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V Reunión Nacional de Avances en Cáncer de Próstata Neoadyuvancia y Adyuvancia con Hormonoterapia y Quimioterapia en la Enfermedad Localizada y Localmente Avanzada Albert Font Servicio de Oncología Médica Institut Català d´Oncologia Hospital Germans Trias i Pujol, Badalona Guadalajara, 18 de junio del 2009 Treatment of localized and locally-advanced prostate cancer according to risk groups Pisansky et al. NEJM 2006 Relative Risk of Prostate Cancer-Specific Mortality according to Treatment and Risk Group Two multi-institutional databases including 7316 patients Risk Group RR Surgery 95% CI Low 1.0 Intermediate 4.9 1.7-8.1 High 14.2 5.0-23.4 P RR Radiotherapy 95% CI P 1.0 .003 5.6 2.0-9.3 .0012 <.0001 14.3 5.2-24.0 <.0001 D´Amico et al. J Clin Oncol 2003;21:2163-2172 Prostate cancer as a systemic disease (I) Prognostic impact of CK+ prostate cancer cells in bone marrow before prostatectomy Weckermann D, et al. J Clin Oncol 2009;27:1549 Prostate cancer as a systemic disease (II) Cell-free tumor DNA and circulating tumor cells in blood plasma in prostate cancer Schwarzenbach H, et al. Clin Cancer Res 2009;15:1032 Is there a role for chemotherapy in high-risk localized prostate cancer ? • Prostate cancer is a systemic disease even in early stages • Pretreatment clinical factors such as Gleason score, PSA levels and clinical stage can select patients with high risk of PSA recurrence and prostate cancer-related death (D´Amico, 2003) • Treatment options for men with high-risk localized prostate cancer remain inadequate • Chemotherapy is effective in advanced hormone-refractory prostate cancer • Hormonal therapy followed by prostatectomy has not improved long-term outcomes in high-risk patients treated in the neoadjuvant setting Summary of neoadjuvant hormonal therapy trials with > 100 patients enrolled Gomella LG et al. Urology 2003;62(supp6B):46 Adjuvant chemotherapy in high-risk localized prostate cancer Study No pts Schmidt, 1996 184 Regimen Cyclophosphamide vs Surgery Results Yes No difference in OS ADT + Mitox ( 4 c) vs ADT Yes Improvement with Mitox EMP vs Observation Wang, 2000 96 Trials with Docetaxel Rosenbaum, 2005 77 Srinivas, 2006 20 Docetaxel wkly (6 months) Yes Docetaxel wkly (6 months) Surgery/RT EMP: Estramustine ADT: Androgen deprivation therapy Mitox: Mitoxantrone PFS: 15.7 m Well tolerated SWOG 9921: Hormonal therapy vs hormonal therapy plus chemotherapy after prostatectomy High Risk Localized Prostate Cancer after Radical Prostatectomy (n=1360 p) R A N D O M I Z E Hormonal Therapy ( 2 years) Hormonal Therapy (2 years) plus + mitoxantrone/prednisone Primary Endpoint: Overall Survival Status: Closed (6 cycles) Veteran Affairs CSP 553 study: Adjuvant chemotherapy in high-risk localized prostate cancer High Risk Localized Prostate Cancer after Prostatectomy (pT3b or T4, pT3a+Gleason > 7, PSA > 20 ng/ml or risk of PSA progression > 50% ) Post-RP: PSA < 0.1 (n= 636 p) R A N D O M I Z E Docetaxel (75 mg/m2 every 3 weeks) + prednisone ( 6 cycles) Observation Primary Endpoint: Progression-free survival Study start: June 2006 Hormonal and radiation therapy or hormonal and radiation therapy followed by docetaxel: RTOG 0521 study High Risk Prostate Cancer: • Gleason 7-8/PSA 20-150 •Gleason 8/PSA < 20/T2-4 •Gleason>9/ PSA< 150 R A N D O M I Z E ADT ( 8 weeks) RT (72-75 Gy) + ADT (20 months) ADT ( 8 weeks) RT (72-75 Gy) + Docetaxel ( 6 cycles)+ ADT (20 m) N= 600 p Primary Endpoint: Survival at 4 years Start Date: December 2005 Rationale for neoadjuvant treatment of prostate cancer Neoadjuvant trials in high-risk localized prostate cancer • Non-docetaxel based chemotherapy with/without hormonal therapy • Docetaxel-based chemotherapy without hormonal therapy • Docetaxel-based chemotherapy with hormonal therapy • Ongoing phase III trials • Trials