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PSA Screening controversy

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David Canes

on 16 June 2015

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Transcript of PSA Screening controversy

USPSTF
A political firestorm
Epidemiology, History
(roots of the problem)
PSA screening
more background
Ten years...
the importance of long term f/u
Where do we go from here?
The trials:
what do they really show?
Seeing the forest for the trees...
A rational approach
Final thoughts
Does Surgery Save Lives?
Yes, if you're selective about who gets surgery
PIVOT trial, SPCG-4, both randomized trials of surgery vs watchful waiting
PSA Screening
The Prostate Cancer
Screening Controversy

David Canes, M.D.
Lahey Institute of Urology
Nothing to disclose
In the US
2014 stats
233,000 men will be diagnosed
30,000 will die

Many men will develop (nonlethal) prostate ca:
50% of men in 60s
70% of men in 80s
Risks
16% (1/6 men) will be found to have CaP
3% lifetime risk of dying from it
All prostate cancer deaths:
2%... age < 55
28%... age 55-74
70%... age 75+
Risk factors
Age
African American ancestry
Family history (esp first degree relatives receiving dx early in life)
History
PSA introduced to evaluate treatment response in 1987
Soon widely adopted for screening
Pre-2009
Quality of evidence for DRE and PSA screening mortality effect was low-moderate
Conflicting observational data
2009
Two important LARGE randomized trials published in NEJM
The PLCO or "American" trial
76,685 men randomized
The ERSPC or "European" trial
182,160 men randomized

"CONFLICTING" RESULTS
2012 USPSTF
Grade D
Benefits & Harms
of Screening
Shift to earlier stages at diagnosis
Improved oncologic outcomes
lower CaP mortality rates
lower rates of metastatic disease
False-positive PSA tests (anxiety)
Side effects from biopsy (pain, fever, UTI, sepsis)
Over-diagnosis of insignificant cancers
Over-treatment of those cancers
Side effects from cancer treatment (incontinence, impotence)
Re: Prostate cancer screening:
"The harm can be managed and the good can be retained."
Peter Scardino, M.D.
Chairman of Surgery, MSKCC
Why do we screen?
If wait until
symptoms
, survival is
<4 years
on average
Has screening worked?
Good News
Death rates from prostate cancer are falling dramatically
Bad News
The # deaths will
TRIPLE
in the future


Important questions
Does PSA testing save lives?
Yes & No
Can PSA testing do more harm than good?
Yes & No
PSA testing saves lives
IMPACT on CLINICAL STAGE AT DX:

1990:
Localized,
68%
Bone mets,
21%
(1 in 5)

2009:
Localized,
91%
Bone mets
4%
(1 in 25)
Decline in CaP deaths since 1990
Mortality decline from
(1) early detection
(2) improved treatment of high grade disease

So why the controversy?
Urologists and Radiation Oncologists historically did not embrace active surveillance, which has caused some harm
Today's men, lower risk
Most still were treated aggressively (1994-2007)
Stamey et al, NEJM 1987;317: 909-916
(CaP diagnosed
at older age)
Change in life expectancy between 1975-2000
White men: 69 to 76
Black men: 64 to 73
Average age at death from CaP: 80
More men are living long enough to die from the cancer!!


10y f/u is TOO SHORT
If you have
curable prostate ca
, and nobody treats you, most
won't die in <10y
Curable CaP doesn't progress in <10y
Observational study of 223 men with early, low risk prostate cancer
47% not palpable (T1c)
Followed for 30 years without initial treatment
Hormone therapy eventually if progressed
Bottom line
If prostate cancer death (cancer specific mortality) is the end point, the followup must be
>20 years


(more on this later...)
USPSTF mission
"
to evaluate the benefits of individual services based on age, gender, and risk factors for disease; make recommendations about which preventive services should be incorporated routinely into primary medical care and for which populations; and identify a research agenda for clinical preventive care
."

Recs are reviewed q5y
USPSTF
Formed in 1984
Government-appointed panel of 16 volunteer members
Each serves 4 year term
From primary care, preventive medicine, family medicine, internal medicine, pediatrics, obstetrics and gyn, behavioral health, nursing
NO SPECIALTY FIELDS REPRESENTED
Prior to 2012
Prostate cancer had been given an "I" rating
May 2012
Concluded harms of PSA screening outweighed the potential benefits
Gave PSA screening for early detection of prostate cancer a
Grade D
recommendation
Based primarily on PLCO and ERSPC
Did not consider modeling studies (more on this later)
Examples
D
: Vitamin E to prevent cancer
D
: Screen asymptomatic adolescents for testicular ca
UPSTF & Breast Ca
Nov 2009, routine mammograms for women 40-49 given grade D despite confirmation of mortality benefit
NNI 1904 to extend 1 pt's life
Biennial screening mammograms recommended for women 50-74 (Grade B)
UPSTF & Breast Ca
Within 1 month -- LANGUAGE CHANGED (Grade D kept)

Reflected individual nature of the decision, without recommending against it...

