Prostate Cancer. Prostate Cancer. Prostate Cancer. Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

Prostate Cancer Prostate Cancer • • • • • • Edward P. Gelmann, MD Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastat...
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Prostate Cancer

Prostate Cancer

• • • • • •

Edward P. Gelmann, MD

Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease © EPG ©EPG

RNASEL, MSR1, or

normal prostate epithelium GSTP1 CpG island hypermethylation

other germline mutation

Prostate Cancer

ETS Translocation (AR-Dependent) 9 P27

prostatic intraepithelial neoplasia localized prostate cancer

decrease in NKX3.1 DNA damage ↑ Survival signal

AR

metastatic prostate cancer

PTEN, P53, RB, MYC

castration resistant cancer © EPG ©EPG

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

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Prostate Cancer

Prostate Cancer

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SEER

Prostate Cancer

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

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SEER

Prostate Cancer

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JNCI 95:1357, 2003

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Prostate Cancer • • • • • •

Epithelial Cells

Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

PSA

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PSA

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PSA

Serine protease

Refinements: PSA Density

Indicator of cancer activity post treatment Free/Total PSA Screening tool

PSA Velocity © EPG ©EPG

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Reasons to Initiate Mass Screening for Cancer

Reasons to Initiate Mass Screening for Cancer

1. The disease should represent a substantial public health burden and have a prevalent, asymptomatic premetastatic phase.

There are >200,000 new cases of prostate cancer/year. Early stage prostate cancer is curable.

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 Cancer

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Reasons to Initiate Mass Screening for Cancer

3. A good screening test that has reasonable predictive value, low cost and is acceptable to screener and

4. Curative potential should be better in early than in late state disease.

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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10-Yr progression-free survival with: organ-confined disease - 69% with regional extension - 38.5%, with distant metastases - 15%.

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Prostate Cancer Screening

Reasons 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 Screening

Andriole NEJM 360:1310, 2009

Andriole NEJM 360:1310, 2009

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Prostate Cancer Screening

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Schroder NEJM 360:1320, 2009

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Prostate Cancer Screening

Prostate Cancer • • • • • •

Schroder NEJM 360:1320, 2009

Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

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Prostate Histology - Gleason Grading

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Prostate Histology - Gleason Grading

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Localized Prostate Cancer

Prostate Pathology

Natural History

Albertsen JAMA 293: 2095, 2005

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Prostate Cancer • • • • • • •

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Prostate - TUR

Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease Other Considerations in Management © EPG ©EPG

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Staging – AJCC 6th Edition T1

- Incidental histologic finding a - 5% of tissue c - PSA detection

T2

- Clinically present limited to prostate a – ≤ ½ lobe b - > ½ of one lobe c – both lobes

Staging – AJCC 6th Edition

T3 -

Invades beyond apex, capsule, bladder neck or SV, but not fixed a – ECE b - SV

T4

Nodal status N0 - no nodes involved N1 – regional nodes

Metastases

– Fixed or invades other structures or fixed

M0 M1a – distant nodes M1b – bone M1c – other sites w/ or w/o bone © EPG ©EPG

Prostate Cancer • • • • • •

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Pelvic Anatomy

Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease © EPG ©EPG

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Trends in Treatment of Primary Prostate Cancer

Treatment 19831983-1995

CaPSURE

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Cooperberg JNCI 95:981, 2003

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

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Treatment of Local Prostate Cancer

LeadLead-Time Bias

Radical Retropubic Prostatectomy

Symptoms Screen Detection Lead

Death

Time Bias

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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 Prostatectomy

http://prostate.urol.jhu.edu/surgical_techniques/radical_prostatectomy/index.html

Radical Retropubic Prostatectomy

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Treatment of Local Prostate Cancer

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Prostate – RRP Survival

Radical Retropubic Prostatectomy

http://prostate.urol.jhu.edu/surgical_techniques/radical_prostatectomy/index.html

http://prostate.urol.jhu.edu/surgical_techniques/radical_prostatectomy/index.html

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Zhang Cancer 100:300, 2004

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Prostate Cancer

Prostatectomy v. Watchful Waiting

Disease Extent and Survival

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Bill-Axelson JNCI 100:1144, 2008

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Progressive Disease

Prostatectomy v. Watchful Waiting

PSA after RRP should < 0.01ng/ml Two successive ↑ = recurrence Salvage XRT

Bill-Axelson JNCI 100:1144, 2008

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Treatment of Local Prostate Cancer

Treatment of Local Prostate Cancer

Morbidity of RRP

Begg NEJM 346:1138, 2002

Morbidity of RRP

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Treatment of Local Prostate Cancer

Begg NEJM 346:1138, 2002

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Treatment of Local Prostate Cancer

Conformal RT

Conformal RT

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Treatment of Local Prostate Cancer

Treatment of Local Prostate Cancer

Conformal RT

IMRT

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 © EPG ©EPG

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Treatment of Local Prostate Cancer Brachytherapy

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Treatment of Localized Prostate Cancer

Treatment of Localized Prostate Cancer

Morbidity at 2 yr

Acute Morbidity

prostatectomy incontinence impotence

Potosky et al JNCI 92:1582, 2000

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Prostate Cancer • • • • • •

radiotherapy

9.6%

3.5%

79.6%

61.5%

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Potosky et al JNCI 92:1582, 2000

Endocrine Axis in Prostate Cancer

Epidemiology and Etiology Screening Pathology Staging Localized Disease (Locally Advanced) Metastatic Disease

GnRH agonist

Adrenal Blockade

Antiandrogens

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Orchiectomy

Finasteride

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Neoadjuvant Therapy

Neoadjuvant Therapy

Surgery

Irradiation for Stage C

RT + Goserelin (3 yr)

Diminish the size of large cancers Four Randomized trials increased rate of negative margins

v.

There was no effect on lymph node metastases

RT followed by appropriate Rx

No effect on DFS © EPG ©EPG

Neoadjuvant Therapy

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Neoadjuvant Therapy

Stage C

Bolla Lancet 360:103, 2003

Bolla et al,NEJM 337:295-300, 1997

Stage C

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Bolla Lancet 360:103, 2003

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Locally Advanced Prostate Cancer

Prostate Cancer

RT + HT

• • • • • •

d’Amico Urology 60:32 2002

Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

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Hormonal Therapy

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Progressive Disease

Progressive Disease

Early v. delayed androgen ablation

Metastatic Disease

Benefits of cancer control vs. morbidity of androgen ablation

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Progressive Disease

Early Androgen Ablation

Morbidity of androgen ablation Bone mineral density Fatigue Diabetes mellitus Cardiovascular risk

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Total Androgen Ablation

Rx

N=

7 yr Survival

Surgery

51

65%

Surgery + AA

47

85%

p=0.001

Messing et al,NEJM 341:1781-8, 1999

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Hormonal Therapy – Metastatic CaP nilutamide

Adrenal androgens 5-10% circulating androgens

flutamide

CPA

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Lancet 355:1491, 2000

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Prostate Cancer

Progressive Metastatic Prostate Cancer

INT 0105

Rx

N

MD/ED

PSA< 4.0 *

PFS All/GR

Orch + F

697

141/556

80%

20/48.1 33.5/52 mo mo

Orch + P

685

146/539

68%

18.6/46 mo

Androgen ablation should not be discontinued

Survival All/GR

Even after progression on a GnRH agonist

30/51 mo

AR expression persists * p