Download Prostate Cancer Screening in the Post-USPSTF Era

Prostate Cancer Screening in the
Post-USPSTF Era
Alon Z. Weizer, MD, MS
Associate Professor of Urology
Associate Chair, Surgical Services,
Department of Urology, University of Michigan
Disclosures
• Summus (eConsult Platform): Advisory Board
Outline
• Case presentation
• US Preventative Services Task Force
Recommendations as a Wake-Up Call
• Goals of Cancer Screening
• PSA and Prostate Cancer Basics
• Impact of USPSTF on Screening
• Improvements to Screening Process/Recommendations
Learning Objectives
• Understand the rationale behind prostate cancer
screening
• Understand the implications of USPSTF
recommendations on screening
• Appreciate current recommendations and options
to improve screening
• Learn a proposed algorithm for appropriate
screening for prostate cancer
Case Presentation
• 54 year old Caucasian man presents to your office for annual health
maintenance
– On review of systems, he reports nocturia x 3
• Past medical history: hypertension controlled on lisinopril, mild
obesity (BMI 31)
• Past surgical history: right shoulder surgery, appendectomy as a
child
• Social history: machinist, married, 2 kids in college, quit smoking
10 years ago, minimal alcohol use
• Medications: lisinopril, ibuprofen as needed
• Allergies: none
Case Presentation
• Physical examination: prostate 50 grams, no
nodules but left lobe is larger than the right
• Urinalysis, CBC, basic metabolic panel:
normal
• Next steps…
United States Preventative Services Task
Force Recommendations
• US Preventative Services Task Force
recommendations:
– 2008: Against PSA screening for men >75 years
– October 2011: Draft recommendations against
screening in all asymptomatic men
– May 2012: Final recommendations of Grade D for
PSA screening in all asymptomatic men
– Why: Harms of Screening Outweigh the Benefits
What was the USPSTF’s Evidence?
• Screening trials show increased diagnosis without improved
overall or CaP-specific mortality
• Treatment significantly impacts a man’s QOL
– We have over-treated prostate cancer and likely still do today in several
venues
– The PCa screening trials were completed prior to AS – recent data: up
to 50% of men diagnosed with localized prostate cancer go on AS
– As RALP techniques mature, functional outcomes will continue to
improve
• Politically motivated?
– Treatment costs $11 billion per year
American Urologic Association Early Detection
of Prostate Cancer 2013 Guidelines
• No PSA screening in men under 40
• No routine screening of men 40-54
– Consider family history and African American race
• Men 55-69 have the greatest benefit from screening
– Shared decision making based on patients values and preferences
– Can increase screening interval to every 2 years
• No routine screening for men 70+ or any man with <1015 year life expectancy
– Consider population baseline age-adjusted life expectancy and
adjust according to patient comorbidities
American Cancer Society Guidelines for
Prostate Cancer Early Detection
• Main emphasis: discuss the risks and uncertainties of
screening to promote an informed decision:
– Chance that cancer is diagnosed
– We don’t know which low-risk cancers progress and pose a
threat to a patient’s health
– Diagnosis could compel the patient to undergo treatment
that could ultimately be unnecessary
– Treatments come with significant risks to quality of life
(e.g. urinary incontinence, urinary and bowel symptoms,
worsening erectile function)
Who’s Right When it Comes to Screening?
• Principles of Screening:
– Disease should have a high incidence √
– Biological behavior and natural history of the disease should be known
√
– Test should have high sensitivity, specificity, and positive predictive
value ?
– Test should be rapid, inexpensive, noninvasive, and acceptable to
patients √
– Acceptable and efficacious method of treatment must exist for patients
diagnosed with disease √
– Screening should lower the disease-specific morbidity and increase
survival ?
