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A Prostate Cancer Update: Screening,
Over Diagnosis, and Treatment
Matthew D. Katz, M.D.
Assistant Professor
Urologic Oncology
Robotic and Laparoscopic Surgery
University of Arkansas for Medical Sciences
Winthrop P. Rockefeller Cancer Center
Anatomy Genitourinary System
Campbell-Walsh UROLOGY, 9th edition
Prostate Cancer
• Most common non-skin cancer in men
• Second leading cause of cancer death in U.S.
men
• About 25% of prostate cancers are thought to
be clinically significant
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
New Cases and Death Estimates
Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4
.
Trends in Incidence Rates for Selected Cancers by Sex, United
States, 1975 to 2010
Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4
.
Trends in Death Rates Overall and for Selected Sites by Sex,
United States, 1930 to 2010
Jemal et al. Cancer statistics, 2014. CA cancer J clin, 2014 Mar-Apr;61(2):133-4
Lifetime Risk of Developing CaP
Probability of Developing Invasive Cancers Within Selected Age Intervals by Sex, United States, 2004–2006*
BIRTH TO 39 (%)
40 TO 59 (%)
60 TO 69 (%)
70 AND
OLDER (%)
BIRTH TO DEATH (%)
Male
1.43 (1 in 70)
8.42 (1 in 12)
15.61 (1 in 6)
37.84 (1 in 3)
44.05 (1 in 2)
Female
2.10 (1 in 48)
8.97 (1 in 11)
10.18 (1 in 10)
26.47 (1 in 4)
37.63 (1 in 3)
Male
0.02 (1 in 4,741)
0.39 (1 in 257)
0.95 (1 in 106)
3.66 (1 in 27)
3.81 (1 in 26)
Female
0.01 (1 in 10,613)
0.12 (1 in 815)
0.26 (1 in 385)
1.01 (1 in 99)
1.18 (1 in 84)
Female
0.49 (1 in 206)
3.75 (1 in 27)
3.40 (1 in 29)
6.50 (1 in 15)
12.08 (1 in 8)
Male
0.08 (1 in 1,269)
0.91 (1 in 110)
1.48 (1 in 67)
4.50 (1 in 22)
5.39 (1 in 19)
Female
0.08 (1 in 1,300)
0.72 (1 in 139)
1.07 (1 in 94)
4.09 (1 in 24)
5.03 (1 in 20)
Male
0.17 (1 in 603)
0.21 (1 in 475)
0.33 (1 in 299)
1.19 (1 in 84)
1.51 (1 in 66)
Female
0.13 (1 in 798)
0.15 (1 in 690)
0.20 (1 in 504)
0.78 (1 in 128)
1.08 (1 in 92)
Male
0.03 (1 in 3,461)
0.95 (1 in 105)
2.35 (1 in 43)
6.71 (1 in 15)
7.73 (1 in 13)
Female
0.03 (1 in 3,066)
0.79 (1 in 126)
1.75 (1 in 57)
4.83 (1 in 21)
6.31 (1 in 16)
Male
0.16 (1 in 638)
0.64 (1 in 155)
0.72 (1 in 138)
1.77 (1 in 56)
2.67 (1 in 37)
Female
0.28 (1 in 360)
0.55 (1 in 183)
0.36 (1 in 274)
0.79 (1 in 126)
1.79 (1 in 56)
Male
0.13 (1 in 782)
0.44 (1 in 225)
0.59 (1 in 171)
1.71 (1 in 58)
2.28 (1 in 44)
Female
0.09 (1 in 1,172)
0.32 (1 in 315)
0.44 (1 in 227)
1.39 (1 in 72)
1.92 (1 in 52)
Prostate
Male
0.01 (1 in 9,422)
2.44 (1 in 41)
6.45 (1 in 16)
12.48 (1 in 8)
15.90 (1 in 6)
Uterine cervix
Female
0.15 (1 in 648)
0.27 (1 in 374)
0.13 (1 in 755)
0.19 (1 in 552)
0.69 (1 in 145)
Uterine corpus
Female
0.07 (1 in 1,453)
0.73 (1 in 136)
0.83 (1 in 121)
1.23 (1 in 81)
2.53 (1 in 40
All sites†
Urinary bladder‡
Breast
Colorectum
Leukemia
Lung & bronchus
Melanoma of the skin§
Non-Hodgkin lymphona
Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4
.
