Prostate CancerProstate Cancer
Edward P. Gelmann, MD
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Prostate CancerProstate Cancer
• Epidemiology and Etiology• Screening• Pathology• Staging• Localized Disease• Metastatic Disease
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normalprostateepithelium
prostaticintraepithelial
neoplasia
localizedprostatecancer
metastaticprostatecancer
castrationresistantcancer
RNASEL, MSR1, orother germline
mutation
GSTP1 CpG islandhypermethylation
decrease in NKX3.1
DNA damage↑ Survival signal
ETS Translocation(AR-Dependent)
9 P27
PTEN, P53, RB, MYC
AR
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Prostate CancerProstate Cancer
http://seer.cancer.gov/publications/prostate
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Prostate CancerProstate Cancer
SEER ©©©EPGEPGEPG
Prostate CancerProstate Cancer
SEER
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Prostate CancerProstate Cancer
http://seer.cancer.gov/publications/prostate ©©©EPGEPGEPG
Prostate CancerProstate Cancer
JNCI 95:1357, 2003
©©©EPGEPGEPG
Prostate CancerProstate Cancer
• Epidemiology and Etiology• Screening• Pathology• Staging• Localized Disease• Metastatic Disease
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Epithelial CellsEpithelial Cells
PSA
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PSAPSA
Serine protease
Indicator of cancer activity post treatment
Screening tool
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PSAPSA
Refinements:PSA Density
Free/Total PSA
PSA Velocity
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Reasons to Initiate Mass Screening for CancerReasons to Initiate Mass Screening for Cancer
1. The disease should represent a substantial public health burden and have a prevalent, asymptomatic premetastaticphase.
There are >200,000 new cases of prostate cancer/year.Early stage prostate cancer is curable.
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Reasons to Initiate Mass Screening for CancerReasons to Initiate Mass Screening for Cancer
2. The asymptomatic premetastatic phase should be recognizable.
Early stage prostate cancer can be detected using DRE and PSA.
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Reasons to Initiate Mass Screening for CancerReasons to Initiate Mass Screening for Cancer
3. A good screening test that has reasonable predictive value, low cost and is acceptable to screener and subject.
For a man >50, positive predictive value of a PSA > 4.0 is 20-30%, and PSA > 10, 42-64%. PSA detection rate is 3%.
PSA costs $25-60.
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Reasons to Initiate Mass Screening for CancerReasons to Initiate Mass Screening for Cancer
4. Curative potential should be better in early than in late state disease.
10-Yr progression-free survival with:organ-confined disease - 69%with regional extension - 38.5%,with distant metastases - 15%.
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Reasons to Initiate Mass Screening for CancerReasons to Initiate Mass Screening for Cancer
5. Screening should improve outcome as measured by cause-specific mortality.
No randomized trial data to support the use of screening for prostate cancer.
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Prostate Cancer ScreeningProstate Cancer Screening
Andriole NEJM 360:1310, 2009
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Prostate Cancer ScreeningProstate Cancer Screening
Andriole NEJM 360:1310, 2009 ©©©EPGEPGEPG
Prostate Cancer ScreeningProstate Cancer Screening
Schroder NEJM 360:1320, 2009
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Prostate Cancer ScreeningProstate Cancer Screening
Schroder NEJM 360:1320, 2009 ©©©EPGEPGEPG
Prostate CancerProstate Cancer
• Epidemiology and Etiology• Screening• Pathology• Staging• Localized Disease• Metastatic Disease
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Prostate Histology Prostate Histology -- Gleason GradingGleason Grading
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Prostate Histology Prostate Histology -- Gleason GradingGleason Grading
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Localized Prostate CancerLocalized Prostate CancerNatural HistoryNatural History
Albertsen JAMA 293: 2095, 2005 ©©©EPGEPGEPG
Prostate PathologyProstate Pathology
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Prostate CancerProstate Cancer
• Epidemiology and Etiology• Screening• Pathology• Staging• Localized Disease• Metastatic Disease• Other Considerations in Management
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Prostate Prostate -- TURTUR
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Staging Staging –– AJCC 6AJCC 6thth EditionEdition
T1 - Incidental histologicfinding
a - <5% of tissueb ->5% of tissuec - PSA detection
T2 - Clinically presentlimited to prostate
a – ≤ ½ lobeb - > ½ of one lobec – both lobes
T3 - Invades beyond apex, capsule, bladder neck or SV, but not fixed
a – ECEb - SV
T4 – Fixed or invades other structures or fixed
