Prostate Cancer
Ralph Hauke, M.D.
April 25, 2007
Diseases of the Prostate
• Prostatitis (usually infectious)
• Benign prostatic hyperplasia (BPH):
nonmalignant enlargement of the prostate
(most common)
• Prostate cancer
Epidemiology, Screening,
and Diagnosis
Prevalence of Prostate Cancer
• Most common cancer in men in US
– 33% of new cancers in men
– ∼230,000 new cases will occur in 2006
• Second leading cause of cancer deaths in men
– 10% of cancer deaths in men
– ∼30,000 deaths due to prostate cancer
in 2007
• Ratio of 7.7 newly diagnosed cases to every
1 prostate cancer−specific death
American Cancer Society, Inc. Available at:
http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf
Probability of Developing
Invasive Prostate Cancer
Increases With Age
Age (Male)
Birth−39 yr
40−59 yr
60−79 yr
Lifetime risk
All Sites
1 in 73
1 in 12
1 in 3
1 in 2
American Cancer Society, Inc. Available at:
http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf
Prostate
1 in 12,833
1 in 44
1 in 7
1 in 6
Predisposing Factors for
Developing Prostate Cancer
Advancing age
•
>70% of cases in men >65 yr
Ethnicity
•
•
•
Highest incidence in African American and Jamaican men of African descent
Common in North America and Western Europe
Rare in Asia and South America
Family history of prostate cancer
•
•
5%−10% of prostate cancers
Specific genes and polymorphisms
(eg, BRCA2, GSTT1, CYP1B1)
Infectious Causes?
American Cancer Society, Inc. Available at:
http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf
Sigurdsson S et al. J Mol Med. 1997;75:758
Kelada SN et al. Cancer Epidemiol Biomarkers Prev. 2000;9:1329
Tanaka Y et al. Biochem Biophys Res Commun. 2002;296:820
Factors That May Increase Risk
for Developing Prostate Cancer
•
•
•
•
•
•
•
•
Obesity
Dietary fat
Smoking
High testosterone levels
Benign prostatic hyperplasia
Diabetes
Infectious agents
Occupational exposures
Giovannucci E et al. J Natl Cancer Inst. 2003;95:1240
Giovannucci E et al. J Natl Cancer Inst. 1993;85:1571
Sharpe CR et al. Epidemiology. 2001;12:546
Hoffman RM et al. J Natl Cancer Inst. 2001;93:388
Siddiqui MK et al. Biomed Environ Sci. 2002;15:298
Preventing Prostate Cancer
• Prostate Cancer Prevention Trial (PCPT)
– Evaluated the potential of finasteride to decrease the
incidence of PRCA
– Result: decrease in PCA by about 25% but increase in
higher Gleason grade tumors
• Selenium and Vitamin E Chemoprevention
Trial (SELECT)
– Evaluating the role of selenium and vitamin E in
preventing PRCA
• Dietary modification: soy, lycopene (studies
underway)
Early Diagnosis and Outcomes
• Majority (86%) of cases diagnosed in local and
regional stages
• Usually no symptoms
• Early detection methods
– Digital rectal exam
– Prostate-specific antigen (PSA) blood test
• 5-yr survival with early detection: 100%
• Survival rates for all stages combined:
5 yr = 98%, 10 yr = 84%, 15 yr = 56%
• Sites of metastases: lymph nodes, bone
American Cancer Society, Inc. Available at:
http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf
American Cancer Society
Guidelines for Screening
Annual Digital Rectal Exam/PSA Screening
• Age 50
• Age 45: family history or African American
• PSA <2.0 at yr 1 of screening, screen
q 2 yr
American Cancer Society, Inc. Available at:
http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf
Han M et al. Med Clin North Am. 2004;88:245
Serum Prostate-Specific
Antigen (PSA)
• Normal PSA: <4.0 ng/mL
– Age- and race-based
reference ranges
• Sensitivity: 67.5%−80%
• Improve sensitivity:
use lower PSA cut-off level
of 2.5 ng/mL (higher false
positive, decreased specificity)
• Improve specificity:
measure % free PSA,
complexed PSA (c-PSA)
American Urological Association. Oncology. 2000;14:267
Tanguay S. Urology. 2002;59:261
