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 Metastatic evaluation (CT, BS) negative

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

Case Presentation 1 Question 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

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

Case Presentation 2 Question 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%

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

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

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

High Risk Prostate Cancer RTOG 9202 Disease-free survival

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

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

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.

Memorial Sloan Kettering Cancer Center 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

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

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

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

RTOG 0521 Objectives 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

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

RTOG 0521 Key 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

RTOG 0521 Treatment 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

RTOG 0521 Treatment Plan Arm 1 Arm 2 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

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

Validated PSA Recurrence Nomogram Graefen JCO 20:2002;951

Post-Prostatectomy Treatment Trials SWOG 8794/RTOG 9019 EORTC 22911

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

Adjuvant Radiotherapy SWOG 8794/RTOG 9019 Results Adjuvant Radiotherapy Observation Event 10 years 10 yrs HR P-value PSA-free survival (<0.4 ng/ml) 47% 23% 0.51 <0.001 Relapse-free survival 67% 48% 0.59 0.001 Metastasis-free survival 71% 61% 0.80 0.17 Overall survival 74% 63% 0.76 0.11

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

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

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

Post-Prostatectomy Tumor and Target Volume

Post-Prostatectomy Tumor and Target Volume

Isodose Distribution

Isodose Distribution

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

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

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

Case Presentation 1 Question 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

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

Case Presentation 2 Question 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%

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

New Perspectives on the Application of Chemotherapy in Prostate Cancer Therapy for Advanced Prostate Cancer DISCUSSION