No similar public outcry with prostate
UPSTF & Breast Ca
"Outcry from professional organizations, patient advocacy groups, media, public at large was strident and defiant"


2009
PLCO
ERSPC
Kaffenberger, Penson, Urol Clin N Am 41 (2014): 249-255
Kaffenberger, Penson, Urol Clin N Am 41 (2014): 249-255
Current recommendations
Alphabet soup
PLCO
Not a screening study
THIS IS A STUDY COMPARING
INTENSE
SCREENING
VS
LESS INTENSE
SCREENING
(yeah, there's no benefit for more intense screening)
The details
76,685 men 55-74 yrs old
Annual
PSA's for 6 years
DRE for 4 years
After 13 years, CaP 11% in the screened, 10% in the "control" group
CaP mortality 0.4% in BOTH groups
Limitations
<50% of men with suspicious results (
PSA cutoff 4
) got biopsied (low compliance)
Contamination
No reduction in CaP mortality was a
PREDICTABLE
result
USPSTF

However, it's clear
this is NOT a screening trial

"The American study that showed no mortality benefit to screening."

Perceived conflict of interest
A Urologist discussing PSA screening will be perceived as self-serving
And urologists are culpable for the PSA calamity
“It has been painful to see many urologists reject active surveillance of prostate cancer and treat many men inappropriately. In fact I would posit that
as a group we have contributed to the PSA screening conundrum
precisely because we
failed to promote active surveillance of slow growing prostate cancer tumors

We need screening, and we can make it better
.”
Forbes editorial, 7/7/14

Ben Davies, M.D.
Associate Professor of Urology, U Pitt

Subsequent mathematical
simulation of the trial:

....showed that even IF screening --> reduction in prostate cancer mortality, there was only a
10-20% chance a trial designed like this would show it
.
Etzioni, Thompson, Urol Clin N Am 41 (2014) 223-228
ERSPC
"The European study that showed a mortality benefit to screening."
That was 2009...

...updated in 2012
PLCO was not a screening trial
Should not be included in meta-analyses of screening trials

Failure of USPSTF to recognize this reflects a
critical error
in understanding
KEY POINT:

Gulati, Mariotto, Chen, Gore, Etzioni,
J Clin Epidemiol
2011; 64 (12)1412-7
20-30 years is the time horizon for a 55 year old, and NND compares favorably with ALL well accepted interventions in preventive medicine
.... AND...
BOTH PLCO and ERSPC include only 1/6 of CaP deaths that will eventually occur (short followup)
Goteborg
"The trial USPSTF ignored."
Described as a "subset of ERSPC"
(60% of these pts are in ERSPC)
But avg age younger (56)
The younger men in Goteborg were NOT included in ERSPC
20,000 men aged 50-64
PSA cutoff 3.4 (later reduced to 2.9 --> 2.5)
93% of men with elevated PSA had a biopsy
Control group VERY low rates of contamination
How good is NND of 12?
Since dawn of PSA screening:
40% decline in prostate cancer mortality rates
(only other cancer with similar decline is
lung ca
, attributable to smoking cessation)
Historically, PSA screening has been poorly executed
Men screened have been:
TOO OLD
This DILUTES the benefits of screening
Optimal approach:
Screen healthy men at a young age by high volume providers only if high-risk cancer found
Drazer et al. JCO, 2011
HISTORICAL PCP SCREENING PRACTICES
Peak @ 45% of men 70-74
Men over 85 as likely as men aged 50-54 to be screened
Better than breast and colorectal cancer screening.
NNS,mammograms: 377 (age 60-69)
1339 (age 50-59)
NNS, fecal occult blood: 1173
NNS, flex sig: 489-850 to prevent 1 death