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Staging Staging –– AJCC 6AJCC 6thth EditionEdition
Nodal statusN0 - no nodes involvedN1 – regional nodes
MetastasesM0M1a – distant nodesM1b – boneM1c – other sites w/ or w/o bone
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Prostate CancerProstate Cancer
• Epidemiology and Etiology• Screening• Pathology• Staging• Localized Disease• Metastatic Disease
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Pelvic AnatomyPelvic Anatomy
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Trends in Treatment of Primary Prostate CancerTrends in Treatment of Primary Prostate CancerCaPSURECaPSURE
Cooperberg JNCI 95:981, 2003©©©EPGEPGEPG
Treatment 1983Treatment 1983--19951995
http://seer.cancer.gov/publications/prostate
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LeadLead--Time BiasTime Bias
Symptoms
Screen Detection
Lead
Time
Bias
Death
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Treatment of Local Prostate CancerTreatment of Local Prostate CancerRadical Retropubic ProstatectomyRadical Retropubic Prostatectomy
http://prostate.urol.jhu.edu/surgical_techniques/radical_prostatectomy/index.html
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Treatment of Local Prostate CancerTreatment of Local Prostate CancerRadical Retropubic ProstatectomyRadical Retropubic Prostatectomy
http://prostate.urol.jhu.edu/surgical_techniques/radical_prostatectomy/index.html©©©EPGEPGEPG
Treatment of Local Prostate Cancer Treatment of Local Prostate Cancer Radical Retropubic ProstatectomyRadical Retropubic Prostatectomy
http://prostate.urol.jhu.edu/surgical_techniques/radical_prostatectomy/index.html
©©©EPGEPGEPG
Treatment of Local Prostate Cancer Treatment of Local Prostate Cancer Radical Retropubic ProstatectomyRadical Retropubic Prostatectomy
http://prostate.urol.jhu.edu/surgical_techniques/radical_prostatectomy/index.html ©©©EPGEPGEPG
Prostate Prostate –– RRP SurvivalRRP Survival
Zhang Cancer 100:300, 2004
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Prostate CancerProstate CancerDisease Extent and SurvivalDisease Extent and Survival
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Prostatectomy v. Watchful WaitingProstatectomy v. Watchful Waiting
Bill-Axelson JNCI 100:1144, 2008
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Prostatectomy v. Watchful WaitingProstatectomy v. Watchful Waiting
Bill-Axelson JNCI 100:1144, 2008 ©©©EPGEPGEPG
Progressive DiseaseProgressive Disease
PSA after RRP should < 0.01ng/ml
Two successive ↑ = recurrence
Salvage XRT
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Treatment of Local Prostate Cancer Treatment of Local Prostate Cancer Morbidity of RRPMorbidity of RRP
Begg NEJM 346:1138, 2002 ©©©EPGEPGEPG
Treatment of Local Prostate Cancer Treatment of Local Prostate Cancer Morbidity of RRPMorbidity of RRP
Begg NEJM 346:1138, 2002
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Treatment of Local Prostate CancerTreatment of Local Prostate CancerConformal RTConformal RT
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Treatment of Local Prostate CancerTreatment of Local Prostate CancerConformal RTConformal RT
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Treatment of Local Prostate CancerTreatment of Local Prostate CancerConformal RTConformal RT
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Treatment of Local Prostate CancerTreatment of Local Prostate CancerIMRTIMRT
One of several strategies to improve risk benefit ratio
Need to worry about potential downside
If imaging (MR) can identify regions of more cancer, IMRT can tailor the dose accordingly
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Treatment of Local Prostate CancerTreatment of Local Prostate CancerBrachytherapyBrachytherapy
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Treatment of Localized Prostate CancerTreatment of Localized Prostate CancerAcute MorbidityAcute Morbidity
Potosky et al JNCI 92:1582, 2000 ©©©EPGEPGEPG
Treatment of Localized Prostate CancerTreatment of Localized Prostate CancerMorbidity at 2 yrMorbidity at 2 yr
Potosky et al JNCI 92:1582, 2000
prostatectomy radiotherapy
incontinence 9.6% 3.5%
impotence 79.6% 61.5%
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Prostate CancerProstate Cancer
• Epidemiology and Etiology• Screening• Pathology• Staging• Localized Disease (Locally Advanced)• Metastatic Disease
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Endocrine Axis in Prostate CancerEndocrine Axis in Prostate Cancer
Orchiectomy
GnRH agonist
Adrenal Blockade
FinasterideAntiandrogens
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Neoadjuvant TherapyNeoadjuvant TherapySurgerySurgery
Diminish the size of large cancers
Four Randomized trials -increased rate of negative margins
There was no effect onlymph node metastases
No effect on DFS
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Neoadjuvant TherapyNeoadjuvant TherapyIrradiation for Stage CIrradiation for Stage C
Bolla et al,NEJM 337:295-300, 1997
RT + Goserelin (3 yr)
v.
