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Albert Font Servicio de Oncología Médica Institut Català d´Oncologia

Albert Font Servicio de Oncología Médica Institut Català d´Oncologia Hospital Germans Trias i Pujol, Badalona Guadalajara, 18 de junio del 2009. Neoadyuvancia y Adyuvancia con Hormonoterapia y Quimioterapia en la Enfermedad Localizada y Localmente Avanzada.

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Albert Font Servicio de Oncología Médica Institut Català d´Oncologia

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  1. Albert Font Servicio de Oncología Médica Institut Català d´Oncologia Hospital Germans Trias i Pujol, Badalona Guadalajara, 18 de junio del 2009 Neoadyuvancia y Adyuvancia con Hormonoterapia y Quimioterapia en la Enfermedad Localizada y Localmente Avanzada V Reunión Nacional de Avances en Cáncer de Próstata

  2. Treatment of localized and locally-advanced prostate cancer according to risk groups Pisansky et al. NEJM 2006

  3. Relative Risk of Prostate Cancer-Specific Mortality according to Treatment and Risk Group Two multi-institutional databases including 7316 patients D´Amico et al. J Clin Oncol 2003;21:2163-2172

  4. 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

  5. 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

  6. 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 Is there a role for chemotherapy in high-risk localized prostate cancer ?

  7. Summary of neoadjuvant hormonal therapy trials with > 100 patients enrolled Gomella LG et al. Urology 2003;62(supp6B):46

  8. Study No pts Regimen Surgery Results Schmidt, 1996 184 Cyclophosphamide vs Yes No difference in OS EMP vs Observation Wang, 2000 96 ADT + Mitox ( 4 c) vs ADT Yes Improvement with Mitox Rosenbaum, 2005 77 Docetaxel wkly (6 months) Yes PFS: 15.7 m Srinivas, 2006 20 Docetaxel wkly (6 months) Surgery/RT Well tolerated EMP: Estramustine ADT: Androgen deprivation therapy Mitox: Mitoxantrone Adjuvant chemotherapy in high-risk localized prostate cancer Trials with Docetaxel

  9. SWOG 9921: Hormonal therapy vs hormonal therapy plus chemotherapy after prostatectomy Hormonal Therapy ( 2 years) R A N D O M I Z E High Risk Localized Prostate Cancer after Radical Prostatectomy Hormonal Therapy (2 years) plus + mitoxantrone/prednisone (6 cycles) (n=1360 p) Primary Endpoint: Overall Survival Status: Closed

  10. Veteran Affairs CSP 553 study: Adjuvant chemotherapy in high-risk localized prostate cancer Docetaxel (75 mg/m2 every 3 weeks) + prednisone ( 6 cycles) R A N D O M I Z E 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 Observation (n= 636 p) Primary Endpoint: Progression-free survival Study start: June 2006

  11. Hormonal and radiation therapy or hormonal and radiation therapy followed by docetaxel: RTOG 0521 study R A N D O M I Z E ADT ( 8 weeks) RT (72-75 Gy) + ADT (20 months) • High Risk Prostate Cancer: • Gleason 7-8/PSA 20-150 • Gleason 8/PSA < 20/T2-4 • Gleason>9/ PSA< 150 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

  12. Rationale for neoadjuvant treatment of prostate cancer

  13. 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 Neoadjuvant trials in high-risk localized prostate cancer

  14. Phase II trials of non-docetaxel-based chemotherapy (I) ECE: extracapsular extension LN: Lymph nodes SM+: Surgical margins involved

  15. Phase II trials of docetaxel-based chemotherapy without hormonal therapy (II)

  16. Phase II trials of docetaxel-based chemotherapy with hormonal therapy (III)

  17. Phase II trials of docetaxel-based chemotherapy with hormonal therapy

  18. Docetaxel-based chemotherapy with hormonal therapy in high-risk localized prostate cancer (I)

  19. Docetaxel-based chemotherapy with hormonal therapy in high-risk localized prostate cancer (II) 26% (*) Significant PR: <5%-10% tumor or less by volume in prostatectomy

  20. Neoadjuvant hormonal and radiation therapy with/without docetaxel in high-risk prostate cancer: Dana-Farber Institute study R A N D O M I Z E ADT ( 6 months ) + Docetaxel x 3cycles followed by RT (70 Gy) + Docetaxel (20 mg/m2/wkly) • High Risk Prostate Cancer: • T1b-2a + PSA> 10 or Gleason >7 • T2c-T4 ADT ( 6 months ) + RT (70 Gy) N= 350 p Primary Endpoint: Overall survival Start Date: June 2005

  21. Neoadjuvant docetaxel and hormonal therapy vs prostatectomy alone in high-risk localized prostate cancer: CALGB 90203 study R A N D O M I Z E • High Risk Prostate Cancer: • Biochemical PFS < 60% by Kattan nomogram • PSA < 100 ng/ml • Clinical stage: T1-3a 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

  22. Genetic markers involved in prostate cancer biology Potential for new targeted therapies Efstathiou et al. Clin Cancer Res 2007

  23. Why may new therapies be explored in high-risk localized prostate cancer?

  24. Impact of new targeted therapies as neoadjuvant therapy for high-risk prostate cancer

  25. Median decline in tumor volume was 46% • 36% of patients had a partial response by erMRI • 9 p (22%) had a PSA declines > 50%

  26. Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk localized prostate cancer (I)

  27. Ongoing trials with new targeted therapies as neoadjuvant treament in high-risk localized prostate cancer (II)

  28. Genetic markers to predict eficacy of neoadjuvant therapies Role of BRCA 1 Kennedy RD, et al. JNCI 2004;96:1659-68

  29. (A) PACLITAXEL (1000x) (B) VINORELBINE (10000x) 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 Reconstitution of wild-type BRCA1 results in sensitivity to antimicrotubule agents paclitaxel and vinorelbine in BRCA1 mutant HCC1937 cell line (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

  30. 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

  31. BRCA1 mRNA expression predict survival in ovarian cancer patients treated with chemotherapy Quinn JE, et al. Clin Cancer Res 2007;13:7413-20

  32. 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

  33. 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. Conclusions

  34. 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

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