Okihara K. J Urol. 2002;167:2017
Age range
Reference Range
(ng/mL)
Whites
Blacks
(yr)
40−49
50−59
60−69
70−79
0−2.5
0−3.5
0−4.5
0−6.5
0−2.0
0−4.0
0−4.5
0−5.5
PSA Derivatives
• PSA velocity: rise in PSA over time (>0.75
ng/ml/yr associated with cancer; useful for men
with PSA <4)
• PSA density: PSA/prostate volume (>0.15 is
associated with cancer; useful in men with large
glands)
• Free PSA: measures “unbound” PSA (<25% is
associated with cancer; useful in men with PSA
between 4-10 ng/ml)
Optimized Prostate Biopsy
Schemes
Sextant
78%
Lateral
sextant
83%
Presti JC Jr et al. J Urol. 2003;169:125
8-core
92%
10-core
96%
Clinical and Pathologic Staging
Prostate Cancer Detection
and Diagnosis
• Digital rectal examination
• PSA
• History and physical examination
• Transrectal ultrasound (TRUS) and biopsy
• Lymph node biopsy
• Blood tests
• Imaging (CT and/or MRI)
• Radionuclide bone scan
American Urological Association. Oncology. 2000;14:267
TNM Staging System for
Prostate Cancer (T Criteria)
Primary
Tumor (T)
WhitmoreJewett
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
A
T1
T1a
T1b
T1c
Tumor not palpable or visible
Histologic evidence of tumor in <5% of tissue
Histologic evidence of tumor in >5% of tissue
Nonpalpable tumor diagnosed by needle biopsy
A1
A2
T2
T2a
T2b
T2c
Tumor confined to prostate
Tumor involves ½ lobe or less
Tumor involves >½ lobe but not both lobes
Tumor involves both lobes
B
B1
B2
T3
T3a
T3b
Tumor extends through prostatic capsule
Extracapsular extension
Seminal vesicle invasion
C1
C1
C1
T4
Tumor fixed or invades structures other than seminal vesicles:
Bladder neck, external sphincter, rectum, levator muscles, and/or
pelvic wall
Greene FL et al. AJCC Staging Manual. 6th ed. New York: Springer-Verlag; 2002
C2
2002 AJCC Stage Grouping
Stage I
T1a N0
M0
G1
Stage II
T1a
T1b
T1c
T1
T2
N0
N0
N0
N0
N0
M0
M0
M0
M0
M0
G2, 3-4
Any G
Any G
Any G
Any G
Stage III
T3
N0
M0
Any G
Stage IV
T4
Any T
Any T
N0
N1
N1
M0
M0
M0
Any G
Any G
Any G
Greene FL et al. AJCC Staging Manual. 6th ed. New York: Springer-Verlag; 2002
Risk Classification for PSA
Failure After RP or RT
Classification
Low Risk
Intermediate
Risk
High Risk
Criteria
PSA <10 ng/mL and Gleason <7
and AJCC ≤T2a
PSA 10–20 ng/mL or Gleason 7
or AJCC T2b
PSA >20 ng/mL or Gleason
>7 or AJCC ≥T2c
5-yr Outcome
<25% PSA
Failure
25%−50%
PSA Failure
>50% PSA
Failure
The most clinically relevant prognostic factors
are: Gleason, PSA and stage
Adapted with permission from D'Amico AV et al. JAMA. 1998;280:969
CaPSURE: Risk Category
at Diagnosis
100
Patients (%)
80
High risk
36.6%
30.2%
Intermediate risk
20
16.0%
37.2%
60
40
25.1%
37.3%
38.5%
33.8%
46.8%
Low risk
29.5%
32.5%
36.4%
0
1989 1990 1991 1992 1993 1994 1995 1996 1997 1999 2000 2001 2002
Reprinted with permission from Cooperberg MR et al. J Urol. 2003;170:S21
Risk Stratification:
Localized Prostate Cancer
High Risk
100
100
90
90
80
80
70
60
50
40
30
20
10
0
164
109
10
6
147
77
8
4
117
42
5
3
83
17
2
3
55
4
1
2
36
2
0
1
0
1
2
3
4
5
PSA Survival (%)
PSA Survival (%)
Low Risk
70
60
50
40
30
20
10
0
239
309
23
19
158
218
14
13
0
1
Time (yr)
102
99
3
4
2
47
38
0
0
26
12
0
0
11
0
0
0
3
4
5
Time (yr)
RP
Implant and Neoadjuvant Hormonal Therapy
External Beam RT
Implant
Reprinted with permission from D’Amico AV et al. JAMA. 1998;280:969
Staging of Prostate Cancer at
Time of Diagnosis
Pathologic
Clinical
• Age
• Health status
• Anticipated life
expectancy
• Symptoms
• Serum PSA
• TNM clinical stage
• Gleason scores (GS),
1o and 2o
• # cores involved and
tumor volume in biopsy
• Extracapsular, perineural
invasion
• Histopathologic TNM
NCCN Prostate Cancer Panel Members. Available at:
http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf
NCCN Treatment Guidelines
for Prostate Cancer