Examining the Evidence
• Understanding PSA
• Prostate Cancer Incidence and Mortality over
time
• Randomized Controlled Trials of PSA
Screening
PSA Facts
• Discovered in 1970
• Most widely used
oncologic biomarker
• 3/4 men over 50 have
had a PSA
• Member of the human
kallikrein family of
glycoproteins
PSA Facts
•
•
•
•
Produced by the glandular epithelium of the prostate
Trace amounts in salivary, pancreatic and breast tissue
Found in semen, urine and blood
Serine protease that liquefies semen to improve sperm
mobility
• Found in 3 forms in serum:
– Bound to α-1-Antichymotrypsin
– Bound to α-2-Macroglobulin
– Free PSA
PSA is NOT Perfect
• Poor sensitivity (35–70%), specificity (60–90%)
for prostate cancer
• Sensitivity of biopsy in screened is 60-80% at best
• The traditional PSA cut-off of 4.0 is no longer an
absolute indication for biopsy
• Other factors that affect PSA:
–
–
–
–
Infection/Inflammation/Instrumentation
Urinary retention
Ejaculation/Vigorous massage
Advanced age/Benign enlargement
Prostate Cancer Facts (SEER)
Incidence compared to other common cancers
Prostate Cancer Incidence over Time
Prostate Cancer Mortality over Time
The screening studies
• European Randomized Study of Screening for
Prostate Cancer (Europe)
• Goteborg Study (Sweden)
• Prostate, Lung, Colon and Ovarian Cancer
Screening trial (U.S.)
ERSPC: “The European study”
• Random assignment of men between 50 and
74 in 7 European countries
– 83,000 in the screened group; 99,000 in the control
– PSA on average once every 4 years in screened cohort
• During the median follow up of 11 years, PCa
diagnosed in 9.6% of the screened group and
6.0% of controls
Schröder FH, NEJM 2012
ERSPC findings 2012
• Screened group was 29% less likely to die from CAP
• 1055 men would need to be screened and 37 cases of
prostate cancer treated to prevent 1 death
Issues with this Study
• Positive PSA defined as 3.0 ng/ml in most centers
• 6-core biopsy used: prostate cancer diagnosis is
up to 20% higher with an extended biopsy scheme
(10-18 cores)
• Localized prostate cancer more common in the
screened group
A definite benefit of avoiding metastatic disease
Goteborg Study
• F/U 14 years, decrease risk of death 40%
• 227 screened, 12 dx to prevent 1 death
PLCO: “The US trial”
• 38,000 men each randomly assigned to annual
screening or “usual care”
– Compliance rates for PSA and DRE were 85% and 86%,
respectively
– Usual care included up to 52% getting annual PSA and
46% getting yearly DRE
– Follow up was for 7 to 10 years
Andriole GL, NEJM 2009; 360:1310-1319
PLCO results 2009
116 vs. 95 incident cases per 10,000 PY in S vs. C
2.0 vs. 1.7 deaths per 10,000 PY in S vs. C
Issues with this Study
• High rate of screening in the control group –
diluted results
• Follow up of 7 to 10 years not long enough to
realize a mortality advantage from screening
• Using an absolute value of 4.0 ng/ml as a
“positive” PSA may lead to under-diagnosis
• 18% fewer Gleason 8-10 prostate cancers in the
screening group
Where do we go from here?
• Utilizing PSA better
• New Biomarkers that can aid in selection for
biopsy
• Prostate MRI/Fusion Biopsy
• New Genomic testing helps better define risk
• Quality Collaboratives Improve Outcomes
Improving Specificity of PSA
• Repeat PSA before reacting
• PSA Density
– ≥ 0.15 ng/mL/cm3 associated with CaP
• PSA velocity
– A rate of change > 0.75 ng/mL/yr (4 < PSA < 10)
– A rate of change > 0.35 ng/ml/yr (PSA < 2.5)
– Rates > 2 ng/mL/year have been associated with a quicker time to death
from recurrent disease
• Percent free PSA
– < 10% more likely CaP
– > 25% more likely BPH
• Age-Specific Thresholds
Biomarkers
• Developed an algorithm to
combine serum PSA and
urine TMPRSS2:ERG fusion
and PCA3 to predict prostate
cancer on subsequent biopsy
• Improved cancer prediction
(AUC=0.88; specificity
90%; sensitivity 80%)
MiPS Test
Michigan Prostate Score
• PCA3 and TMPRSS2:ERG are urine test collected after a
prostate exam
• Another piece of data to help determine if a patient needs a
prostate biopsy
Example of a MIPS Test Summary Report
Serum PSA: 7.26 ng/ml (Provided by client)
PCA3 Score: 26
TMPRSS2:ERG Score: 9
MiPS Prostate Cancer Risk: 50% (95% CI 46-55% )
MiPS High Grade Prostate Cancer Risk: 28% (95% CI 24-32%)
Other Biomarkers/Tests
Oncology, Crawford et al, 2014
Imaging
Multi-parametric Prostate MRI
• Technique and sequences are crucial – 3 phases obtained
1. T2: peripheral zone exhibits high signal intensity
•
•
2.