NCCN
PSA screening should be offered to healthy, well-informed men aged 45-70, in some cases over age 70
EAU
Mass screening not indicated (public health POV)
Individual screening requires informed consent, shared-decision making
Individualized risk-adapted strategy for well-informed man with 10-15y life expectancy might be offered
Baseline PSA age 40-45
Result determines screening interval (2-4y vs 8y)
American Cancer Society
Informed decision w/provider
Not if <10y life expectancy
Age 50+ if average risk
Age 45+ if high risk
Age 40+ if highest risk
Every 2y if PSA <2.5 ng/ml
AUA
2013 guideline
Offer to men age 55-69 through shared decision making
Men <40 and >69 should not be screened
**some men >70 with excellent life expectancy may benefit
Age 40-54 can be screened if risk factors (African American or strong fam history)
BIENNIAL screening for most men
Panel: academic urologic oncologists, internal medicine, med onc, rad onc, biostatisticians
USPSTF
Grade D
No screening
AAFP
Recommends AGAINST PSA screening
References the USPSTF analysis
Tells us that early detection plus selective treatment based on risk can lower mortality rates without uniformly treating all cancers
This may be underestimated, because of high age at first PSA (60), low intensity of screening (q4y)
SPCG-4
Sweden, Finland, Iceland
Pre-PSA era
695 T2 (75% of group) - i.e.
most had palpable cancer
, very few PSA diagnosed
Mean age 64 years old
Mean followup 18 years

Need to treat 8 people to prevent 1 death (any cause)
Need to treat 4 patients <65 yrs old to prevent 1 death (any cause)
Prostatectomy group: less death from prostate cancer, and distant metastasis, need for ADT, radiation, or chemotherapy
PIVOT
NEJM 2012
731 men with localized prostate ca 1994-2002 assigned to prostatectomy or observation
Median PSA 7.8 ng/ml
Mean age 67
Prostatectomy did NOT reduce CaP mortality
Planned for 2,000 men (underpowered)
DID result in 60% decrease in metastasis
Subgroups DO benefit
64% reduction in cancer-specific mortality if PSA >10
60% reduction for high risk patients
NO BENEFIT to surgery if low risk prostate cancer

PIVOT punchline: RP not effective

Pre-2012
Status quo:
Infrequent screening of young men
Intense screening of older men
Low focus on QOL outcomes of screening
THIS IS UNSUSTAINABLE
Take a closer look
Need to uncouple screening from treatment
Screening is essential to diagnose high risk patients within window of cure
Many men with low-risk CaP do not need immediate treatment
Active Surveillance essential
DO NOT CONFUSE HARMS OF TREATMENT WITH HARMS OF SCREENING
Ways forward
Abandon PSA screening altogether (USPSTF)
Mortality rates will increase to pre-screening-era levels
This would amount to a public health disaster
OR.....
Screen smarter
Treat smarter
What you have learned today
Benefits & Harms
of Screening
Shift to earlier stages at diagnosis
Improved oncologic outcomes
lower CaP mortality rates
lower rates of metastatic disease
False-positive PSA tests (anxiety)
Side effects from biopsy (pain, fever, UTI, sepsis)
Over-diagnosis of insignificant cancers
Over-treatment of those cancers
Side effects from cancer treatment (incontinence, impotence)
These are not harms from screening
They are harms from treatment!!!
Note: if urologists/rad onc are overly aggressive in your community, then screening and treatment will be linked, and this can have dire consequences
USPSTF
Extreme view amongst organizations
Critically misinterpreted data
Stated there is an "inability to reliably distinguish tumors that will remain indolent from those destined to be lethal."
This is false
CaP can be risk stratified with up to 80% accuracy (likelihood of progression using nomograms, scores, etc)
Do you have time for it?
Shared decision making -- crucial---but is it a myth?
Send to urology for discussion
Baseline PSA at age 45 or 50
Single PSA at age 45-55 HIGHLY predictive of mortality in next 25 years
Keep in mind:
Age medians matter
90% of cancer deaths occur in men with
PSA >2 at age 60
Single PSA <1.0 at age 60 has NPV of 99.8%
If PSA below age median, no PSA for 5-10 years
PSA density, fPSA, PSA velocity still valid - it's multifactorial
Urology: PCA3, 4K score, PHI, nomograms
Tell men up front:
"Prostate cancer can be friendly or lethal. The purpose of screening is to find HIGH RISK CaP early. We frequently find low risk CaP which is suitable for monitoring at least as initial strategy."
The Urologists & Radiation oncologists who serve you and your patients play a vital role.

They must advise
active surveillance
to appropriate patients with
low risk prostate cancer
,
else the above paradigm is likely to fail
.