Lifetime Risk of Dying from CaP
• Risk of dying from prostate cancer is ~3%
• Once metastatic disease develops there is no cure
• Prior to PSA screening only 25% of CaP presented
confined to prostate vs. 91% since
• 5 year CSS rates increased from ~70% to 100% (from
1980s to early 2000s)
Jemal et al. Cancer statistics, 2010. CA cancer J clin, 2011 Mar-Apr;61(2):133-4
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Catalona et al. Detection of organ-confined prostate cancer is increased through
prostate-specific antigen-based screening. JAMA 1993; 270(8):948
.
Presentation
• Most patients are asymptomatic
• Diagnosed due to elevated PSA or abnormal
DRE
• Advanced cancer may present with bone pain,
unintentional weight loss, hematuria, worsening
LUTS, urinary retention, hydronephrosis, LE
weakness/leg numbness/difficulty with
ambulation
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Risk Factors
• Age
• + Family history
• African American
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Prevention
• PCPT (Prostate Cancer Prevention Trial)
– 18,000 men randomized to placebo vs. Proscar 5mg
qDay
– 7 year follow-up
– Decreased risk of prostate cancer by 25%
– Found small increase in high-grade cancer development
– Further subset analysis did NOT show this to be true
Thomson IM et al. The influence of finasteride on the
development of prostate cancer. N Engl J Med, 349, 2003
Kaplan SA et al. PCPT- Evidence that finasteride reduces the
risk of most frequently detected intermediate and grade
(Gleason score 6 and 7) cancer. Urology, 73, 2009
Prevention
• REDUCE trial (Reduction by Dutasteride of Prostate Cancer
Events)
– 8,000 men >50 yrs old were randomized to placebo vs.
Dutasteride 0.5mg qDay
– Follow-up 4 years
– Decreased risk of developing Gleason score 5-6 cancer by
27%
– Did not reduce risk of Gleason 7-10 cancer
– Did not increase risk of developing high grade cancer
– Enhanced ability of PSA to detect high grade cancers
Andriole GL et al. Effect of dutasteride on the risk of prostate cancer.
N Engl J Med. 362, 2010
Screening
Guideline
Age to start CaP screening
Suggested Screening Tests
AUA 2009
40
PSA and DRE
NCCN 2010
40
PSA and DRE
EAU
45
PSA and DRE
ACS 2010
40-50 (depends on risk)
PSA with or without DRE
American Urological Association 2009, National Comprehensive
Cancer Network 2010, European Association of Urology 2009,
American Cancer Society 2010
Screening
•
•
•
•
Should you screen at all?
What age should you stop screening?
Some advocate men >75 should not be screened*
AUA and NCCN guidelines state that screening
should be individualized based on overall health
(life expectancy >10yrs, FH of longevity, minimal
competing medical comorbidities)
American Urological Association 2009, National Comprehensive
Cancer Network 2010, European Association of Urology 2009,
American Cancer Society 2010
*U.S. Preventative Service Task Force Guidelines, 2008
Screening
• Controversial
• Does PSA-based screening lead to decrease in risk of
death from prostate cancer?
• Advantages
– May prolong survival and save lives
– Save men from long painful death with little effective
treatments available (costs?)
• Disadvantages
– Overdiagnosis which leads to Overtreatment
– Potential decrease in QOL from treatment (costs?)
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
USPSTF To Downgrade PSA Screening
From "I" to "D" — As In "Don't Do It"
• U.S. Preventative Service Task Force
recommended NOT to use PSA to screen for
prostate cancer
• Based on meta-analysis of available literature
The Cancer Letter, Oct. 7, 2011
Screening for Prostate Cancer:
A Review of the Evidence for the U.S.
Preventive Services Task Force
ABSTRACT
Background: Prostate specific antigen-based screening can detect prostate cancer in earlier, asymptomatic stages, when treatments might
be more effective.
Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate
cancer.
Data Sources: MEDLINE (2002 to July 2011), the Cochrane Library Database (through the 2nd quarter of 2011) and reference lists.