3.
Peripheral zone cancers have low T2 signal intensity – the lower the intensity the higher
grade the disease
Cancer more difficult to discern in the transition zone due to signal heterogeneity in this
region
Diffusion weighted MR measures random motion of water molecules – DWI
can help identify high-risk disease
Dynamic contrast enhanced (gadolinium) MR allows evaluation of contrast
kinetics – cancer enhances quickly, more intensely and with a faster washout
MP-MRI sensitivity is 80% for detecting 0.2cm3 disease ≥ Gleason 4+3 or 0.5cm3
Gleason 3+4.
• 170 patients with negative biopsy but persistent suspicion of prostate
cancer
• Blinded standard systematic prostate biopsy performed
• Receiver Operating Characteristic (ROC) analysis showed that MPMRI contributed most to the prediction model (AUC 0.936)
• MP-MRI only significant independent predictor of prostate cancer
diagnosis
• Can a MP-MRI without lesion negate the need for repeat prostate
biopsy?
Prostate Biopsy
Prostate Biopsy
• > 1.2 million prostate biopsies are performed
yearly in the US
• Elevated PSA most frequently triggers biopsy
• 30% of men referred for biopsy are diagnosed
with prostate cancer
• Relies on random sampling
Shortcomings of Standard Systematic
Prostate Biopsy
•
•
•
•
•
False-negative rate
Incorrect risk stratification (up to 45%)
Detection of clinically insignificant disease
Need for repeat biopsy
Disease overtreatment
Increasing the core number (saturation or repeat biopsy) does not significantly
reduce the risk of under sampling and incorrect risk stratification
More biopsy episodes increases the risk of detecting indolent cancers
Goal: Detect high-grade disease while avoiding low risk disease
Types of MRI-Guided Prostate Biopsies
• Cognitive
• In-bore
• Co-registered fusion
biopsy
– Patients with low,
intermediate and high
suspicion lesions had
cancer diagnosed 28%,
67% and 90% of the
time
– Fusion biopsy detected
more cancer per core
than 12-core biopsy
•
•
•
•
•
•
•
•
153 men with suspicion for PCa underwent 3T MP-MRI
105 had lesions classified as low or mod/high risk
Targeted and systematic 12-core biopsy
PCa in 72% of high risk and 48% of low risk lesions
Mean tumor core length 4.6mm for targeted and 3.7mm for standard biopsy
Targeted biopsy diagnosed disease in 14% that were missed on systematic
87% of these were clinically significant
Upgraded 24% of clinically insignificant cancers on 12-core biopsy to
clinically significant
• 195 men with previous negative biopsy with targets on
MP-MRI underwent MR/US fusion and 12-core biopsy
• 37% were found to have cancer
• 11% had high-grade (Gleason 8+) – 55% of these were
missed with standard biopsy
• 39% were upgraded on fusion biopsy vs standard
biopsy
UroNav Fusion Prostate Biopsy –
Our Next Step
• MP-MRI obtained prior to the biopsy session
• Radiologist outlines targets and contours of the
prostate
• Live US image is overlaid on MR images and
contours are matched
• Standard TRUS side-fire probe with sensor fixed
to handle
• Electromagnetic sensor (satellite) fixed above
probe (GPS) detects position of probe in space
• Targeted and 12-core biopsies obtained
Genetic Profiling
Risk Stratifying
• We don’t know which low (Gleason 6) or intermediate
(3+4 or 4+3) risk disease are a true risk to a patient
• Trying to go beyond Gleason score alone
• Ongoing trial looking at a commercially available
cancer genetic profiling test (Prolaris) to see if it
impacts treatment decisions
– Measures RNA expression level of cell cycle genes
– 46 gene expression signature of cell proliferation
CONFIDENTIAL
MMM79958
Prolaris ® Biopsy Test Result
Prolaris Score: -0.7
Consistent With Average AUA
Intermediate Risk
10-Year Prostate Cancer-Specific
Mortality Risk: 4% (95% CI:3-7%)
Interpretation: The Prolaris Score of -0.7 indicates that the
aggressiveness of this cancer is consistent with the average
cancer in the American Urology Association (AUA)¹
Intermediate Risk category.
