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2nd Annual Prostate Cancer Forum
September 10, 2011 • Robert H. Lurie Medical Research Center • Chicago, IL
Keynote Address
Overview of Prostate
Cancer Treatment Options
William Catalona, MD
Professor
Northwestern University
Feinberg School of Medicine Department of
Urology
Overview of Prostate Cancer
Treatment Options
William J Catalona MD
Director, Clinical Prostate Cancer Program
Robert H Lurie Comprehensive Cancer Center
Northwestern
Purpose
1. Provide brief overview of treatments,
discussing advantages and disadvantages
2. In reporting differences, attempt to be
objective
3. Acknowledge my personal editorial
perspective
4. For balance, refer to contrary opinions
Disclose Partners from Industry
• Beckman Coulter, Inc – manufacturer of PSA
tests
• OHMX, Inc - developer of urine PSA test
• deCODE genetics, Inc - developer of genetic
tests for prostate cancer
U.S. Prostate Cancer Statistics 2010
• 217,730 new cases
• Most common malignancy
•Accounts for 28% of all male cancer
• 32,050 deaths from prostate cancer
•11% of all male cancer deaths
•Second only to lung cancer
Ca: Cancer Journal for Clinicians 2010;60:277-300
2010 Prostate Cancer Statistics
DD
Incidence
DD
Deaths
PSA ERA
DD
Relative 5-Year Survival
DD
Early Detection
PSA Screening Saves Lives
In the European Randomized Study of
Screening for Prostate Cancer (ERSPC)
• Screened men had 40% fewer
advanced PC at diagnosis
• 20% lower prostate cancer death
rate in screening arm
–(27% lower in men actually screened)
• Mortality benefit observed largely in
men aged 55-69
Schroder FH et al, NEJM 360:1320, 2009
Prostate Cancer-Specific Mortality with Minimal or No
Co-Morbidity in PLCO Trial
44% ↓ in PCaSpecific
Mortality
Crawford ED et al. J Clin Oncol 29:355,
2010
Controls
Screene
d
Göteborg Results
• 41% decrease in advanced disease
in screening arm
– 66% lower in men actually screened
• 44% decrease in PCa mortality in
screening arm
–56% lower in men actually screened
Hugosson, J, et al. Lancet Oncol 2010; 11: 725–
732
Active Surveillance
Rationale for Active Surveillance
Low-risk tumors generally grow slowly,
so there may be time to “watch”
them while retaining option for
treatment if they show signs of
progression on repeat PSA testing or
repeat biopsy
Caveats
1. There may be biopsy sampling errors, i.e., the tumor
may be worse than the biopsy shows
2. Some low-grade tumors may become more
aggressive over time
3. In watchful-waiting studies, prostate cancer death
rates are generally low for men with a low-grade
tumors in the short term, but a marked increase in
prostate cancer progression and death with longterm follow-up has been reported
With time, all active surveillance
studies have shown
a) Significant under-grading or
under-staging of some tumors
b) Some patients develop
metastases
c) Some die of prostate cancer
The criteria for low-risk prostate cancer are
wrong 1/3 of the time
• Biopsy is correct 95% of the time
when it shows “high-risk” tumor
features
• But is correct only 66% of the
time when the biopsy suggests
low-risk features
Epstein et al J Urol 160: 2407, 1998;Epstein et al, JAMA 271:368, 1994
Diffusion Weighted Imaging with MRI
• Lower Apparent diffusion
coefficient (ADC) correlated
with grade and % tumor
involvement on biopsy
T2W MRI and ADC map
• Tumors more likely to be visible on DWI if higher grade
• True sometimes, but not highly accurate
Woodfield et al. AJR 194:316-22, 2011
An example of misleading MRI
imaging studies
• In 96 potential candidates for active surveillance who
had MRI imaging but chose to have surgery instead
– 24% had a high Gleason grade or cancer that had
spread beyond the prostate
– MRI did not significantly which patients had these
adverse tumor features
NCCN Guidelines: “The timing and value of
periodic imaging studies in AS has not been
determined.”
