ECCLU 2011 - K. Fizazi - Prostate cancer: Locally advanced disease and patient advocacy - Integrating systemic therapy into high-risk disease
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ECCLU 2011 - K. Fizazi - Prostate cancer: Locally advanced disease and patient advocacy - Integrating systemic therapy into high-risk disease
- 1. High-risk prostate cancer: Integrating systemic treatment Karim Fizazi, MD, PhD Department of Medicine Institut Gustave Roussy Villejuif, France
- 2. What to do? You should have a prostatectomy ! No ! Radiation therapy ! Yes, but they also talk about hormones A patient with high-risk prostate cancer
- 7. Pilepitch, Int J Radiat Oncol Biol Phys 2005, 61: 1285-90
- 9. Immediate ADT Improves OS in pN+ patients Messing EM, et al. New Engl J Med . 1999;341(24):1781-1788. Patients (n) Immediate therapy 47 47 40 8 Observation 51 49 37 5 P = .02 0 0.2 0.4 0.6 0.8 1.0 0 20 40 60 80 100 120 Months Observation Immediate therapy
- 10. Incidence of metastases RTOG 85-31: pN+ patients Overall survival (p= 0.03) All pN+ pN+, no RP n = 173 R Immediate LHRHa Surveillance Lawton CA, J Clin Oncol 2005, 23: 800-807
- 11. Short-term or Long-term ADT combined with radiotherapy?
- 12. RTOG 8610: Phase III trial of short term ADT + RT Overall survival (p=0.12) Disease-specific mortality (<0.01) N= 456 (median age: 70 y) 1987-1992 Bulky (5 x 5 cm) tumors Mack Roach III et al., J Clin Oncol 2008; 26: 585-91 4 month ADT + RT RT R
- 13. Trans-Taman ROG 96-01: S hort term ADT + RT vs RT n= 818 T2b-T4 (all Gleason, all PSA) 85% high risk, RT: 66 Gy Median FU: 5.9 y 6 month ADT better Distant failure (p=0.047) Cancer-specific survival (p=0.04) Denham JW, Lancet Oncol 2005; 6: 841-50 RT RT + 3 months CAB RT + 6 months CAB R
- 14. D’Amico Phase III trial of short term ADT + RT vs RT Overall survival (88% vs 78% at 5 y) D'Amico, A. V. et al. JAMA 2004;292:821-827. N= 206 (1995-2001) PSA>10 (<40) or Gleason ≥ 7 or T3 (MRI) Conformal RT (70 Gy) RT RT + 6 month ADT R
- 16. RTOG 94-08: Overall Survival 62% 57%
- 19. RTOG 92-02: 10 year update Cancer-specific survival (p=0.004) Distant metastases failure (p<0.0001) Biochemichal PFS (p<0.0001) OS (p=NS) (p=0.006 if Gleason ≥8) Horwitz EM, J Clin Oncol 2008; 26: 2497-2504
- 21. Randomized EORTC Phase III Trial 22961 Locally Advanced Prostate Cancer N = 970 No further ADT ADT for 2.5 years RT, external beam radiation therapy; ADT, androgen deprivation therapy; PFS, progression-free survival; OS, overall survival. Bolla M et al. JCO , 2007. 25(18S):5014; www.clinicaltrials.gov RT + 6 mo ADT Patients assessed for PFS and OS No disease progression “ Short-term ADT” “ Long-term ADT ”
- 22. Long-Term ADT prolongs clinical PFS Long-term ADT (n = 487) Short-term ADT (n = 483) Time, years 0 1 2 3 4 5 6 7 8 9 0 10 20 30 40 50 60 70 80 90 100 HR= 1.93, P <.0001 Patients alive, % Bolla, ASCO 2007, Abstr 5014
- 23. Long-Term ADT prolongs OS Time, years 0 1 2 3 4 5 6 7 8 9 0 10 20 30 40 50 60 70 80 90 100 Long-term ADT (n = 487) Short-term ADT (n = 483) P = .019 (H0: Long ADT superior) HR: 1.43 P = .6543 (H0: Short ADT non-inferior) Patients alive, % Bolla, ASCO 2007, Abstr 5014
- 24. Endocrine therapy: Is there an alternative to ADT?