Interpretation: The patient has a 10-year mortality risk of 4% if
managed conservatively. Mortality risks could be altered by
various therapeutic interventions.
The above chart illustrates the AUA Intermediate Risk
category, which is composed of patients with varying degrees
of cancer aggressiveness. Cancer aggressiveness can be
stratified within this category based upon Prolaris Scores,
which are indicated below the graph.²
US Distribution Percentile: 36%
(For AUA Intermediate Risk)
Interpretation: 36% of patients in the AUA Intermediate Risk
category have a lower Prolaris Score.
CLINICO-PATHOLOGIC FEATURES USED FOR ANALYSIS
PSA Prior to This Biopsy: 9.5
Clinical T Stage: T1c
Gleason Score: 3+4=7
Patients with similar clinico-pathologic features, as defined by
their CAPRA score, have the same a priori 10-year prostate
cancer-specific mortality risk. The addition of the Prolaris
Score further differentiates this risk, as illustrated in the above
graph, which is specific to this patient's CAPRA score. 2-4 The
orange line depicts the relationship between the Prolaris
Score and the mortality risk with the 95% confidence interval
indicated by dashed lines and the patient's Prolaris
Score indicated by the orange dot.
CLINICO-PATHOLOGIC FEATURES USED FOR ANALYSIS
Patient Age: 52
PSA Prior to This Biopsy: 9.5
Clinical T Stage: T1c
% Positive Cores: 41% (5/12)
Gleason Score: 3+4=7
MUSIC
Michigan Urologic Surgery Improvement Collaborative
Vital statistics
l
MUSIC Participants:
• 42 practices
• 225 urologists
• 4 patient advocates
l
Data Collection:
• 36 practices
• More than 13,000 cases in the registry
– > 13,000 biopsies and 2,600 radical prostatectomies
Pathways for addressing FQ resistance
Collaborative-wide Hospitalization Rates
2%
Prostate Biopsy Infectious Hospitalization Rate
P = 0.0017
1.19%
1%
n = 65
n = 65
0.56%
n n= =2525
0%
Pre-Intervention
(5,028 biopsies)
Post-Intervention
(4,087 biopsies)
Patient Reported Outcomes (PRO)
A statewide infrastructure for measuring and improving functional
outcomes after radical prostatectomy
Patients
Providers
Practices
Collaborative
54
Patient Trend Report
Only in Michigan:
Prostatectomy Video Review Assessment
Methods-Incidence
• Ecological study using SEER cancer registry
– Data from 2005-2012
• N = 446,009
– Identified incident cases of local/regional or distant prostate
cancer
– Merged SEER data with CDC data to examine changes in
incidence by age
– Incidence Rations (IR)
• Compare relative change in incidence between consecutive years
for age standardized rates
Methods-PSA testing
• National Health Interview Surveys (NHIS) data
– Nationally representative household cross-sectional
sample
– Collected 2005, 2008, 2010, 2013
• N = 18,385
– Rate of self-reported PSA testing in past year
– Screening Rate Ratios (SRR)
• Age and Race adjusted comparison of relative change in
screening between years
9%
16%
• Similar decline in white and black men
• Data from single registry (Georgia) showed continued 6% decrease in 2013
18%
Conclusions
• Population-based incidence and PSA screening
decreased significantly in response to USPSTF
– Decrease in both white and black individuals
– 33,519 fewer men were diagnosed in 2011 compared to
2012
– Alternative reason for decline unlikely
• Unclear how this decrease affects balance between
overdiagnosis/overtreatment and missed opportunity of
detecting significant cancers
