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