The Evolving Definition of Advanced Prostate Cancer

1
The Evolving Definition of Advanced Prostate
Cancer

• Judd W. Moul, MD
• Professor and ChiefDivision of Urologic
  SurgeryDuke UniversityDurham, North Carolina

2
First a Poster-Boy for Contemporary Advanced
Disease

• Hormonal therapy (HT)
• Brachytherapy
• External beam radiotherapy
• MULTIMODAL THERAPY

Bumiller E. Guiliani opts for hormones for
cancer. New York Times. August 2, 2000A24.
3
Another Poster Boy forContemporary Advanced
Disease

• Arnold Palmer
• Radical prostatectomy and PSA recurrence

4
The Evolving Faceof Prostate Cancer

• Many younger, healthier menrisk vs benefit of
  Rx more important
• Rx based on risk stratification
• Neoadjuvant/adjuvant HT use
• Risk stratified early Rx in biochemical
  recurrence
• Earlier use of HT in advanced PC
• Traditional vs non-traditional HT LHRH vs
  antiandrogen monotherapy vs IHT

5
The Evolving Definition of Advanced Prostate
Cancer

• Younger, healthier, better informed patients
• Stage migration less D2 disease
• Broadened definition of advanced disease with
  longer survival expected
• Potential for longer-term use of HT
• Less blanket acceptance of traditional
  HTside-effects, especially over many years
• More need to balance risk vs benefit of Rx
  decisions

6
Age MigrationMore Patients Diagnosed at Younger
Age(DoD CPDR National Database)
50
gt70
40
30
65 70
Constituent Age Ratio ()
20
60 65
55 60
10
lt55
0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Diagnosis Year
7
Stage Migration Marked by Fewer Patients
Presenting with Clinical Metastasis (Stage D1/D2)
at Diagnosis (DoD CPDR National Database)
12
8
Rate of Bone Metastasis at Diagnosis
4
0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Diagnosis Year (N10686)
8
Risk Stratification inClinically Localized
Disease

• LOW RISK PSA lt 10 ng/mL and biopsy Gleason 6
  and 1992 AJCC T1c, 2a
• INT RISK PSA gt 10 - 20 ng/mL or biopsy Gleason 7
  or 1992 AJCC T2b
• HIGH RISK PSA gt 20 ng/mL or biopsy Gleason 8
  or 1992 AJCC T2c

DAmico AV, Whittington R, Malkowicz, et al. J
Clin Oncol. 20001811641172.
9
(No Transcript)
10
HIGH RP
11
HIGH XRT
12
Rising PSA PSA Only or Biochemical
Recurrence...
most common stage of advanced disease
13
(No Transcript)
14
PSA Relapse

• New CaP cases/year 231,000
• 3/4 who receive localized 173,250disease
  treatment annually
• 35 who may experience 60,600PSA-only
  recurrence/yr

More men are younger and healthierat time of
PSA-only recurrence
Based on SEER statistics. 2004.
15
PSA RelapseArguments for Early HT

• Most common presentation of advanced prostate
  cancer
• Relatively easy to define clinical condition
• Likely to impact natural lifespan for many
  contemporary patients
• Survival advantage to early hormonal therapyfor
  advanced disease becoming more clear
• Watchful waiting not acceptable for many men

16
PSA RelapseArguments Against Early HT

• Long natural history of rising PSA before
  clinical metastases and death for most men
• No randomized controlled clinical trials to
  address this issue
• Side effects of hormonal therapy
• Cost of hormonal therapy

17
PSA RelapseNatural History of Untreated Men
Radical prostatectomy (N1997 between 1982 and
1997) PSA-only recurrence (N315 15)
Clinical metastases Death from prostate
cancer
8 years median
5 years median
Pound CR et al. JAMA. 19992811591-1597.
18
(No Transcript)
19
(No Transcript)
20
Study Cohort Diagram Illustrating Exclusion and
Inclusion of Patients
Primary Radical Prostatectomy Patients Overalln
5,382
Primary RP Patients Diagnosed in PSA-Era
(1988-2002)n 4,967
Primary RP Patients Diagnosed in PSA-Era with
Follow-upn 528 Excluded due to post RP
follow-up lt 6 monthsn 363 Excluded due to a
salvage XRT after PSARn 49 Excluded due to no
follow-up after PSAR
PSA Recurrences (Study Cohort)n 1,352
Moul JW et al. J Urol. 20041711141-1147.
Groups not mutually exclusive
21
PSA Only Recurrence Cohort to Illustrate PSA at
Initiation of HT
PSA Recurrence Patientsn 1,352
Started HT gt 0.2 2.5 ng/mLn 221 (16.3)
Started HT gt 2.6 5.0 ng/mLn 47 (3.5)
Started HT gt 5.1 10.0 ng/mLn 39 (2.9)
Started HT PSA gt 10.0 ng/mLn 48 (3.6)
No HT (Median/mean follow-up 5.2/4.7 years after
radical prostatectomy)n 997 (73.7)
Moul JW et al. J Urol. 20041711141-1147.
22
Early HT Administered at PSA gt5 ng/mL Affects
Clinical Metastasis-Free Survival

• Patients with pathological Gleason sum gt 7 or
  PSA-DT lt 12 Months

Moul JW et al. J Urol. 20041711141-1147.
23
Early HT Administered at PSA lt10 ng/mL Affects
Clinical Metastasis-Free Survival

• Patients with pathological Gleason sum gt 7 or
  PSA-DT lt 12 Months

Moul JW et al. J Urol. 20041711141-1147.
24
Early HT Administered at lt5 ng/mL Did Not Affect
Clinical Metastasis-Free Survival

• Overall cohort with PSAR at current follow-up

Moul JW et al. J Urol. 20041711141-1147.
25

• Good News
• First study to show clinical DFS benefit to early
  HT for PSAR
• Emphasizes the importance of risk
  stratification in PSA relapse
• Supports that men with high-grade disease
  (Gleason 8-10) and quick PSA-DT (lt12 months) are
  high risk of clinical failure

• Bad News
• Not a randomized controlled trial
• Overall, there was no benefit to early HT
• Database study is a moving target and results
  may change over time
• Follow-up too short to determine overall survival
  impact

26
(No Transcript)
27
CPDR/CaPSURE/Harvard PSA-DT Study
100
Surgery, PSA DT ?3 months
Radiation, PSA DT ?3 months
80
60
Surgery, PSA DT lt3 months
Prostate CancerSpecific Survival
40
20
Radiation, PSA DT lt3 months
0
10
0
1
2
3
4
5
6
7
8
9
Time (Years) Following PSA Failure
537 509 433 358 282 206 144 95 52 26 12668 635 53
6 430 306 200 130 65 34 18 8 74 62 49
41 33 22 15 10 6 2 1172 154 127 99 75
54 33 18 10 4 1
Number at Risk
DAmico AV, et al. J Natl Cancer Inst.
2003951376-1383.
28
Take-Home Messages

• Changing face of advanced prostate cancer is
  profound
• High-risk localized and PSA recurrence most
  common advanced prostate cancer
• No randomized controlled trials to guide our
  clinical decisions in PSA recurrence
• Our recent work emphasizes that we take a risk
  stratified approach to PSA relapse
• Men with high grade disease (Gleason 8-10) and
  those with short PSA-DT (lt12 months) have delayed
  clinical metastases if they receive early HT
• Unknown if early HT for PSA relapse will
  improvecancer-specific or overall survival

Moul et al. J. Urol. March 2004.