RT followed by appropriate Rx
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Neoadjuvant TherapyNeoadjuvant TherapyStage CStage C
Bolla Lancet 360:103, 2003 ©©©EPGEPGEPG
Neoadjuvant TherapyNeoadjuvant TherapyStage CStage C
Bolla Lancet 360:103, 2003
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Locally Advanced Prostate CancerLocally Advanced Prostate CancerRT + HTRT + HT
d’Amico Urology 60:32 2002 ©©©EPGEPGEPG
Prostate CancerProstate Cancer
• Epidemiology and Etiology• Screening• Pathology• Staging• Localized Disease• Metastatic Disease
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Hormonal TherapyHormonal Therapy
Progressive Disease
Metastatic Disease
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Progressive DiseaseProgressive Disease
Early v. delayed androgen ablation
Benefits of cancer control vs. morbidity of androgen ablation
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Progressive DiseaseProgressive Disease
Morbidity of androgen ablation
Bone mineral densityFatigueDiabetes mellitusCardiovascular risk
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Early Androgen AblationEarly Androgen Ablation
Rx N= 7 yrSurvival
Surgery 51 65%
Surgery +AA
47 85%p=0.001
Messing et al,NEJM 341:1781-8, 1999
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Total Androgen AblationTotal Androgen Ablation
Adrenal androgens5-10% circulating androgens
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Hormonal Therapy Hormonal Therapy –– Metastatic Metastatic CaPCaP
Lancet 355:1491, 2000
nilutamide
flutamide
CPA
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Prostate CancerProstate CancerINT 0105INT 0105
Rx N MD/ED PSA<4.0 *
PFSAll/GR
SurvivalAll/GR
Orch + F 697 141/556 80% 20/48.1mo
33.5/52mo
Orch + P 685 146/539 68% 18.6/46mo
30/51mo
* p<0.01
EisenbergerEisenberger et al, NEJM 339:1036et al, NEJM 339:1036--42, 199842, 1998 ©©©EPGEPGEPG
Progressive Metastatic Prostate CancerProgressive Metastatic Prostate Cancer
Androgen ablation should notbe discontinued
Even after progression on a GnRHagonist
AR expression persists
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AR Structure AR Structure
DNA-binding
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Activation of TranscriptionActivation of Transcription
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AndrogenAndrogen--Independent Prostate CancerIndependent Prostate Cancer
Androgen receptor gene amplification
AR mutations
AR phosphorylation
AR coactivator over expression
Increased expression of androgen synthetic enzymes
Alternate splicing to generate ligand-independence©©©EPGEPGEPG
SecondSecond--Line Hormonal RxLine Hormonal Rx
AAW
Ketoconazole
Adrenal BlockadeSteroidsAminoglutethimide
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Progressive Prostate CancerProgressive Prostate CancerManagementManagement
Bone mets - locationprophylaxis
Pain management
Second-line hormonal Rx
Chemotherapy
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CRPCCRPC
Petrylack NEJM 351:1513, 2004
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CRPCCRPC
Petrylack NEJM 351:1513, 2004©©©EPGEPGEPG
SummarySummary
Screening is common and may be more of a problem than a solution
Prognostic markers are insufficient to identify cancers that need treatment
Local therapy still has significant morbidity
Systemic therapy carries risks and benefits
Better targeting of the AR may be beneficial
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