasesdeath of prostate cancerPound et al., JAMA 1999Hormone-independent prostate cancerhormone independenthormonesensitivehormone dependenthormone withdrawalhormone naive

18、hormone independentdefinition 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

19、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 1993P.Walsh 1995:This is going to be an extremely short dis

20、cussion. 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

21、 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 survivalchemotherapy for prostate cancer mitoxantrone for HRPC?Tannock et al. 1996Kantoff et al. 1999m

22、itoxantrone approved by FDA as standard chemotherapy in HRPCdocetaxelTAX 327SWOG 9916both studies showed overall survival advantage for docetaxelPetrylak, N Engl J Med 2004Tannock, N Engl J Med 200420%40%60%80%100%012243648monthsD + EM + Pno. at Risk 338 336217235median survival(months)1816HR: 0.80

23、(95% CI 0.67, 0.97), p = 0.01med. F/U: 1 Jdocetaxel chemotherapyoverall survival SWOG 9916no (n)diedPetrylak et al, N Engl J Med 2004SWOG 99-16Petrylak J NCI 2006Survival in subgroupsdocetaxel 3 weekly vs mitoxantrone0.811.21.4Intent to Treatage 50%):EMP48%docetaxel52%5-FU20%cyclophosphamid

24、en.d.doxorubicine50% (CAVE: only 1 study!)mitoxantrone 33%vinorelbinen.d.Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006only DOC = overall survival ( Mit + Predquality of life DOC Mit + Predresultsauthors conclusion:At the present time this* probably represents the best chemotherapeutic

25、 regime available for men with HRPC“*- docetaxel q3wShelley M, Harrison C et al. Cochrane Database Syst Rev 2006secondary hormone manipulation or chemotherapy?secondary hormone manipulationchemotherapyCALGB9583SWOG 9916TAX-327AAW + KetokonazolEMP docetaxel vs MPDP q3w vs DP q1w vs MPn2607701006overa

26、ll survival in better arm 16.7 months17.5 months18.9 monthsoverall survival in worse arm15.3 months15.6 months16.5 monthsBellmunt, Eur Urol Suppl 2021open questionswhen to start with chemotherapy?should asymptomatic M+ patients be treated?how long to continue treatment?secondary treatment?intermitte

27、nt 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 di

28、fference in survival between symptomatic vs asymptomatic patients (TAX327)forms of HRPCindications for starting with chemotherapyonly rising PSAasymptomatic, low metastatic loadasymptomatic, large metastatic loadsymptomatic metastases no indication PSA doubling time? individual decisioninclusion in study? yes yesEstimating the prognosis in CPRCPSA doubling timegnstigTAX 327:PSA-DT 55 Tage Oudard et al:PSA-DT 45 Tage Armstrong et al, Clin Cancer Res 2007Oudard et al, Ann Oncol 2007