Study Selection: Randomized trials of PSA-based screening; randomized trials and cohort studies of prostatectomy or radiation therapy
versus watchful waiting for localized prostate cancer; and large (n>1000), uncontrolled observational studies of perioperative harms.
Data Extraction: Investigators abstracted details about the patient population, study design, data analysis, and results and assessed quality
using predefined criteria.
Conclusions: After about 10 years, PSA-based screening results in
small or no reduction in prostate cancer-specific mortality and is
associated with harms related to subsequent evaluation and
treatments, some of which may be unnecessary.
The Cancer Letter, Oct. 7, 2011
Screening
• Two large trials done recently looking at survival
benefit from screening:
• PLCO screening trial (U.S.) and ERSPC screening
trial (European)
• These two RCT were largely basis for USPSTF
recommendations
Andriole GL et al. Mortality results from a randomized prostate
cancer screening trial. N Engl J Med, 360 (13): 1310, 2009
Schroder FH et al. Screening and prostate cancer mortality in a
randomized european study. N Engl J Med, 360 (13): 1320, 2009
PLCO (US trial)
• Prostate, lung, colorectal, ovarian Cancer screening trial
(U.S.)
–
–
–
–
76,693 men randomized
Ages 55-74 included
After 7 years risk of death same
Significant flaws in study makes conclusions
questionable
• Found no survival benefit for PSA based screening
Andriole GL et al. Mortality results from a randomized prostate
cancer screening trial. N Engl J Med, 360 (13): 1310, 2009
PLCO trial flaws
• Significant rates of screening in “control” arm
– 52% contamination (men were screened prior to study)
• Relatively low rate of biopsy in men who had
“abnormal” screening results in screen arm
– Less than 50% of men in screened arm with indication had
biopsy done
• Short follow-up (less than 10 yrs)
Andriole GL et al. Mortality results from a randomized prostate
cancer screening trial. N Engl J Med, 360 (13): 1310, 2009
ERSPC screening trial (European)
• European Randomized Study of Screening for
Prostate Cancer
– 182,000 men randomized
– Ages 50-74 included
– Median f/up of 9 years there was 20% reduction in
CaP deaths in screened group
– 41 % reduction in metastases at presentation
Schroder FH et al. Screening and prostate cancer mortality in a
randomized european study. N Engl J Med, 360 (13): 1320, 2009
ERSPC screening trial (European) flaws
• Numerous sites of trial entry (7 countries)
• Mortality reduction of 20% came with large
investment
• To prevent one cancer death, need over 1400 men to
be screened over decade and 48 men would require
treatment
Schroder FH et al. Screening and prostate cancer mortality in a
randomized european study. N Engl J Med, 360 (13): 1320, 2009
Screening
• Problems with both studies
– Short follow-up <10 years (mortality from CaP is
very low in first 10 years)
– Subset analysis not done for high risk men (i.e. those
with +FH, AA)
Andriole GL et al. Mortality results from a randomized prostate
cancer screening trial. N Engl J Med, 360 (13): 1310, 2009
Schroder FH et al. Screening and prostate cancer mortality in a
randomized european study. N Engl J Med, 360 (13): 1320, 2009
Göteborg Screening Trial
• Göteborg randomized population-based prostate screening
trial
–
–
–
–
20,000 men randomized
Ages 50-64 included (median 56)
Median follow-up 14 years
Found 44% risk reduction in CaP specific death in screened
group
– NNT analysis revealed that 293 men needed to be screened
and 12 men need to be diagnosed in order to prevent 1 death
Hugosson et al. Mortality results from the Göteborg randomised
Population-based prostate-cancer screening trial.
Lancet Oncol 2010;11:725-32.