- 25. Bicalutamide instead of ADT? Trial 24 Europe / RoW (N=3603) Trial 25 Scandinavia (N=1218) Trial 23 N. America (N=3292) Standard care (radiotherapy, radical prostatectomy or watchful waiting) initiated by investigator as per local practice Bicalutamide EPC Programme (N=8113) 1:1 randomisation to bicalutamide 150 mg or standard care alone Follow-up for overall survival and time to objective disease progression
- 26. Bicalutamide instead of ADT in association with radiotherapy? 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 8 9 10 HR=0.65 (0.44, 0.95) p=0.028 placebo Bicalutamide 0 Time to death (years) Proportion surviving EPC program 2006 Overall survival
- 27. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
- 29. ADJUVANT Docetaxel après prostatectomie
- 30. Sanofi-Aventis XRP6976J/3501 Study P.I. Mario Eisenberger - Primary endpoint: PFS - N= 228/ 1696 (high-risk localized disease, ) - Stratification: Age (> 65 vs < 65) / Predicted prob. of 5-y FFP / Country Observation Leuprolide 18 months Leuprolide 18 months + Docetaxel 75 q3w x 6 cycles Deferred arm PROGRESSION P R O G R E S S I O N P R O G R E S S I O N Leuprolide 18 months Leuprolide 18 months + Docetaxel 75 q3w x 6 cycles Immediate arm R A N D O M I Z E RP ACCRUAL STOPPED
- 31. Phase III trials of Docetaxel in Localized prostate cancer Study name PI Local treatment # patients ( enrolled / planned) Status GETUG 12 K. Fizazi (France) XRT 413 / 400 Accrual completed RTOG 0521 H. Sandler (USA) XRT 600 /600 Accrual completed TAX 3501 M. Eisenberger (USA) RP 228 /1700 Early accrual termination AdPro Ahlgren (Sweden) RP 361 /396 Ongoing DANA FARBER A. D’Amico (USA) XRT 191 /350 Ongoing VA # 553 CAP Montgomery (USA) RP 152 /636 Ongoing CALGB 90203 Eastham (USA) RP 126 /750 Ongoing AdRad Kellokumpu-Lehtinen (Fin) XRT 108 /924 Ongoing NCIC Mc Kenzie (Can) XRT 24 / 530 Ongoing
- 32. High risk prostate cancer GETUG 12 trial ADT (3 years) + RXT Docetaxel + Estramustine (4 cycles) RANDOMI ZE Primary endpoint: Progression-free survival n = 413/400 pts Stratification - Gleason 8 - PSA>20 - T3 - pN+ / pN- ADT (3 years) + RXT PI: K. Fizazi
- 33. Docetaxel Phase III trial in localized CaP PSA response (GETUG 12 trial) PSA 3 months ≤ 0.2 ng/mL: 34% vs 15% p< 0.0001 Fizazi et al., ASCO GU Symposium 2010, Abstr 7 n= 413
- 36. ADJUVANT Docetaxel après Radiothérapie
- 39. NEO-ADJUVANT Docetaxel avant Prostatectomie
- 40. High risk: Predicted bPFS<60 (Kattan nomogram) PSA<100 RANDOMI ZE Docetaxel 75 x 6 cycles + AS (6 months) No medical treatment CALGB 90203 PI: J. Eastham (US) Prostatectomy N = 126 / 750 Endpoint: 3 year bPFS
- 41. NEO-ADJUVANT Docetaxel avant Radiothérapie
- 42. High risk: any of: - Gleason > 8 - T3-T4 - PSA>20 - pN+ LN dissection: all pts RANDOMI ZE Docetaxel 70 q3w + Estramustine x 4 cycles + AS (3 years) AS (3 years) GETUG 12 PI: K. Fizazi (FRA) Local treatment at 3 months (RT) N = 413 / 400 Started 11/02, Accrual completed 11/06 Endpoint: PFS
- 45. Inclusion high risk: - Gleason ≥ 8 - T ≥ 3a - PSA>20 ng/mL RANDOMI ZE Docetaxel x 4 cycles + AS (3 years) AS (3 years) NCIC CTG (DART) Study Chair: M. McKenzie (CAN) Radiotherapy N = 24 / 530 Endpoint: DFS
- 47. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Bone targeting agents? High risk localized prostate cancer
- 48. Zoledronic Acid- Preventing Bone Metastasis in the Adjuvant Setting
- 49. Zoledronic Acid Can Inhibit this Process at Several Key Steps Adapted from Mundy GR, et al. Nature Reviews Cancer . 2002;2:584-593. Invasion Angiogenesis Primary tumor Metastases Adhesion & extravasation Arrest in distant capillary Micrometastases Inhibits angiogenesis Decreases adhesion to bone Synergy with anticancer drugs Induces tumor cell apoptosis Stimulates immune surveillance Decreases matrix invasion Direct antitumor effect Indirect antitumor effect
- 53. A multi-arm trial: STAMPEDE
- 55. STAMPEDE Study Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (PI: N James) R A N D O M I S E Hormones (H) H + D + Z H + Docetaxel (D) H + Zoledronate (Z) H + Celecoxib H + Celecoxib + Z Endpoints: FFS Stages 1-3 Reject arms not improving FFS >50% Confirm safety Pilot Safety N= 1085/ 3300-6000
Editor's Notes
- RTOG 9408 was a randomized Phase III trial designed to evaluate if the addition of 4 months of Androgen Deprivation Therapy to standard external beam radiation would result in an improvement in overall survival. Patients studied had localized (T1b-T2b) adenocarcinoma of the prostate and a PSA of < 20. Patients were stratified by PSA, by Grade and by whether the nodes were negative by clinical or surgical evaluation. The study asked for re-biopsies of the prostate at two years after treatment. (45 seconds)
- Here is the overall survival curve demonstrating the superiority of the hormone + RT arm. (10 seconds)
- The veterans affairs study is designed to prospectively evaluate the efficacy of early adjuvant chemotherapy using docetaxel and prednisone added to the standard of care for patients who are potentially cured by radical prostatectomy but who are at high risk of relapse. Patients are stratified for PSA, GS, tumour stage and the presence of positive margins. Almost 700 patients are planned to be enrolled. Chemotherapy will be given for 4 months. Patients will be followed for a minimum of 1 and a maximum of 5 years. JUST LAUNCHED. INVESTIGATORS’MEETING APRIL. FIRST PATIENT EXPECTED Q3 2006.
