Transcript NEW PARADIGMS TO IMPROVE OUTCOMES IN HEAD AND …

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?
1.
2.
3.
4.
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:
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 2
Question 1
•
In Bolla’s EORTC study, adjuvant RT improves the 5-year
biochemical failure rate from 53% to:
1.
2.
3.
4.
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:
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 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.
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
Eligibility
• Metastatic PC
• T <50ng/ml
• No prior chemo
• Adequate hem,
renal, and liver
function
N = 1020
CALGB, ECOG, NCIC
Stratification
Halabi
nomogram
R
A
N
D
O
M
I
Z
E
Docetaxel 75 mg/m2
Prednisone 5mg, PO BID
Placebo
every 3 wks
Docetaxel 75 mg/m2
Prednisone 5mg, PO BID
Bevacizumab 15mg/kg
every 3 wks
Hypothesis
• Adjuvant chemotherapy will prolong life when
given in addition to LTAD following RT for high
risk prostate cancer
RTOG 0521
Schema
High Risk
(n=600)
R
A
N
D
O
M
I
Z
E
Primary Endpoint: Overall Survival
ADT x 2 yrs + RT
ADT x 2 yrs + RT
6 cycles docetaxel 75 mg/m2 and
prednisone starting 1 mo after RT
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
• 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
SWOG 8794/RTOG 9019
Results
Adjuvant
Radiotherapy
Observation
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
Event
SWOG 8794/RTOG 9019
Metastasis-Free Survival by Treatment Arm
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?
1.
2.
3.
4.
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:
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