Transcript Prostate_Cancer

Prostate Cancer for the
non-Oncologist
1
Overview
• Epidemiology
• Risk Factors/Genetics
• Screening
• Diagnosis and Treatment
• Consequences of Disease and Treatment
2
Why You Should Try and Stay
Awake/Not Page Yourself Out
• You will manage patients who have
prostrate cancer
• You will know people who have prostate
cancer and they will ask your advice
3
Case 1 & 2
“My dad had prostate cancer at age 52. What
does that mean for me?”
“I am about to turn 74. Do I still need a PSA
checked?”
4
Introduction
• 192,280 new cases expected in 2009
• 27,360 deaths expected in 2009
• 1 in 6 men will develop clinically significant
prostate cancer
• 20% of men with prostate cancer die from their
disease
Jemal et al, CA Cancer, 2009
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FIGURE 1 Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex,
United States, 2009
From Jemal, A. et al.
CA Cancer J Clin 2009;59:225-249.
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Copyright ©2009 American Cancer Society
Familial/Hereditary Prostate
Cancer vs. Sporadic Disease
• Diagnosed 6-7 years earlier
• Usually lower grade (less aggressive)
• No differences in PSA, stage, or PSA at
recurrence
7
Nieder et al. Clin Genet , 2003
Prostate Cancer Risks
Relative risk of Getting Prostate Cancer
Compared
No Family History
1
1st degree relative (1)
2.57
Relative diagnosed
<65
3.34
Relative diagnosed
≥65
2.35
2+ 1st degree relatives
5.08
2nd-degree relative
1.68
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Nieder et al. Clin Genet, 2003
Risks and Ethnicity
• Risk of Prostate cancer varies with ethnicity
(diagnosis per 1000 people)
• African Americans
– 257
• Caucasians
– 159
• Asian
– 101
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Powell IJ et al. Urology 2001
Screening Recommendations
• American Urologic Association
– Rectal Exams and PSA at age 50
– If a family history:
Rectal Exams and PSA at age 40
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Carroll et al. Urology, 2001
Screening Recommendations
• American Cancer Society
– Rectal Exams and PSA at age 50
– If any family history or African American:
Rectal Exams and PSA at age 45
– If a first degree relative:
Rectal Exams and PSA at age 45
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Smith RA et al. CA Cancer J Clin , 2002
Screening Recommendations
• American College of Physicians
and
• American College of Preventative Medicine
– No Routine Screening Recommended!
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Screening Recommendations
• We do not know!
• Several Studies are investigating this now.
• Rate of rise more important than absolute
number
13
Nieder et al. Clin Genet, 2003
Detection
• May be detected due to symptoms, physical
findings or through PSA screening
• Most patients in the US are asymptomatic at the
time of diagnosis.
14
Digital Rectal Exam
A – Central zone
B – Fibromuscular zone
C – Transitional zone
D – Peripheral zone
E – Periurethral zone
Seminal Vesicles
Prostate
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Incidence vs. Mortality
New Prostate Cancer Cases and Deaths
(per 100,000 men)
Prostate Cancer in the U.S.
PSA Screening
250
200
150
New cases
100
50
0
Deaths
1975
1980
1985
1990
1995
2000
(G. Welch, “Should I Be Tested for Cancer?”, 2004)
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Does Screening Save Lives?
• PLCO Trial
– N=76,693 men (screen vs. no screen)
– After 7 years 50 vs. 44 deaths from PC
– ?Too early
– PSA test too available?
• ERSPC Trial
– N=182,000 (screen vs. no screen)
– At a median of 9 years, a 20% reduction in PC death
– Different patient population than US?
Schroder et al., NEJM 2009 & Andriole et al., NEJM 2009
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Screening Recommendations
“Health care providers can identify those men
at an increased risk for developing prostate
cancer. These men are candidates for
increased surveillance using screening.
However, there may be inherent emotional
and physical risks involved with diagnosing
and treating prostate cancer.”
18
Nieder et al. Clin Genet, 2003
Screening: Conclusions
• Patients at risk should be identified
– Detailed family history
– Age of diagnosis of family members
• Implications:
– A positive family history does not necessarily change
course of disease if that disease actually occurs
• When to stop?
– When life expectancy less than 10 years
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Nieder et al. Clin Genet , 2003
Case 1 & 2
“My dad had prostate cancer at age 52. What
does that mean for me?”
“I am about to turn 74. Do I still need a PSA
checked?”
20
Which is more concerning?