- TAB, AA will be discontinued at the end of RT. LHRHA will continue for 24 months from initiation. RT will begin 8 weeks after the initiation of HT. STUDY OPENED WITH 8 PATIENTS ENROLLED.
- 7 38 Radiation + 6 months of HT is one standard way of treating high risk prostate cancer. In the trial we want to see wether or not adding TXT will make the treatment more effective.
- Metastasis to bone occurs via a multi-step process, and inhibition of any of these steps could prevent metastasis to bone 1 The primary malignant neoplasm promotes new blood vessel formation (angiogenesis) Cancer cells must then invade the blood vessels, wherein they form multi-celled aggregates Aggregates of tumor cells form emboli that lodge in capillary beds in bone Cancer cells can adhere to vascular epithelial cells to escape the blood vessels and must extravasate through the extracellular matrices to enter the bone microenvironment As cancer cells enter the bone, they are exposed to factors in the bone microenvironment, such as growth factors released from the bone matrix during osteolysis, which may promote tumor growth Zoledronic acid can inhibit multiple steps in the metastatic process and has demonstrated direct and indirect antitumor activities in preclinical assays 2 Reference Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer . 2002;2(8):584-593. Lipton A. Emerging role of bisphosphonates in the clinic-Antitumor activity and prevention of metastasis to bone. Cancer Treat Rev . 2008. May 15. [Epub ahead of print]
- Overview of Zoledronic acid in other antitumor and prevention trials ABCSG-12 Stage I, II breast cancer patients in a randomized, open-label, multi-center, active-control, parallel-assignment, 4-arm, efficacy study of DFS and RFS at 5 years and OS at 3 years (N = 1,803) AZURE Stage II, III breast cancer patients in a randomized, open-label, multi-center, active-control, parallel-group trial of DFS, time to bone metastases, OS and SREs (N = 3,360) SUCCESS Stage I, II, III breast cancer patients in a randomized, open-label, multi-center, 2x2 factorial design, controlled study of DFS, OS, metastases-free survival, and safety (N = 3754) SWOG 0307 Stage I, II, III breast cancer patients in a randomized, active-control, multi-center study of DFS, OS, time to progression, safety, and compliance (N = 4,500). Bone markers and dental substudies NATAN Stage II, III refractory breast cancer patients in a randomized, open-label, multi-center, active-control, parallel-assignment, safety/efficacy study of EFS, OS, bone metastases-free survival, safety, compliance and breast tumor response (N = 654) ZEUS Prostate cancer patients with no distant metastases in a randomized, open-label, multi-center study of proportion of patients with bone metastases at 2 years, time to bone metastases, OS, PSA doubling time, bone markers, and BMD (N = 1,434) RADAR Stage T2b-4 prostate adenocarcinoma patients in a randomized, open-label, multi-center, active-control, factorial-assignment, safety/efficacy study of PSA-RRFS and OS (N = 1,071) 2419 Study Stage III NSCLC patients in a randomized, open-label, active control, parallel assignment, safety/efficacy study of time to occurrence of bone metastases, rate of bone metastases at 6, 12, 18, and 24 months, TTP, rate and risk of SREs, time to first SRE, OS at 12 and 24 months, BSP expression in primary tumor (substudy) of ZOL vs no ZOL (N = 446) STAMPEDE A multi-arm cooperative trial in patients undergoing androgen-deprivation therapy for high-risk prostate cancer; multiple endpoints throughout the study; trial design is subject to change