• Treatment depends on
– Life expectancy (age, co-morbidities)
– Risk of recurrence as determined by stage, grade, and PSA
Localized Disease
Recurrence
Metastatic Disease
• Watchful waiting
• Watchful waiting
• Supportive care
• Cryotherapy
• Salvage
prostatectomy
• Hormonal therapies
• Radiation therapy
• Brachytherapy
• Prostatectomy
• Hormonal therapy,
androgen ablation
• Radiation therapy ±
hormonal therapy
• Hormonal therapy
alone
NCCN Prostate Cancer Panel Members. Available at:
http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf
• Second-line hormonal therapy
• Chemotherapy
• Systemic radiation therapy
• Investigational agents
Watchful Waiting
• Other terms: “expectant management”
• Suitable for low-risk patients:
– Gleason 6 or less
– PSA less than 10 +/- PSA-DT greater than 10
months
– Low volume disease
Definitive Treatment
• The best chance for a cure is diagnosing the
disease in early stages (localized within the
organ)
• Options:
– Prostatectomy
– Radiation therapy
Radical Prostatectomy
• Retropubic
– Nerve sparing, reduced risk for erectile dysfunction
• Perineal
– Nerve-sparing procedures are difficult
• Laparoscopic/Robotic
– Decreased blood loss
– Longer procedure and more expensive
– Learning curve
NCCN Prostate Cancer Panel Members. Available at:
http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf
Bickert D, Frickel D. AORN J. 2002;75:762
Krongrad A. Curr Urol Rep. 2000;1:36
Radical Prostatectomy:
Outcomes
Long-Term Survival Following
Anatomic Radical Retropubic Prostatectomy
Likelihood of
Undetectable PSA
1.00
T1a
T1c
0.75
T1b
T2a
T2c
0.50
T3a
T2b
0.25
0
0
5
10
15
Years Post-operative
Reprinted with permission from Han M et al. Urol Clin North Am. 2001;28:555
20
Hormone Ablation with
Prostatectomy
• Increases the rate of negative surgical
margins in patients with locally advanced
disease
• Not proven to confer a survival advantage
1Fradet
Y. Urol Clin North Am. 1996;23(4):575-585. 2Cher ML, et al. Br J Urol.
1995;75(6):771-777. 3Abbas F, Scardino PT. Urol Clin North Am. 1996;23(4):587-604.
Radiation Therapy
• External beam radiation therapy (EBRT)
– Whole pelvic radiation therapy
– Prostate-only radiation therapy
– Intensity-modulated radiation therapy (IMRT) with
or w/o BAT
– 3-dimensional conformal therapy
• Brachytherapy
– Low-dose rate (permanent seed) brachytherapy
– High-dose rate brachytherapy
NCCN Prostate Cancer Panel Members. Available at:
http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf
Radiation Therapy
• Higher doses are associated with improved
DFS and OS
• Neoadjuvant/adjuvant hormone therapy
effective, particularly for high-risk patients
• Evolving improvements: brachytherapy, IMRT,
BAT
Disease Course of Prostate
Cancer
AIPC
PS
A
Local Treatment
ng P
SA
Androgen Ablation
Risi
Ri
si n
g
Tumor Burden
2° Hormonal Therapy
Chemotherapy
Time
AIPC=androgen-independent prostate cancer
Adapted with permission from Goodin S et al. Oncologist. 2002;7:360
Hormonal Therapies
• Bilateral orchiectomy
• Medical castration with luteinizing hormone-releasing
hormone (LHRH) analogues
– Leuprolide, goserelin
• GnRH (LHRH) antagonist: abarelix
• Diethylstilbestrol
• Steroidal anti-androgen: cyproterone acetate
• Non-steroidal anti-androgens
– Bicalutamide
– Flutamide
– Nilutamide
Stege R. Prostate Suppl. 2000;10:38
Kolvenbag GJCM et al. Urology. 2001;58(2 suppl 1):16
Sites of Action of Different
Hormonal Therapies
Estrogens
Hypothalamus
LHRH agonists
Orchiectomy
Anti-androgens
Pituitary
Testes
Adrenal glands
Prostate
Reprinted with permission from Taub M et al. Postgrad Med. 1996;100:139
Common Complications of
Hormonal Therapy
•
•
•
•
•
•
•
Hot flashes
Osteoporosis
Anemia
Impotence
Weakness
Muscle wasting
Hyperlipidemia (cardiovascular events?)