Ploussard G, et al. BJU Int 2010. Epub
Active surveillance has risks
a) Risks of repeat prostate biopsies
a) Discomfort of having repeated prostate biopsies
b) Infections, bleeding, urinary difficulties
c) Possible erectile dysfunction with multiple biopsies
b) Anxiety of living with untreated prostate cancer
c) Non-compliance with regular follow-up protocol
d) Possible increased complexity of delayed treatment
with more side effects (postoperative radiation or
hormone therapy)
e) Progression to metastases or prostate cancer death
while on surveillance
1Finelli
A, et al. Eur Urol 2011;59:509-14
Treatment is compromised for some
a) For some patients, active surveillance
amounts to delayed treatment of cancer
b) Repeated biopsies are:
1) Still subject to sampling errors
2) may induce inflammation that cause
increased PSA levels
3) may cause scarring that makes nerve-sparing
surgery difficult or impossible and may
compromise surgical margins
An example of low cure rate with
delayed treatment
a) The University of Toronto
b) 50% of patients who received
delayed treatment had PSA failure
c) They are beginning to see some
prostate cancer deaths
Klotz L et al ,J Clin Oncol 28:126,2009
Johansson JE et al JAMA
291:2713,2004
Early treatment has advantages
a) Patients are more likely to be cured
with fewer side effects from treatment
b) Patients are less likely to require
multiple types of treatment to control
the cancer
An example of early RP decreasing
progression to metastases and reducing
cancer-specific and all-cause mortality
Radical Prostatectomy versus Watchful
Waiting for Early Prostate Cancer
Surgery vs.
Watchful Waiting
Metastasis
Prostate
Cancer Death
All Cause
Death
All
41%
38%
25%
< age 65
53%
51%
48%
57%
47%
47%
Low Risk
Conclusion
Active surveillance is a reasonable option
in men with a limited life expectancy, but
should be considered investigational in
men with >10 year life expectancy
(younger than 73 years old)
Surgical Approaches to
Radical Prostatectomy
OPEN VS DA VINCI ROBOTIC
Long-Term Results
• The long-term results of open
radical prostatectomy are well
documented
• Long-term robotic prostatectomy
results are not yet available
Continence (No Pads)
Age
T1A/B
T1C
<50
--
95.4%
50-59
100%
96.6%
60-69
90.2%
95.6%
≥70
86.7%
90.2%
Potency (with or without Viagra-like
drugs)
Age
T1A/B
T1C
<50
--
95%
50-59
89%
89%
60-69
65%
81%
≥70
67%
73%
Recurrence-Free Survival (PSA <0.1)
• PSA recurrence- Overall
Population
10 year
RFS (%)
T1a
T1b
T1c
79
74
78
Prostate Cancer-Specific
Survival
• Prostate-cancer
specific survival
% 10 yr
CSS
T1a
T1b
T1c
100
95
100
Robotic Laparoscopic
Prostatectomy
• Console
Marketing the Robot
• Quicker recovery
– Less pain
– Shorter hospital stay
– Quicker return to normal
activity
– Shorter catheterization
•
•
•
•
•
•
Better visualization
Less bleeding
Better potency
Better continence
Fewer positive margins
Better cosmesis
It is claimed that 70% of radical
prostateactomies are performed robotically
In 2008, in Florida 4,542 radical
prostatectomies were performed 1,188
(26%) were robotic and 3,354 (74%) were
open
Eur Urol. 2010 Jun;57(6):930-7. Epub 2010 Jan 26.
Low quality of evidence for robot-assisted
laparoscopic prostatectomy: results of a
systematic review of the published literature.
Kang DC, Hardee MJ, Fesperman SF, Stoffs TL, Dahm P.
Department of Urology, University of Florida, Gainesville, FL 32610-0247, USA.
12 surgeons co-authored 72% of the published studies
on robotic prostatectomy.
“The published RALP literature is limited to
observational studies of mostly low methodologic
quality.”
“Our findings draw into question to what extent valid
conclusions about the relative superiority or equivalence of
robotic prostatectomy to other surgical approaches can be
drawn and whether published outcomes can be generalized to
the broader community. “
4.45-fold more RALP patients
regretted their decision to have
that type of surgery
“Patients who underwent RALP were
more likely to be regretful and dissatisfied,
possibly because of higher expectation of
an ‘innovative’ procedure.”
Care Path
Essentially equivalent
“The results of this prospective study have
shown that both robotic and conventional
radical prostatectomy provide comparable
short-term postdischarge recovery, including
time to normal and full activity, driving, and
post-discharge narcotic use.”