Advise your patients get a
second opinion
before opting for treatment if you see fit
Clinical Case
Example of what I do
55 year old man
PSA 3.9 (no ejaculation)
Father had prostate cancer age 65
Normal DRE
Never had a prostate biopsy
Caucasian
Calculate median
PCPT risk calculator
Individualized risk
Take home points
No population wide PSA screening
Informed consent is key
Do not screen older men or men with significant comorbidity
Screening and treatment are DIFFERENT concepts
Active Surveillance for most low risk prostate cancers
PSA is not perfect, and over-treatment of prostate cancer is a major concern
PSA --> BIOPSY --> TREATMENT is not an inevitable cascade
Ask Urology for help (we have adjunctive tests, MRI fusion biopsy)
Our pledge: we aim not to overdiagnose or overtreat prostate cancer
Be skeptical of outcomes data with <10y followup for prostate cancer
If USPSTF (a highly credible group to you, I know!) is followed, we will return to pre-PSA metastatic disease rates by 2025
A balanced, rational approach:
the most benefit (lives saved) can be achieved by
less intensive
(q2y) screening of
at-risk groups
(55-69), looking for
high risk cancer
Remember high risk groups (family history, African American men)
Yes & no
MEN ARE LIVING LONGER
Why? Age at diagnosis is higher than for other cancers and while the death rate is falling, there are more OLDER men in the population, so there will be MORE TOTAL DEATHS
Age-adjusted death rate in 1990 was 39/100,000
If apply this to 2009, if there had been NO PSA TESTING or TREATMENT IMPROVEMENTS, s/b 59,000 deaths
However, there were 35,000 in 2007 and 29,700 in 2013
The test isn't perfect (no absolute threshold, low specificity)
Need confirmatory (invasive) biopsy after
Treatment is by low volume practitioners
Men with high risk CaP:
UNDERTREATED
Men with low risk CaP:
OVERTREATED
Generally accepted: screening and Rx not indicated in men with life span of < 10Y
WHY? Most men who die from prostate cancer in <10 years of diagnosis have
INCURABLE
disease when diagnosed.
They won't benefit from screening
A
: All adults screen for tobacco use and provide cessation intervention
A
: Tell pregnant women not to smoke
A
: cervical ca screen in sexually active
A
: Fecal occult blood testing, 50-75
B
: Promote healthy diet and exercise for obese patients
C
: Mammograms before age 50
Very few cancers in the group overall
Low proportion of African American men
not surprising
mortality rates no different
not surprising
two groups not very different prostate ca detection rates
not surprising
small absolute #cases found in each group
Low proportion of men with family history of prostate ca
Contamination in the "control" group was estimated at ~74% (patients receiving a PSA at some point)
Average number of screening tests was 5 in the screened arm, 2.7 in the control
Sorting out anything meaningful from it is
impossible
Concluded, from PLCO, that 0-1 life is saved for every 1000 men screened, a stat that has been widely repeated since.
9 years NND 48
11 years NND 33
Modeling studies:
NND between between 2 and 9 over a period of 20-30 years
NNS is 293, NND is 12 to save 1 prostate cancer death
RRR for cancer mortality 44%
14-year median followup
44% of the men in screening arm managed initially with active surveillance (this is a good thing)
Biennial screening until age 69
PIVOT conclusion should be:
Men with <10y life expectancy and low volume disease, surgery is not an option
For healthy men in 40s, 50s, 60s, PIVOT provides NO ANSWER
(~10% in each group were under age 60)

BUT... PIVOT randomized older sick men who should have been observed to surgery,
instead of
healthy men candidates for surgery randomized to observation
Hayes & Barry, JAMA 2014; 311(11):1143-49
1. Biopsy threshold 3 ng/ml
2. Contamination <15%
NNS 235, 10-14dx (50-70)

Year 2010:

Single PSA at age 60
REFS
We have a robust active surveillance program in our department
Best model for high quality honest care at the lowest cost
Large multi-specialty clinic, MD's salaried
Consider my environment
:
No matter what I say, you're likely to be skeptical (a good thing), and I'm likely to lose (like spousal argument)
Basic Recommendations
Focus on ages 55-69 [ERSPC]
Default = every other year
If you must have a threshold, 3 ng/ml [ERSPC]
Majority of low risk CaP, active surveillance
Goal is SECONDARY PREVENTION: identify malignancy earlier in its course and rapidly initiate effective therapies that affect outcomes
What's the difference? P.O.V.
PUBLIC HEALTH: populations
PATIENT CARE: individuals
There is tension between these
Not allowed to judge cost-effectiveness
A little more to it
For African American men or men with family history, starting at 40 makes sense
No one-size fits all threshold
3.9 ng/ml is
96.4th %ile for age
Full transcript