Diagnosis
• PSA can be elevated secondary to BPH, prostatitis,
recent ejaculation, prostate trauma (massage, biopsy,
urethral instrumentation, cycling, etc…)
• Use of age and ethnicity adjusted PSA values
Age
Caucasian
African-American
Asian-American
40-49
0-2.5
0-2.0
0-2.0
50-59
0-3.5
0-4.0
0-3.0
60-69
0-4.5
0-4.5
0-4.0
70-79
0-6.5
0-5.5
0-5.0
Campbell-Walsh UROLOGY, 9th edition
Diagnosis
• PSA not perfect and can only be used to define
risk of prostate cancer NOT diagnosis
• No universally accepted threshold value
• Decision to biopsy based on many different
criteria (age, overall health, PSA velocity,
PSADT, FH, race, etc…)
Campbell-Walsh UROLOGY, 9th edition
Indications for Prostate Biopsy
• Suspicious DRE
• Age, ethnicity, +FH
• Abnormal total PSA
Campbell-Walsh UROLOGY, 9th edition
When to Perform Imaging to Evaluate
for Metastatic Disease
• Bone scan
– Indicated: PSA>20, Gleason score ≥8, Bone pain
• Pelvic CT/MRI
– Indicated: PSA>20, Gleason score ≥8
• Newer data suggests fused PET/CT with 11C- Acetate may
be much better at detecting microscopic +LN
Campbell-Walsh UROLOGY, 9th edition
Oyama et al. 11C-Acetate PET imaging of prostate
Cancer: detection of recurrent disease at PSA
relapse. 2003. J Nuc Med. 44; 549
When to Perform Imaging to Evaluate
for Metastatic Disease (bone scan)
Total PSA
Probability of +Bone
Scan
<10
2.3%
10-20
5.3%
20-50
16%
>50
>35%
Biopsy
Gleason
Score
Probability of +Bone
Scan
≤7
5.5%
≥8
28%
Campbell-Walsh UROLOGY, 9th edition
Pet Imaging in Prostate Cancer
Example of Positive LN
Prostate Cancer—Indolent vs.
Aggressive?
• Risk based on individual results
– PSA
– DRE
– Gleason Score: major score + minor score = sum score
• (1-5) + (1-5) = (2-10)
– Number of + biopsies
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Prostate Cancer—Indolent vs.
Aggressive?
• Low Risk
– PSA < 10
– Gleason score ≤6
• Intermediate Risk
– PSA 10-20, Gleason 7 or Gleason 6 with PSA >10
• High Risk
– PSA > 20, Gleason 8-10
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Treatment options for Localized
Prostate Cancer
•
•
•
•
Active Surveillance
Surgery
Radiation
Cryoablation
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Active Surveillance
• Not discussed enough in this country
• Strict selection criteria
• Low risk: cT1-2a, PSA<10, life expectancy
<10yrs, Gleason 6 or less
• Very low risk: cT1-2a, PSA<10, life expectancy
up to 20yrs, Gleason 6 or less, <3 cores +, <50%
of each core involved
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Cryoablation (freezing of prostate)
• Cancer-specific outcomes not as mature as surgery or
radiation
– Almost all men will have significant ED after Tx
– Not good option for locally advanced or high risk
patients
– Useful for men with previous pelvic radiation, rectal
disorders, or inflammatory bowel disease
• Good salvage therapy option for men with recurrent disease
after radiation, brachytherapy or cryoablation
Campbell-Walsh UROLOGY, 9th edition
Radiation
• Various delivery methods
– XRT (external beam radiotherapy)
• Whole pelvis, 3-D conformal, IMRT (intensity
modulated radiation therapy)
– Brachytherapy (radioactive seeds)
• Temporary high dose rate (usually combined with
XRT boost)
• permanent low dose rate
Campbell-Walsh UROLOGY, 9th edition
Radiation
• For low risk disease IMRT or Brachytherapy good
treatment choices
– No need to add ADT
• For intermediate risk disease should add ADT
– 2 months before, during, and for 6 months after XRT
• For high risk disease should add longer course of ADT
– Just before, during, and for 3 years after XRT
• No randomized prospective trials comparing surgery to
radiation
D’Amico et al. Androgen suppression and radiation vs. radiation alone
for prostate cancer. JAMA, 299, 2008
Bolla et al. Three years of adjuvant androgen deprivation with goserelin
in patients with locally advanced prostate cancer treated with
radiotherapy. N Engl J Med, 337, 1997
Surgery
• Different approaches to remove prostate
– Open
– Laparoscopic (use straight instruments)
– Robotic (use wristed instruments with 7
degrees of freedom)
Campbell-Walsh UROLOGY, 9th edition
Comprehensive Textbook of Genitourinary Oncology, 3rd edition
Surgery
• Only form of treatment with randomized trial
revealing CSS and OS advantage when
compared to surveillance
• Survival benefit was seen for men <65 yrs of
age
Bill-Axelson A et al. Radical prostatectomy versus
watchful waiting in localized prostate cancer: the
Scandinavian Prostate Cancer Group 4 randomized trial.
