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Howard M. Sandler, MD University of Michigan Medical School

New Perspectives on the Application of Chemotherapy in Prostate Cancer Therapy for Advanced Prostate Cancer. Howard M. Sandler, MD University of Michigan Medical School. Case Presentation 1. 65 year old man with prostate cancer PSA 55 ng/ml cT3a Gleason 4+4=8

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Howard M. Sandler, MD University of Michigan Medical School

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  1. New Perspectives on the Application of Chemotherapy in Prostate CancerTherapy for Advanced Prostate Cancer Howard M. Sandler, MD University of Michigan Medical School

  2. Case Presentation 1 • 65 year old man with prostate cancer • PSA 55 ng/ml • cT3a • Gleason 4+4=8 • Metastatic evaluation (CT, BS) negative

  3. Case Presentation 1Question 1 • If the patient is treated with RT and long term androgen ablation, what is the 5 year bNED rate? • 80% • 60% • 40% • 20%

  4. Case Presentation 1Question 2 • You’re asked about the role of adjuvant chemotherapy along with LTAD and RT for the patient. Which of the following is correct: • Adjuvant chemotherapy has been shown to improve survival • Adjuvant chemotherapy has been shown to be appropriate for use in selected cases • There is no proven survival benefit to adjuvant chemotherapy

  5. Case Presentation 2 • 70 year old man s/p radical prostatectomy for cT2a, PSA 15, Gleason 7 prostate cancer • Pathology • pT3a • Gleason 7 • Positive margin at base and apex • Negative SV • Negative LN • Postoperative PSA <0.1 ng/ml

  6. Case Presentation 2Question 1 • In Bolla’s EORTC study, adjuvant RT improves the 5-year biochemical failure rate from 53% to: • 55% (i.e., no improvement) • 65% • 75% • 85%

  7. Case Presentation 2Question 2 • In Bolla’s EORTC study, adjuvant RT improves the 5-year overall survival rate from 93% to: • 93% (i.e., no improvement) • 98%

  8. New Perspectives on the Application of Chemotherapy in Prostate CancerTherapy for Advanced Prostate Cancer Howard M. Sandler, MD University of Michigan Medical School

  9. Rationale for Chemotherapy in Localized Prostate Cancer • Locally advanced/high risk prostate cancer is usually treated with radiotherapy (RT) and long term androgen ablation (LTAD) • RTOG 9202, Bolla studies • Despite advances, biochemical failure and cancer-specific mortality is still high

  10. RTOG 9202 Disease-free survival High Risk Prostate Cancer

  11. Rationale • Chemotherapy has been shown to prolong life in hormone-refractory prostate cancer • Petrylak – SWOG 9916 • Tannock – TAX 327

  12. Docetaxel/Estramustine vs Mitoxantrone/Prednisone for Advanced Refractory Prostate Cancer Petrylak et al., N Engl J Med 2004;351:1513-20

  13. Mitoxantrone Every 3 Weeks vs Docetaxel Every 3 weeks vs Weekly Docetaxel for Metastatic Hormone Refractory Prostate Cancer Tannock et al., N Engl J Med 2004;351:1502-12.

  14. CALGB 90401 A Randomized Double-Blinded Placebo Controlled Phase III Trial Comparing Docetaxel and Prednisone with and without Bevacizumab (IND#7921, NSC#704865) in Men with Hormone Refractory Prostate Cancer Study Chair: Wm Kevin Kelly, DO Memorial Sloan Kettering Cancer Center New York, NY

  15. R A N D O M I Z E Docetaxel 75 mg/m2 Prednisone 5mg, PO BID Placebo every 3 wks • Eligibility • Metastatic PC • T <50ng/ml • No prior chemo • Adequate hem, renal, and liver function Stratification Halabi nomogram Docetaxel 75 mg/m2 Prednisone 5mg, PO BID Bevacizumab 15mg/kg every 3 wks N = 1020 CALGB, ECOG, NCIC CALGB 90401Study Design