• PSA = 3.8 (ULN =4.0)
• PSA rise from 1.2 to 2.6 in 1 year
• PSA rise from 2.0 to 2.5 in 1 year
• PSA rise from 1.5 to 2.8, then decline to
1.5
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“Hey Doc, What Can I take to
prevent prostate cancer? I heard
about some things on TV. My
family has a lot of prostate cancer
and I want to minimize my risk.”
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Prevention
• 5--reductase inhibitors
– Finasteride
• Selective inhibitor of type II enzyme
• Decreases DHT by about 70%
• PCPT (Prostate Cancer Prevention Trial)
– Dutasteride
• Inhibits type I and II enzymes
• Decreases DHT by >90%
• REDUCE trial (Reduction by Dutasteride of Prostate Cancer
Events)
• SELECT Trial (Vitamin E and Selenium)
• (Lippman et al, JAMA 2009)
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Histologic Grading
• Gleason Grade
– most common grading
system
– Tumors are graded from
1-5 with the
– higher number indicates a
more aggressive tumor
– Two most predominant
patterns added together
for a score from 2-10
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Staging
Stage
TNM
Description
I (A)
T1a (incidental)
Localized
II (B)
T1b, T1c, T2a,b,c
(within prostate)
III (C)
T3a (through capsule)
T3b (seminal vesicles)
Locally
Advanced
IV (D) T4 (fixed, invades)
N1, M1
Metastatic
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Prognosis
•
•
•
•
PSA at diagnosis
percent of tumor in a biopsy specimen
number of positive biopsies
Gleason Score (aggressiveness of
pathology)
• clinical stage
26
Treatment
• Patients with a life expectancy of less than
10 years and low grade/ low stage lesions
may be candidates for active surveillance
• Primary hormone therapy is an option for
patients not suitable for definitive local
therapy
27
Active Surveillance
The chance of dying of
prostate cancer decreases
with:
•Lower Gleason score
•Older age (more
competing causes of
mortality)
Albertsen, P. C. et al.
JAMA 2005;293:2095-2101.
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Definitive Treatment
• Eradication of the cancer is the goal of therapy
in patients with a life expectancy greater than
10 years
– Radical Prostatectomy
– External-beam Radiation
– Brachytherapy
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Radical Prostatectomy
• Surgical removal of the prostate
• May be done with a retropubic, perineal, or
laproscopic approach
• Most common side effects are impotence and
incontinence
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Randomized Trial Comparing
Surgery and Watchful Waiting
• Early stage prostate cancer (n=695)
• Deaths at median 8.2 years of follow-up
Deaths from
Surgery
WW
P
Prostate Cancer
30
50
0.01
All causes
83
106
0.04
– Also less metastasis (RR of Surg 0.60)
• Caveats:
– More advanced clinically then current US patients
• Only 5% of men had screen detected PC
– Advantage largely in men <65 y.o.
Bill-Axelson et al, NEJM, 2005
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External-beam Radiation
• Radiation to the prostate (and pelvis) from outside
the body
• Evidence that higher doses are associated with
better efficacy
• Newer techniques (such as IMRT) aim to increase
radiation delivery and to decrease toxicity
• Most common side effects are impotence and
rectal irritation
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Brachytherapy
• Radiation implants placed directly into the
prostate under ultrasound or CT guidance
• Very high dose radiation to the prostate with
little radiation outside the prostatic bed
• Acute urinary symptoms common, some
patients with impotence
• Procedure completed in one day
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“Biochemical Recurrence”
• May be occult local or metastatic disease
• Options include additional local therapy,
hormonal treatment or watchful waiting
• Virtually impossible to predict the impact of
treatment on survival
34
What happens after PSA
Recurrence?
• Over 15 years 1,997 patients underwent a
radical prostatectomy, with 304 (15%)
experiencing a PSA relapse.
• Of the 304, 103 (34 %) developed metastatic
disease.
Pound et al, JAMA, 1999
Freedland et al. JAMA, 2005
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Natural History of the Disease
(circa 1995)
• No patients received hormonal therapy without clinically evident
metastatic disease.
• Median time from PSA elevation to metastatic disease was 8
years
• Median time to death after metastatic disease was 5 years.
• Prognostic factors predictive of outcome included the Gleason
score in the surgical specimen, and PSA doubling time.
RP
Biochemical failure
2 years
8 Years
Death
Metastasis
5 years
Pound et al, JAMA, 1999
Freedland et al. JAMA, 2005
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Spinal Cord Compression
• The “rule out MI” of oncology
• Classic Triad
– Back pain
– Incontinence (urine and stool)
– Lower Extremity Weakness
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Case 3 (ER Rotation)
• 66 yo male hx of CAD, COPD, OSA, HTN,
HLD, DM and prostate cancer dx 4 years ago.