• Difference-in-differences analysis found significant decrease in PSA screening
using NHIS
• 28% decrease in incident prostate cancer cases in the year following the USPSTF
recommendations using the NCDB database
• 38% decrease in low risk cancers; 28% in intermediate risk; 23% in high risk
How do we improve screening
• Shared decision making around screening in men
50/55-69 years old
• Obtain a confirmatory test prior to proceeding
with biopsy to help refine risk
• Obtain MRI to help improve the yield of biopsy
• Promote active surveillance as front line treatment
in appropriate patients
– Consider use of genomic tests to better define risk
Treatment Appropriateness
Rationale: great concern regarding overtreatment
Variation is appropriate when it can be explained by factors that are considered
relevant in treatment decisions
Variation is inappropriate when
based on ethnicity, insurance,
choice of doctor, ancillary profit,
etc
Active Surveillance for low risk: practice patterns in Michigan
Womble et al, Eur Urol, 2014
Appropriateness Focus
Watchful Waiting
(WW)
Initial
Treatment
RLE<10y
Dx Low or
Low/Int
Risk PC
Our focus
Age and
Comorbidity
RLE>10y
Consider
AS
What is the question?
• It is NOT: Treatment vs. No Treatment
• It is: Initial Treatment vs. Consideration of AS
Confirmatory
tests for AS
Panel Key points:
AS for GL 6 or low volume Gl 3+4
• None of the scenarios assessed by the panel were deemed “inappropriate”
for AS
• All low volume Gleason 6 scenarios were deemed “appropriate” or “highly
appropriate” for AS, with minimal disagreement
• 73% of Intermediate Volume Gleason 6 scenarios were deemed
“appropriate” or “highly appropriate” for AS
• Panel members were more “uncertain” about the appropriateness of AS in
high volume Gleason 6 and low volume Gleason 7 patients
Distribution of Pca patients
% of Pca Patients
100%
52% of MUSIC Pca cases
meet the tumor criteria for the
scenarios considered by the panel
48.3%
50%
25.2%
n = 1,425
n = 533
0%
Low Vol, Gl 6
15.5%
9.4%
Int Vol, Gl 6
1.5%
High Vol, Gl 6
n = 83
Low Vol, Gl 7
Appropriateness Groupings
n = 877
Other
Proposed simplified clinical pathway for
consideration of AS
Tx
AS Score
Low or LowInt risk PC
Standardized
education and
SDM tool
Shared Decision
Making
Consider AS
Stay on AS
Confirmatory
studies
Shared decision making
• Of course, urologists all do this now and do it very
well. We are all well above average.
And yet, remarkably, this is not how we are perceived
in 2015
“Yet there is alarming evidence to indicate that patients
may not be properly informed about their options,
particularly expectant management options such as
watchful waiting or active surveillance.”
Blumenthal-Barby JS, Lee D, and Volk RJ. Toward Ethically Responsible Choice Architecture in Prostate
Cancer Treatment Decision-Making. CA CANCER J CLIN 2015
Shared decision making
• In 2015, the Movember Foundation reviewed PCa
treatment SDM web-based tools and recognized 2
instruments as ideal
1. WiserCare
2. Prostate Personal Patient Profile (“P3P”)
• In Jan 2016, the MUSIC AS working group reviewed
both of these and selected P3P
Implementation next challenge!!
Final Word
• Case: to screen or not to screen? Getting a
PSA for symptoms is not screening
• While better treatments exist for
advanced/metastatic disease, no one has
examined QOL/morbidity/cost compared to
early treatment
• Questions?