prostate cancer: role of systemic therapy in high risk and locally advanced disease robert dreicer,...
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Prostate cancer: Role of systemic therapy in high risk and locally advanced disease
Robert Dreicer, M.D., M.S., FACPChair Dept of Solid Tumor OncologyTaussig Cancer InstituteCleveland ClinicProfessor of Medicine Cleveland Clinic Lerner College of Medicine
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LocallyAdvancedDisease
Rising PSAHormone
Naive
Rising PSACastrate
MetastasesCastrateResistant
Asymptomatic
Metastases
CastrateResistant
Symptomatic
OrganConfined
Metastatic Disease
(De novo)
Clinical States In Prostate Cancer
MetastasesCastrateResistant
Post Docetaxel
MetastasesCastrateResistant
Post Cabazitaxel
Sipuleucel-T
Abiraterone
CabazitaxelDenosumab
Modified from Scher HI, et al. Urology 2000 55:323-7
Alpharadin, MDV- 3100 ?
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Definitions
Locally Advanced prostate cancer: Gleason 8-10 PSA ≥ 15 T3 disease
High risk(for this presentation) - biochemical failure PSA DT < 12 months
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“Is cure possible?
Is cure necessary?
Is cure possible only when it is not necessary ?” Willet Whitmore, Jr.,M.D.
Distinguished Chair of Urology at Memorial Sloan Kettering
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Locally Advanced Prostate Cancer: A clinical dilemma that has not gone away Issues:
High systemic failure rate Poorly controlled by unimodality
therapy Clearly a group at risk of dying from
prostate cancer
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Locally Advanced Prostate Cancer: A clinical dilemma that has not gone away What we know:
Multimodality therapy is the standard of care for these patients Surgery/adjuvant radiotherapy EBRT/ADT
Neoadjuvant hormonal therapy prior to RRP- NOPE
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Locally Advanced Prostate Cancer: A clinical dilemma that has not gone away What we dont know:
Is adjuvant and salvage radiotherapy equal?
Does brachytherapy/ADT = EBRT/ADT Is there a role for perioperative systemic
therapy i.e. does earlier use of docetaxel improve
outcomes
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Bolla et al. Lancet. 2005 ;366):572-8, Thompson et al.
J Urol. 2009;181:956-62
Adjuvant Radiotherapy
EORTC 22911: 1005 pts Adj xrt PFS advantage with early radiotherapy: 74.8%
versus 52.6% (p < 0.001) SWOG 8794: 410 pts
Adj xrt PFS advantage with early radiotherapy: 67% versus 48% (p < 0.001)
metastatic-free survival was 84% vs 69% at 5 yrs, 68% vs 49% at 10 years with an (HR of 0.62 p = 0.001)
Improved OS (median 15.2 yr compared with 13.5 yr, p = 0.031)
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HR 0.73 (95% CI 0.55, 0.97) p=0.031
90%
74%
50%
39%
66%
89%
0%
20%
40%
60%
80%
100%
0 5 10 15 20Years from Registration
Adjuvant RTObservation
At Risk214211
Death87108
Medianin Years
15.213.5
Survival By Treatment ArmSurvival By Treatment Arm
Thompson et al. J Urol. 2009;181:956-62
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High-risk localized
CAP
RP
ADT + docetaxel followed by RP RA
ND
OM
IZE
Primary EPC = 5-year bPFS
bPFS = biochemical progression-free survival.Eastham et al, 2003.
CALGB 90203: Phase III Study of Radical CALGB 90203: Phase III Study of Radical Prostatectomy Alone +/- Docetaxel in High-Risk Prostatectomy Alone +/- Docetaxel in High-Risk
Localized Prostate Cancer (PUNCH)Localized Prostate Cancer (PUNCH)
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What is the Natural History Of Patients Who Relapse After Local Therapy
• 304 men relapsed after surgery• No hormones until (+) bone scan• Time to PSA rise, Gleason, PSADT were predictors
of survival
First Rise in PSA
RP
Bone scan (+)
Death
8 yrs 5 yrs
Pound JAMA 1999Pound CR, et al. JAMA 1999; 281:1591
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Biochemical Failure: Sorting out the relatively good and bad actors Differences in biochemical failure between
surgical and radiotherapy patients PSA bounce Remember to consider the biology
Role of salvage therapies For RRP failure For EBRT/Brachy failure
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Patients with a Rising PSA-Importance of PSADT
Freedland SJ, et al. JAMA. 2005;294(4):433-439.
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Patients with a Rising PSA-Importance of PSADT
PSADT Median Time to Median Survival
(months) Metastases (years) (years)
3 2 6
6 4 8
9 6 10
12 8 12
D'Amico AV, et al. J Natl Cancer Inst. 2004;96(7):509-515.
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Challenges in Managing Patients with PSA only Disease Moving the patient ( and some of his docs)
away from a curative mind set Recognition of limitations of therapy
“really early ADT” Using PSA DT to inform timing of
evaluation/intervention
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Androgen Deprivation TherapySide Effects, Toxicities Loss of libido Muscle mass loss Osteoporosis, osteoporotic related fx Weight gain- increase in abdominal girth Cognitive dysfunction Diabetes/metabolic syndrome Increase in coronary artery disease
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"He is a man of splendid abilities, but utterly corrupt. Like rotten mackerel by moonlight, he shines and stinks."
John Randolph, Representative of Virginia(1773-1833)