• “I don’t like doctors – they always give me a
new disease”
• “My back hurts – but it always hurts. I get
tired when I walk – but I am getting old. Now
I’ve been soiling my pants. Don’t ever get old
Doc!”
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Spinal Cord Compression
• Maintain a high level of suspicion
• MRI of the Spine
• Dexamethasone
– 10 mg IV bolus, then 4 mg q6 hours
• Intervention
– Neurosurgical or Radiation
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Metastatic Prostate Cancer
• Prostate Cancer tends to spread to bone and
lymph nodes
• However metastatic lesions have been found in
virtually every part of the body including
brain, liver and lungs.
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Therapeutics for Metastatic Prostate Cancer
Death
Chemotherapy
Castration
Tumor
volume
&
activity
Local
Therapy
2nd-line
Hormones
Asymptomatic
Non-Metastatic
Symptomatic
Metastatic
Castration Sensitive
Castration Resistant
Time
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ADT Treatment of metastatic
PC
• 1941 Charles Huggins showed that advanced PC was
inhibited by decreasing Testosterone (castration or
estrogen) and activated by adding testosterone.
• 1966 Nobel Prize in Medicine
Huggins and Hodges, Cancer Research, 1941
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ADT Treatment of metastatic
PC
• Testosterone lowering therapies
– Leuprolide and Goserelin GnRH agonists
• Both agents are expensive
• May initially result in an increase in testosterone
– Degarelix GnRH antagonist
• Similar cost issues without an increase in
testosterone
– Orchiectomy- outpatient procedure. Cost
effective if ADT for 6 months or more.
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Side Effects of ADT
Sexual Side Effects
Decreased Libido
Erectile dysfunction
Physical changes
Hot Flashes
Weight Gain
Decreased muscle mass
Hair Changes
Fatigue
Gynecomastia
Decreased bone mineral density
Decrease size of penis / testis
Breast pain
Metabolic Changes
Lipid changes (may lead to heart disease)
Anemia
Increased risk of Diabetes Mellitus
Mental Changes
Lack of Initiative
Decreased memory
Emotional lability
Decreased cognitive function
Sharifi et al, JAMA 2005
Keating et al, JCO 2006
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Androgen Receptor Antagonists
• bicalutamide, nilutamide and flutamide
• Do not ↓Testosterone, bind androgen receptor and
prevent anabolic (growth related) effects
• Different dosing schedules and potency
• Different side effect profile
• Similar activity and all may show “withdrawal
response”
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Combined Androgen Blockade
• Combination of antiandrogen with
orchiectomy or GnRH-A
• Controversial results
• Not significantly more
effective, but more
expensive and may add
toxicity
46
Notable Other Hormonal
Agent
• Ketoconazole
• Patients may respond to multiple sequential
hormonal manipulations
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Chemotherapy
• Studies prior to 2004 disappointing
• Quality of life measurements
• Difficulty in evaluating response
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Mitoxantrone + Glucocorticoids
• Inhibits RNA and DNA synthesis and
intercalates DNA
• Improved quality of life when compared to
Glucocorticoids alone (No survival advantage)
• FDA approval for the palliation of painful
lesions in 1996
Tannock, JCO, 1996
Kantoff, JCO, 1999
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Docetaxel: Preclinical Data
• Docetaxel inhibits the growth of prostate
cancer cell lines LNCaP, PC3, and DU145.
• Mechanism of Action:
– Disruption of the cellular microtubule
network
• promotes assembly of stable
microtubules
• inhibits disassembly
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Castration
Resistant
Prostate
Cancer
RANDOMIZE
TAX327
A Multicenter, Randomized Phase III Study of Intermittent
Docetaxel + Prednisone vs. Weekly Docetaxel +
Prednisone vs. Mitoxantrone + Prednisone in Patients with
Hormone-Refractory Prostate Cancer
Docetaxel 75mg/m2 Q3 +
Prednisone 10mg orally given daily
Docetaxel 30mg/m2 Wkly +
Prednisone 10mg orally given daily
Mitoxantrone 12mg/m2 Q3 +
Prednisone 10mg orally given daily
1006 Patients Entered
Tannock, NEJM, 2004
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Should I get Chemo? I
heard it only improves
survival by 3 months.
What’s the point?
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TAX 327: Survival Advantage Only Shown for
Q3W Docetaxel
1.0
Docetaxel 3 wkly
Probability of Surviving
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
0.5
0.4
0.3
0.2
D 3wkly:
D wkly:
Mitoxantrone
0.1
Median
survival
(mos)
Hazard
ratio
P-value
18.9
17.3
16.4
0.76
0.91
–
0.009
0.3
–
0.0
0
6
12
18
Months
24
30
Tannock, NEJM, 2004
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Its More than a 3 month
Improvement!