with new targeted therapies Phase II trials of non-docetaxel-based chemotherapy (I) No. Pts Regimen Van Poppel, 1995 29 Estramustine 0 41% NR 52% Pettaway, 2000 30 KAVE 0 67% 37% 17% 16 Estramustine/ VP-16 0 56% 13% 13% Study Clark, 2001 Pathological Results pCR ECE LN SM+ Konety, 2004 35 Taxol/estramustine/ carboplatin 0 53% 5% 22% Ko, 2006 12 Taxol/ estramustine 0 NR 8% 25% ECE: extracapsular extension LN: Lymph nodes SM+: Surgical margins involved Phase II trials of docetaxel-based chemotherapy without hormonal therapy (II) Study No. Pts Dreicer, 2004 29 Febbo, 2005 16 22 Garzotto, 2006 Friedman, 2008 15 Regimen Docetaxel (wkly) Pathological Results pCR ECE LN MR+ 0 49% 14% 50% Docetaxel (wkly) 0 62% 0% NR Docetaxel/ Mitoxantrone 0 34% 29% 34% 0 56% 13% 40% Docetaxel/ capecitabine Phase II trials of docetaxel-based chemotherapy with hormonal therapy (III) Study Pathological Results pCR ECE LN MR+ No. Pts Regimen 21 Docetaxel/ Estramustine 0 70% 10% 30% 29 Docetaxel (wkly) 0 82% 14% 39% 22 Docetaxel/ Estramustine 0 36% 23% 27% Chi, 2008 72 Docetaxel (wkly) 3% 44% 6% 27% Mellado, 2009 57 Docetaxel (wkly) 6% 47% 4% 35% Hussain, 2003 Magi-Galluzzi, 2007 Sella, 2008 Phase II trials of docetaxel-based chemotherapy with hormonal therapy Study Pathological Results pCR ECE LN MR+ No. Pts Regimen 21 Docetaxel/ Estramustine 0 70% 10% 30% 29 Docetaxel (wkly) 0 82% 14% 39% 22 Docetaxel/ Estramustine 0 36% 23% 27% Chi, 2008 72 Docetaxel (wkly) 3% 44% 6% 27% Mellado, 2009 57 Docetaxel (wkly) 6% 47% 4% 35% Hussain, 2003 Magi-Galluzzi, 2007 Sella, 2008 Docetaxel-based chemotherapy with hormonal therapy in high-risk localized prostate cancer (I) Chi et al , 2008 Regimen Docetaxel (wkly) plus ADT Mellado et al, 2009 Docetaxel (wkly) plus ADT Treatment Duration 6 months 3 months No of patients 72 57 Risk Factors 1 2 3 41 (65%) 19 (30%) 3 (5%) 33 (58%) 21 (36%) 3 (5%) Median follow-up 42 months 35 months Docetaxel-based chemotherapy with hormonal therapy in high-risk localized prostate cancer (II) Chi et al , 2008 Mellado et al, 2009 Surgical Margins + 17 (27%) 18 (35%) Extracapsular extension 28 (44%) 24 (47%) Lymph nodes involved 4 (6%) 2 (4%) pCR 2 (3%) 3 (6%) Pathological Response Significant PR (*) 26% 16 (25%) 10 (18%) 19 (30%) 18 (31%) Outcome Biochemical relapse BFS in p with significant PR 89% (*) Significant PR: <5%-10% tumor or less by volume in prostatectomy Neoadjuvant hormonal and radiation therapy with/without docetaxel in high-risk prostate cancer: Dana-Farber Institute study High Risk Prostate Cancer: • T1b-2a + PSA> 10 or Gleason >7 •T2c-T4 R A N D O M I Z E ADT ( 6 months ) + Docetaxel x 3 cycles followed by RT (70 Gy) + Docetaxel (20 mg/m2/wkly) ADT ( 6 months ) + RT (70 Gy) N= 350 p Primary Endpoint: Overall survival Start Date: June 2005 Neoadjuvant docetaxel and hormonal therapy vs prostatectomy alone in high-risk localized prostate cancer: CALGB 90203 study High Risk Prostate Cancer: • Biochemical PFS < 60% by Kattan nomogram •PSA < 100 ng/ml •Clinical stage: T1-3a R A N D O M I Z E Prostatectomy Docetaxel ( 6 cycles) + ADT (18-24 weeks) Prostatectomy N= 750 p Primary Endpoint: Biochemical progression free survival at 3 years Start Date: December 2006 Genetic markers involved in prostate cancer biology Potential for new targeted therapies Efstathiou et al. Clin Cancer Res 2007 Why may new therapies be explored in highrisk localized prostate cancer? High-risk localized Advanced hormone-refractory Primary endpoint Pathological response Biochemical-progresion free survival, overall survival No of patients required Low High Follow-up Short Long Tumor tissue available Yes Not usually Predictive genetic markers Yes More difficult Impact of new targeted therapies as neoadjuvant therapy for high-risk prostate cancer Study Vuky J, et al. Cancer 2009 Mathew P, et al. J Urol 2009 Regimen Docetaxel (wkly)/gefitinib (31p) Docetaxel (wkly)/imatinib (36p) Docetaxel/bevacizumab Oh W.K, et al (41 p) Proc ASCO 2009 Results PSA responses: 21 p (68%) Extracapsular extension: 13 p (43%) Positive SM: 11 p (33%) No pT0 was observed Extracapsular extension: 22 p (65%) Positive SM: 6 p (18%) No pT0 was observed Partial responses by erMRI: 36% p No pathological results •Median decline in tumor volume was 46% •36% of patients had a partial response by erMRI •9 p (22%) had a PSA declines > 50% Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk localized prostate cancer (I) Institution U. British Columbia Hoosier Oncology Group M.D Anderson Regimen No. pts Endpoint OGX-011 45 p Pathological complete response Dasatinib 39 p Pathological complete response Sunitinib 42 p Tumor response Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk localized prostate cancer (II) Institution Fred Hutchinson Cancer Research Center NCI Sidney Kimmel Comprehensive Cancer Center MSKCC Regimen No. pts Endpoint Sorafenib 20 p Molecular studies (transcript profiles) Everolimus 30 p Pathological complete responses Sirolimus 60 p Pharmacogenetic studies Vorinostat 38 p Pathological complete responses Genetic markers to predict eficacy of neoadjuvant therapies Role of BRCA 1 Kennedy RD, et al. JNCI 2004;96:1659-68 Reconstitution of wild-type BRCA1 results in sensitivity to antimicrotubule agents paclitaxel and vinorelbine in BRCA1 mutant HCC1937 cell line Dose Response Curves for HCCBR1 and HCCEV Re sponse Curv e (1000x) s for HCCBR116 and HCCEV1 withVINORELBINE Taxol (A)Dose (B) PACLITAXEL (10000x) 100 90 HCCEV1 80 80 70 70 % Control % Control 90 100 HCCBR116 60 HCCBR11660 IC5072h :7.73x10-9M 50 50 72hrs HCCEV1 IC50 : 6.21x10-6M 40 40 30 30 20 20 10 10 HCCBR116 HCCEV1 0 10 -10 10 -9 10 -8 10 -7 10 -6 10 -5 10 -4 10 -3 0 10 -1110 -1010 -910 -810 -710 -610 -510 -410 -3 M olarity of Taxol M olarity of Vinore lbine HCCBR116: IC50 = 7.73 x 10 –9M HCCEV1: IC50 = 6.21 x 10 –6M HCCBR116: IC70 = 1.9 x 10 –9M HCCEV1: IC70 = 1.7 x 10 –5M (A) Dose inhibition curves comparing the IC50-70 values of (A) Paclitaxel and (B) Vinorelbine in the BRCA1 mutant HCC1937 cells reconstituted with exogenous wild type BRCA1 (HCCBR116) compared to HCC1937 cells reconstituted with empty vector (HCCEV1). In each case the HCCBR116 cells display a marked increase in sensitivity to these antimicrotubule agents compared to the HCCEV1 cells. Quinn et al. Cancer Res 2003 siRNA of BRCA1 led to paclitaxel and docetaxel resistance, and reconstitution of BRCA1 enhanced sensitivity to paclitaxel and vinorelbine Abrogation of BRCA1 increases sensitivity to cisplatin and resistance to paclitaxel Quinn et al. Clin Cancer Res 2007 BRCA1 mRNA expression predict survival in ovarian cancer patients treated with chemotherapy Quinn JE, et al. Clin Cancer Res 2007;13:7413-20 BRCA1 expression in prostate cancer BRCA1 – a predictive marker of response to docetaxel-based chemotherapy in prostate cancer Schayek H, et al. Clin Cancer Res 2009;15: 1558 Conclusions • Several phase II trials have confirmed the safety and feasibility of neoadjuvant chemotherapy followed by prostatectomy in high-risk localized prostate cancer • A significant percentage of patients can attain a significant pathological response after neoadjuvant chemotherapy – associated with better prognosis • High-risk patients may be optimal candidates for testing the activity of new therapies in the neoadjuvant setting • The analysis of predictive and prognostic genetics markers should be included in these studies. • Close collaboration between urologists, medical oncologists and radiotherapists is required to develop multimodal strategies. What can we do to improve? We need new strategies in translational research and clinical trials in prostate cancer. We can learn a lesson from investigation in NSCLC or breast cancer