Bleeding
With good open surgical technique,
there is no significant difference in
blood transfusion rate
Positive Surgical Margin Rates with Open and
Robotic Nerve-Sparing Prostatectomy
• 950 cases performed by 2 high-volume surgeons at Brigham and
Women’s Hospital (Harvard)
• Analysis of results was adjusted for known preoperative predictors of
positive surgical margins
NerveSparing
Surgery
(N=908)
Open
Robotic
7.6%
(N=330)
13.5%
(N=578)
Williams SB et al, Urology 2010
Invasiveness and Cosmesis
• Robotic: five 1 inchincisions + one 2 inch
incision
• Open: one 4-5 inch
incision
Human Touch and Access
• Robotic surgery - cannot feel
tissues or appreciate how easily
tissues separate from one
another
• More complete access with open
surgery
“Visual and tactile assessment
during open surgery by an
experienced surgeon provides
valuable information on when
and where it is safe to preserve
the neurovascular bundles…”
Potency
Continence
Burning the Prostate Out Compromises
Nerve Sparing
• The greater use of electricity
or heat with robotic surgery to
control bleeding can cause
irreversible damage to the
neurovascular bundles
Comparative Effectiveness of Robotic vs Open Radical
Prostatectomy
SEER (National Cancer Registry ) Database
Need for Robotic Open
Further
Robotic Open
Percent
Treatment
Urologic Complications
4.0
2.2
18.2
11.9
Incontinence Procedures
9.5
8.5
Erectile Dysfunction (ED)
33.8
18.2
2.8
2.1
Incontinence
ED Procedures
(Adjusted for
Disease
Severity)
Overall
8.2
6.9
Radiation
5.1
4.9
Hormonal
5.3
3.7
Hu JC et al, JAMA 302; 1557, 2009
“… (minimally-invasive
surgery more likely to
require salvage therapy
within 6 months (27.8%
v 9.1%, P < .001 )”
The Most Important Question
What will the cancer
control results be in 10
years?
The Most Important Factor
• The skill and experience of
the surgeon
HIFU AND CRYOABLATION
(FIRE AND ICE)
HIFU
•
•
•
•
•
Heats prostate tissue up to 100 degrees C
Produces cavity over days to months
Can be repeated
Prostate volume is limiting (40 cc)
Frequently requires preliminary transurethral resection (“Roto-Rooter”)
operation
Multi-Center French HIFU Study
•803 patients, minimum 2 year follow-up
•Prostate cancer-specific survival 99%,
DFS at 5 years 83%, 72%, and 52% for
low-, intermed-, high-risk disease
European Urology 2010: 58: 559-566
HIFU
• 43 patients treated in London with 2-year
follow-up
• 48% had treatment failure
• 3 developed severe scar tissue blocking
urination
• 2 developed fistulas between the urinary and
intestinal tracts
• They have abandoned the HIFU program
Challacombe BJ et al, BJU Int 2009; (also see Walsh JU 182:537)
Cryoablation
• Argon gas circulating through hollow
needles to freeze and kill prostate tissue
• Used primarily as salvage after
radiotherapy
• Poor initial results with high complication
rates
Results of Cryoablation
• No long-term
data
• High risk for
erectile
dysfunction
Levy et al, Urol 182: 931, 2009
FOCAL THERAPY (“LUMPECTOMY”)
New approach to treatment between active
surveillance and surgery or radiation therapy:
minimally-invasive ablation and chemosuppression
of residual disease
Middle Ground: Focal Therapy
• Middle-ground treatments for low-risk
patients that can ablate some prostate
cancer cells but not the whole gland
• Focal therapy (cryoablation, HIFU, or
photodynamic therapy + Proscar or
Avodart)
Focal Therapy
• Lack of validated data demonstrating that it
works well
• Has side effects
• Risks compromising subsequent definitive
treatment if it fails to work
• Leaves prostate cancer cells and “normal”
prostate cells behind that can become
cancerous
• Requires repeated biopsies for monitoring
Focal Therapy
• 80% of prostate cancers involve multiple
regions of the prostate gland
• Imaging with MRI is not reliable to localize
microscopic cancer cells
• Cannot be certain that the largest tumor is the
most dangerous one
• >30% of “low-risk” tumors are really “high
risk” tumors
Black P et al, CUAJ 3:331, 2009
Difficulty of Salvage Prostatectomy
after HIFU or Cryo
•
•
•
•
More difficult surgery
Difficult to perform nerve sparing
More complications
Cancer is frequently found to have
extended beyond the prostate gland
5-a-Recuctase Inhibitors
(Proscar, Avodart)
Claims for “Chemosuppression”
FDA Rejects 5ARI
Chemoprevention
Summary
• Focal therapy is unproven and of
questionable efficacy
• Proscar and Avodart may not be safe for
prostate cancer prevention or
suppression
Radiation Therapy
• Not all cancer cells are sensitive to radiation
doses that can be safely delivered to the
patient
• The radiation may “miss” some cancer cells
• Mutations in remaining “normal” prostate
cells can result in second prostate cancers
• There may be bladder, rectal, sexual side
effects
Contemporary Prostate Brachytherapy:
Trans-perineal Approach
Closed procedure –
Day case
Pre- or intra-operative
planning
Smaller tumors
TRUS guidance
Perineal template –
Good geometry
Contemporary Prostate Brachytherapy:
Trans-perineal Approach
The radiation oncologist’s tool:
The linear accelerator
Proton Beam
Degarelix: More rapid medical
castration, nothing more
• 40% of Degarelix patients had
injection site pain or redness
compared to 1% of leuprolide
(Lupron) patients
Prescrire Int. 2010 Jun: 19 (107); 106-108.