• Quality of Life
– Better on docetaxel / prednisone than mitoxantrone
prednisone
• Is it really just 3 months?
– Compared against an active agent (not against placebo)
– Cross over allowed
• If no patients on the mitoxantrone arm had gone on to get
docetaxel at PD, the survival difference might have been much
greater.
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Life on Chemotherapy
• Overall, treatment is well tolerated
• Patients often get treatment and continue to
work
• Administration once every 3 weeks
• Treatment length is indefinite
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On the Horizon
• The next 1-2 years likely will see several
significant changes in the treatment of
metastatic prostate cancer
• Therapeutic Cancer Vaccines (Provenge)
• New Hormonal Agents (Abiraterone)
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Therapeutics for Metastatic Prostate Cancer:
A lot Can Change in 6 months
Death
Chemotherapy
Cabazitaxel
Castration
Provenge
Abiraterone
Tumor
volume
&
activity
Local
Therapy
Abiraterone?
2nd-line
Hormones
Asymptomatic
Non-Metastatic
MDV3100?
MDV3100?
Symptomatic
Metastatic
Castration Sensitive
Castration Resistant
Time
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Therapeutic Cancer Vaccine:
Sipuleucel-T
Day 1
Leukapheresis
Apheresis Center
Day 2-3
sipuleucel-T is
manufactured
Company (Dendreon)
Day 3-4
Patient is infused
Doctor’s Office
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IMPACT Overall Survival: Phase III Trial
100
Percent Survival
P = 0.032 (Cox model)
HR = 0.775 [95% CI: 0.614, 0.979]
75
Median Survival Benefit = 4.1 Mos.
50
Sipuleucel-T (n = 341)
Median Survival: 25.8 Mos.
25
Placebo (n = 171)
Median Survival: 21.7 Mos.
0
0
6
12
18
24
30
36
42
48
Survival (Months)
54
60
66
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Vector Based Vaccines
Infect Antigen Presenting
Cells (APCs)
APCs activate T-cells
T-cell Mediated Tumor
Destruction
60
The median OS was 24.5 mos for vaccine compared to
16.0 mos for placebo (p=0.016)
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1. AR Binding Affinity
LBD
HSP 90
MDV3100: MODERN Androgen Receptor
Antagonist
Ligand
HD
1
•
•
•
DHT
~ 5nM
Bicalutamide ~160 nM
MDV3100
~35 nM
DBD
2. Nuclear Import
NTD
•
•
•
2
DHT:
Bicalutamide:
MDV3100:
++++
++++
++
3. DNA Binding
4
•
•
•
DHT:
Bicalutamide:
MDV3100:
++++
++
-
POL II
4. Coactivator recruitment
3
•
•
•
DHT:
Bicalutamide:
MDV3100:
++++
++
-
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Chen Y, Lancet Oncol, 2009
BACK TO THE FUTURE: Waterfall Plot
of Best Percent PSA Change from Baseline
Chemotherapy-Naïve (N=65)
62% (40/65)
>50% Decline
Post-Chemotherapy (N=75)
51% (38/75)
>50% Decline
63
Bisphosphonates
• Commonly used to treat hypercalcemia, treat osteoporosis
and to decrease bone complications in cancer patients.
• Zoledronate (I.V. bisphosphonate) approved for the
prevention of bone complications in metastatic CRPC.
• May be of value in patients with risk of osteopenia on
long-term hormonal therapy.
64
Zoledronate Reduced the Proportion (%) of Patients
With Skeletal Related Events (SREs)
Zoledronate
Placebo
P = . 021
Percent of patients
50
44%
40
33 %
30
20
10
0
N=
214
208
Saad et al., JNCI, 2002
65
Selected Side Effects
•
•
Renal dysfunction
Osteonecrosis of the Jaw (ONJ)
– Similar to osteoradionecrosis
– Poorly healing bone lesions following invasive dental procedures
– Multifactorial
•
•
•
•
Very frequent micro trauma  increased bone turn over
Thin membrane
Diverse oral flora
Single blood supply in mandible (lower jaw) vs. dual blood supply in
maxilla (upper jaw). Therefore because of its anti-angiogenic
properties of zoledronate  ONJ more frequent in mandible
– All patients should see dentist prior to initiating long term IV
bisphosphonates
66
Future Directions
• Does prevention work?
• Which patients need treatment? And what
treatment?
• Adjuvant therapy for high risk patients
• Timing of hormonal therapy
• Multimodality therapy
• New agents / combinations
67