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 1Question 1

• If the patient is treated with RT and long term androgen ablation, what is the 5 year bNED rate?1. 80%

2. 60%

3. 40%

4. 20%

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:1. Adjuvant chemotherapy has been shown to improve survival

2. Adjuvant chemotherapy has been shown to be appropriate for use in selected cases

3. 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 2Question 1

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

2. 65%

3. 75%

4. 85%

Case Presentation 2Question 2

• In Bolla’s EORTC study, adjuvant RT improves the 5-year overall survival rate from 93% to:1. 93% (i.e., no improvement)

2. 98%

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 9202Disease-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.

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

RANDOMIZE

Docetaxel 75 mg/m2 Prednisone 5mg, PO BIDPlacebo

every 3 wks

Docetaxel 75 mg/m2 Prednisone 5mg, PO BIDBevacizumab 15mg/kg

every 3 wks

StratificationHalabi nomogram

Eligibility• Metastatic PC• T <50ng/ml• No prior chemo• Adequate hem, renal, and liver function

N = 1020CALGB, ECOG, NCIC

Hypothesis

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

RTOG 0521Schema

RANDOMIZE

ADT x 2 yrs + RT

ADT x 2 yrs + RT6 cycles docetaxel 75 mg/m2 andprednisone starting 1 mo after RT

High Risk(n=600)

Primary Endpoint: Overall Survival

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

RTOG 0521Study Design

• Randomized, Phase III study• Sample size = 600 patients• Patients are stratified by

– PSA– Gleason score– T-stage

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

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

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

Post-Prostatectomy RT

• When to use it?– Immediately after surgery?– When PSA rises to detectable levels?

• Morbidity? – Low

• Clinical trial data? – Some

Graefen JCO 20:2002;951

Validated PSA Recurrence Nomogram

Post-Prostatectomy TreatmentTrials

• SWOG 8794/RTOG 9019• EORTC 22911

SWOG 8794/RTOG 9019Schema

• Opened 1988• Closed 1995

• Primary endpoint: metastases-free survival

• N=473 (410 eligible)

• Median FU 9.7 yrs

SWOG 8794/RTOG 9019Results

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 9019Metastasis-Free Survival by Treatment Arm

EORTC 22911Schema

Opened 11/92

Closed 12/01

N=1005

(within 16 wks of surgery)

Bolla Lancet 2005; 366: 572–78

EORTC 22911Failure-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 1Question 1

• If the patient is treated with RT and long term androgen ablation, what is the 5 year bNED rate?1. 80%

2. 60%

3. 40%

4. 20%

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:1. Adjuvant chemotherapy has been shown to improve survival

2. Adjuvant chemotherapy has been shown to be appropriate for use in selected cases

3. There is no proven survival benefit to adjuvant chemotherapy