Phase II Multicenter Study of Abiraterone Acetate Plus
Prednisone Therapy in Patients With Docetaxel-Treated
Castration-Resistant Prostate Cancer
• Evaluated the effectiveness of abiraterone in patients
who have castration resistant PCa who failed
treatment with docetaxel
• Clearly this drug has efficacy and most likely will
replace ketoconazole for use in a similar setting
• Issue about payment if patient has not already had
chemotherapy
Danila, DC, et al. J Clin Oncol 2010; 28: 1496
Antitumor Activity of MDV3100 in CastrationResistant Prostate Cancer
• MDV3100 is an androgen-receptor antagonist
• There were substantial and sustained
decreases in PSA, and many patients had
regression of soft tissue metastases
• Overall, two-thirds of patients had partial
remission or stable disease in radiographicallyevident soft tissue and bone lesions
MDV3100 has a different mechanism of targeting the androgen receptor and
looks promising in early studies. Scher, HI, et al., Lancet 2010; 375: 1437
New (and Perhaps Better) Drugs in the
Pipeline
• There are also other new drugs that similarly
affect the androgen-receptor axis
TAK700
• VN124-1 (now TOK-001)
• BMS-641988
• Each has theoretical advantages that may
make them better than abiraterone
Mohler JL and Pantuck AJ. J Urol 185:783,2011
Cabazitaxel vs. Mitoxantrone after Docetaxel
• Phase III study in men with castrate-resistant disease
progressing through docetaxel (n=755)
• Higher treatmentrelated death rate
with cabazitaxel
de Bono et al. Lancet 376:1147-54, 2010/SL
Phase II Study of Docetaxel Re-Treatment in DocetaxelPretreated Castration-Resistant Prostate Cancer
• 45 patients initially responding to docetaxel and then having
disease progression after a period of biochemical remission of
at least 5 months were enrolled in a prospective multicenter
study and re-treated with docetaxel
• Partial PSA responses in 11 patients (24.5%), 4 (25%) objective
responses
• Docetaxel re-treatment preserves anti-tumor activity
and is well tolerated in a selected population of
pretreated patients with castration-resistant prostate
cancer
Di Lorenzo G, et al. BJU Int. 2011;107:234. doi
Sipuleucel-T (Provenge) Immunotherapy
for Castration-Resistant Prostate Cancer
• Well tolerated, with none of the typical
chemotherapy side effects
• Relatively short course (6 weeks) then allowing men
to try chemotherapy
• Improved overall survival for men by 4 months
• Has no effect on tumor progression
• The drug costs $93,000 and Medicare will cover it
Kantoff, PW, et al. N Engl J Med. 2010;363:411
Other Topics
• Adjuvant versus salvage radiation for patients
with adverse pathology findings after radical
prostatectomy
• Management of patients who have PSA
recurrence
• Treatment of locally-advanced disease
• Website: www.drcatalona.com
Overview of Prostate Cancer
Treatment Options
William J Catalona MD
Director, Clinical Prostate Cancer Program
Robert H Lurie Comprehensive Cancer Center
Northwestern