J Natl Cancer Inst, 100, 2008
Surgery
• Authors of that study recently published
updated 15 year follow-up data
• Again found CSS and OS benefit for men
undergoing RP vs. surveillance in <65 yrs of age
Bill-Axelson A et al. Radical prostatectomy versus
watchful waiting in early prostate cancer. N Engl J Med,
364, 2011
Original Article
Radical Prostatectomy or Watchful Waiting in Early
Prostate Cancer
Anna Bill-Axelson, M.D., Ph.D., Lars Holmberg, M.D., Ph.D., Hans Garmo, Ph.D.,
Jennifer R. Rider, Sc.D., Kimmo Taari, M.D., Ph.D., Christer Busch, M.D., Ph.D., Stig
Nordling, M.D., Ph.D., Michael Häggman, M.D., Ph.D., Swen-Olof Andersson, M.D.,
Ph.D., Anders Spångberg, M.D., Ph.D., Ove Andrén, M.D., Ph.D., Juni Palmgren,
Ph.D., Gunnar Steineck, M.D., Ph.D., Hans-Olov Adami, M.D., Ph.D., and Jan-Erik
Johansson, M.D., Ph.D.
Volume 370(10):932-942 March 6, 2014, N Engl J Med
Original Article
Radical Prostatectomy or Watchful Waiting in Early
Prostate Cancer
• This randomized Swedish trial of prostatectomy
versus watchful waiting in disease detected mainly
clinically (not by PSA screening) continues to show a
benefit for early prostatectomy.
• The number of men younger than 65 needed to treat
to prevent one death is now four.
• Follow-up of 18 years
Volume 370(10):932-942 March 6, 2014, N Engl J Med
Prevalence of Metastases and Use of Palliative Treatment in Men Alive at Various Time Points since
Randomization
Bill-Axelson A et al. N Engl J Med 2014;370:932-942
Volume 370(10):932-942 March 6, 2014, N Engl J Med
PIVOT (Prostate cancer Intervention
Versus Observation Trial)
• Randomized men ≤75yrs old to radical
prostatectomy vs. expectant management with
all-cause mortality as primary end-point
• 731 men studied
• Median f/up 10 years
• Different than Scandinavian trial
– looked at same thing, but now in PSA screening era
Wilt et al. Radical prostatectomy versus observation for localized
prostate cancer. N Engl J Med, 367, 2012
Bill-Axelson A et al. Radical prostatectomy versus watchful
waiting in early prostate cancer. N Engl J Med, 364, 2011
PIVOT (Prostate cancer Intervention
Versus Observation Trial)
• Found 47% (171/364) men died who had surgery vs.
49.9% (183/367) in observation arm
• 5.8% (21) men who had surgery died from CaP or
treatment vs. 8.4% (31) in observation arm
• Essentially NO Difference between groups
– Surgery associated with ↓ all-cause mortality in men with
PSA>10 and possibly in intermediate or high-risk tumors
Wilt et al. Radical prostatectomy versus observation for localized
prostate cancer. N Engl J Med, 367, 2012
Bill-Axelson A et al. Radical prostatectomy versus watchful
waiting in early prostate cancer. N Engl J Med, 364, 2011
ProtecT (Prostate testing for cancer
and Treatment)
• RCT of treatment effectiveness in UK
• Opened 2001 and closed 2008
• 111,000 men randomly assigned to surveillance,
radiation, or surgery
• Primary end-point will be CSS at 10yrs
• With numerous secondary end-points including
QOL analyses
Donovan et al. Prostate testing for cancer and treatment
(ProtecT) feasibility study. Health Technol Assess 2003; 7:14
Conclusions
• Prostate cancer very common problem
• Need to know which men to offer screening, when
to begin and end, and how often to offer screening
• Currently we overdiagnose, which leads to
overtreatment of prostate cancer in U.S.
• Desperately need to find better ways to delineate
aggressive forms of prostate cancer from indolent
disease in order to offer treatment to men who will
benefit and spare those who will not