Prostate Cancer - columbia.edu · Prostate Cancer Edward P. Gelmann, MD ©EPGEPG Prostate Cancer • Epidemiology and Etiology • Screening • Pathology

Prostate CancerProstate Cancer

Edward P. Gelmann, MD

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• 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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http://seer.cancer.gov/publications/prostate

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SEER ©©©EPGEPGEPG


SEER

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http://seer.cancer.gov/publications/prostate ©©©EPGEPGEPG


JNCI 95:1357, 2003

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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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2. The asymptomatic premetastatic phase should be recognizable.

Early stage prostate cancer can be detected using DRE and PSA.

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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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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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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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Andriole NEJM 360:1310, 2009 ©©©EPGEPGEPG


Schroder NEJM 360:1320, 2009

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Schroder NEJM 360:1320, 2009 ©©©EPGEPGEPG



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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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• 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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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

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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 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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• 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



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Hormonal TherapyHormonal Therapy

Progressive Disease

Metastatic Disease

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Early v. delayed androgen ablation

Benefits of cancer control vs. morbidity of androgen ablation

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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

Documents

Prostate Cancer - columbia.edu · Prostate Cancer Edward P. Gelmann, MD ©EPGEPG Prostate Cancer • Epidemiology and Etiology • Screening • Pathology