Stege R. Prostate Suppl. 2000;10:38
Androgen-Independent
Prostate Cancer
• Rising PSA or progressive disease despite
hormonal interventions
• Defined as PSA progression despite castrate
testosterone levels (less than 50) and
withdrawal of direct antagonist
Subpopulations of AIPC
• AIPC includes spectrum of patients
– Rising PSA, no symptoms or clinical evidence of
disease
– Rising PSA, with stable metastatic disease
– Rising PSA, with progressive metastases
• PSA-only recurrence now most common form
of advanced prostate cancer
Kent EC, Hussain MHA. Urology. 2003;62(suppl 6B):134
PSA-Only Recurrence:
Scope of the Problem
• New prostate cancer cases per yr
200,000+
• 2/3 receive localized
disease treatment annually
134,000
• 40% may experience PSA-only
recurrence cumulatively
Moul JW. J Urol. 2000;163:1632
53,600
Treatment Options for AIPC
• Anti-androgen withdrawal
• Secondary hormonal therapy
• Chemotherapy regimens
– Docetaxel +/- estramustine
– Mitoxantrone/prednisone
• Supportive therapy (eg, bisphosphonates
for osteoblastic metastases, palliative
radiation)
• Investigational agents
Disease Course of Prostate
Cancer
AIPC
PS
A
Local Treatment
ng P
SA
Androgen Ablation
Risi
Ri
si n
g
Tumor Burden
2° Hormonal Therapy
Chemotherapy
Time
AIPC=androgen-independent prostate cancer
Adapted with permission from Goodin S et al. Oncologist. 2002;7:360
ANDROGEN ABLATION
Hypothalamus
LHRH
Agonists/
Antagonists
LHRH
Pituitary
Ketoconazole
FHS, LH
Testicles
Direct
antagonists
Testosterone
Prostate cancer cell
Adrenals
Anti-Androgen Withdrawal
Syndrome
• First described with flutamide1
– Also reported after bicalutamide, nilutamide,
ketoconazole, DES, megestrol acetate
• PSA rising on complete androgen blockade
• Stop anti-androgen (not LHRH agonist)
• PSA decreases within
– 4 wk: flutamide
– 6 wk: bicalutamide, nilutamide
DES=diethylstilbestrol
1Kelly
WK et al. J Urol. 1993;149:607
SWOG 99-16: Docetaxel/Estramustine
vs. Mitoxantrone/Prednisone
Randomized Phase III Trial in Men With AIPC
Overall Survival
Progression-free Survival
Stratified by Treatment Arm
60%
# at
# of
Median
100%
Risk Deaths
(mo)
D+E
338
217
17.5
80%
M+P
336
235
15.6
HR: 0.80 (95% CI 0.67, 0.97), P= 0.02
60%
30%
30%
20%
20%
0%
0%
100%
80%
0
12
24
Months
36
48
D+E
M+P
0
12
# at # of Median
Risk Events (mo)
338
311
6.3
336
312
3.2
P<0.0001
24
Months
36
Adapted and reprinted with permission from Petrylak DP et al. N Engl J Med. 2004;351:1513.
48
TAX 327: Docetaxel/Prednisone vs.
Mitoxantrone/Prednisone in AIPC
Overall Survival
Probability of Surviving
1.0
Docetaxel every 3 wk
Docetaxel wkly
Mitoxantrone
0.9
0.8
0.7
0.6
0.5
Median
survival Hazard
(mo)
ratio P value
0.4
0.3
Combined: 18.2
D 3 wkly:
18.9
D wkly:
17.4
Mitoxantrone16.5
0.2
0.1
0.83
0.76
0.91
–
0.04
0.009
0.36
–
0.0
0
6
12
18
24
Months
Adapted with permission from Tannock IF et al. N Engl J Med. 2004;351:1502.
30
Skeletal Preservation
• Skeletal complications are one of the most
devastating effects of prostate cancer or its therapy
– Metastatic diseaseÆbony destruction
– Osteoporosis from testosterone deficiency
• Bisphosphonate therapy reduces skeletal-related
events
– Zoledronate approved for patients with AIPC metastatic
to bone
• Patients should be on vitamin D and calcium
supplements
PALLIATIVE THERAPY
• Radiation to bony metastases
• Radiolabeled therapy (strontium, sumarium)
• Analgesics
Treatment Goals for Patients
With AIPC
• Manage and decrease pain
• Improve or maintain QOL
• Increase symptom-free survival
• Increase survival