1. 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

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 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%

4. 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

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 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%

7. 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%

8. 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

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. High Risk Prostate Cancer
RTOG 9202
Disease-free survival

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:

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:

14. 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

15. 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

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

17. 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

18. 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

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

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

21. RTOG 0521 Treatment Plan Radiotherapy
RT to 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 Gy boost to the prostate

22. 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

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 Treatment Trials
SWOG 8794/RTOG 9019
EORTC 22911

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

27. 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

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

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

30. EORTC 22911 Failure-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 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%

38. 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

39. 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

40. 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%

41. 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%

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