  16. Hypothesis • Adjuvant chemotherapy will prolong life when given in addition to LTAD following RT for high risk prostate cancer

  17. R A N D O M I Z E ADT x 2 yrs + RT High Risk (n=600) ADT x 2 yrs + RT 6 cycles docetaxel 75 mg/m2 and prednisone starting 1 mo after RT RTOG 0521Schema Primary Endpoint: Overall Survival

  18. RTOG 0521Objectives • Primary Objective • To assess the efficacy of AS + RT followed by AS vs AS + RT followed by docetaxel and prednisone + androgen suppression in unfavorable prostate cancer • Primary Endpoint: overall survival

  19. RTOG 0521Study Design • Randomized, Phase III study • Sample size = 600 patients • Patients are stratified by • PSA • Gleason score • T-stage

  20. RTOG 0521Key Eligibility Criteria • Gleason 9-10; Any PSA < 150; Any T-stage • Gleason 8; PSA < 20; T- Stage ≥ T2 • Gleason 8; PSA 20-150; Any T-Stage • Gleason 7; PSA 20-150; Any T-Stage

  21. RTOG 0521Treatment Plan • Radiotherapy • RT to 72.0-75.6 Gy, using either 3DCRT or IMRT treatment. RT will begin 8 weeks following the initiation of AS • 46.8 Gy will be given to the regional lymphatics followed by a 25.2-28.8 Gy boost to the prostate

  22. RTOG 0521Treatment Plan Arm 1 • Patients will receive androgen suppression (AS) (LHRH agonist and oral antiandrogen) • Oral antiandrogen will be DC’d at the end of RT • LHRH agonist will continue for 24 months Arm 2 • Patients will receive AS as in Arm 1 • Patients will also receive 6 cycles of docetaxel and prednisone beginning 28 days after RT: • Docetaxel 75 mg/m2 over 1 hour (day 1 of each cycle) q 21 days • Prednisone 10 mg PO per day until day 21 of the last cycle of chemotherapy

  23. Post-Prostatectomy RT • When to use it? • Immediately after surgery? • When PSA rises to detectable levels? • Morbidity? • Low • Clinical trial data? • Some

  24. Validated PSA Recurrence Nomogram Graefen JCO 20:2002;951

  25. Post-Prostatectomy TreatmentTrials • SWOG 8794/RTOG 9019 • EORTC 22911

  26. SWOG 8794/RTOG 9019Schema • Opened 1988 • Closed 1995 • Primary endpoint: metastases-free survival • N=473 (410 eligible) • Median FU 9.7 yrs

  27. SWOG 8794/RTOG 9019Results

  28. SWOG 8794/RTOG 9019Metastasis-Free Survival by Treatment Arm

  29. (within 16 wks of surgery) EORTC 22911Schema Opened 11/92 Closed 12/01 N=1005 Bolla Lancet 2005; 366: 572–78

  30. EORTC 22911Failure-Free Survival Bolla Lancet 2005; 366: 572–78

  31. Post-Prostatectomy Tumor and Target Volume

  32. Post-Prostatectomy Tumor and Target Volume

  33. Isodose Distribution

  34. Isodose Distribution

  35. Adjuvant RT • Decreases risk of biochemical failure • High risk group can be identified • Positive margins are important • Morbidity is acceptable • Results from large phase III trials are strongly supportive • Adjuvant RT is currently underutilized

  36. Case Presentation 1 • 65 year old man with prostate cancer • PSA 55 ng/ml • cT3a • Gleason 4+4=8 • Metastatic evaluation (CT, BS) negative

  37. Case Presentation 1Question 1 • If the patient is treated with RT and long term androgen ablation, what is the 5 year bNED rate? • 80% • 60% • 40% • 20%

  38. Case Presentation 1Question 2 • You’re asked about the role of adjuvant chemotherapy along with LTAD and RT for the patient. Which of the following is correct: • Adjuvant chemotherapy has been shown to improve survival • Adjuvant chemotherapy has been shown to be appropriate for use in selected cases • There is no proven survival benefit to adjuvant chemotherapy

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