Download December 26, 2004

A Man, a Glove and a Gland: Finding Prostate
Cancer
Mike Thom, MD
Primary Care Conference
March 30, 2005
A Man, a Glove and a Gland: Objectives
• Appreciate the incidence of prostate cancer in one
(i.e. this) general internist’s practice
• Appreciate the controversy that abounds in
applying screening modalities in the diagnosis of
prostate cancer
• Learn to trust your finger (more on that later)
• Agree that we need improved methods to
determine how to differentiate who will die with
their disease from who will die from it.
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Case Outlines
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Patient S.F.
Age: 41
PSA: 1.0
PSA Velocity: NA
Exam: L Sided Nodule
Gleason Score: 3+3=6
Therapy: RRP 3/04
Comments: F/U PSA <0.1
Continence: Dry
Erections: Fully Potent
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Patient D.K.
Age = 47
PSA = 0.6
PSA Velocity = NA
Exam: Nodule R apex
Gleason Score: 3+6=6
Therapy: XRT 9/04
Comments: Pos bx next to
nodule
• Continence: Dry
• Erections: ??
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Case Outlines
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Patient R.F.
Age: 57
PSA: 2.4
PSA Velocity: 0.5ng/yr
Exam: Nodule L base
Gleason Score: 3+3=6
Therapy: RRP 6/04
Comments: Nodule 7/02;
+FH
• Continence: Dry
• Erections: Adequate
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Patient J.F.
Age: 62
PSA: 2.8
PSA Velocity: -0.9ng/yr
Exam: Nodule R apex
Gleason Score: 3+3=6
Therapy: RRP 7/04
Comments: PSA 3.4
11/03; Nodule present in
2001
• Continence: Dry
• Erections: Partial
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Case Outlines
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Patient: C.S
Age: 63
PSA: 6.9
PSA Velocity: 1.0 ng/yr
Exam: L lobe>R lobe BPH
Gleason Score: 3+3=6,
10%
Therapy: Pending
Comments: PSA 7.3,
2001; 5.6, 2003
Continence: NA
Erections: Partial
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Patient J.D.
Age: 65
PSA: 7.0
PSA Velocity: 4.1 ng/yr
Exam: Nodule R lobe
Gleason Score: 3+3=6, 1%
Therapy: XRT 1/04
Comments:
Continence: Dry
Erections: ??
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Case Outlines
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Patient: D.R.
Age: 67
PSA: 5.7
PSA Velocity: 2.2 ng/yr
Exam: BPH, no nodules
Gleason Score: 3+3=6
Therapy: RRP 2/04
Comments: PSA 2.8 to 5.7
in 16 months
• Continence: Dry
• Erections: “80%”
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Patient T.B.
Age: 67
PSA: 6.8
PSA Velocity: 1.7 ng/yr
Exam: BPH me, nodule
urology
Gleason Score: 3+4=7
Therapy: RRP 1/04
Comments: Androgen rx
for hypogonadism 2003
Continence: Dry
Erections: ??
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Case Outlines
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Patient: L.P.
Age: 69
PSA: 7.7
PSA Velocity: 1.2 ng/yr
Exam: BPH, no nodules
Gleason Score: 3+4=6,
50%
Therapy: RRP 8/04
Comments:
Continence: SUI, mild
Erections: on awakening
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Patient C.P.
Age: 70
PSA: 2.4
PSA Velocity: 0.05 ng/yr
Exam: Nodule, R base
Gleason Score: 3+3=6
Therapy: RRP 5/04
Comments: Nodule R base
2002
• Continence: Dry
• Erections: Impotent pre-op
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Case Outlines
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Patient: L.K.
Age: 76
PSA: 4.0
PSA Velocity: 0.27 ng/yr
Exam: Nodule R apex
Gleason Score: 4+3=7, 60%
involved
Therapy: Observation
Comments: Nodule in 2003, hx
CAD, COPD
Continent: NA
Erections: Minimal
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A Man, a Glove and a Gland: Finding Prostate
Cancer
• Financial Conflicts
• Dr. Hedican sent me a Christmas card
• Golden (or brown?) Glove Award nomination?
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Prostate Cancer: To screen or not to screen;
that is the question
• Prostate cancer is the most commonly diagnosed
visceral cancer in the US.
• Second leading cause of cancer death in males
• 17% risk of being diagnosed with prostate cancer
• 3% risk of death from prostate cancer
• Autopsy series reveal prostate cancer present in 1/3
men age 65- 80 and 2/3 men > age 80
– Dorr VJ; Williamson SK; Stephens RL. Arch Intern Med 1993 Nov
22;153(22):2529-37
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Prostate Cancer: To screen or not to screen;
that is the question
• The controversy …
• No studies as of yet have shown clear cut benefit
from screening but …
• There is considerable potential harm from
aggressive treatments
• “Is cure possible in those for whom it is necessary,
and is cure necessary in those for whom it is
possible?
– Whitmore WF Jr. Urol Clin North Am 1990
Nov;17(4):689-9
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Screening for Prostate Cancer: Measurement
of Prostate Specific Antigen (PSA)
• PSA: Glycoprotein expressed by normal and
neoplastic prostate tissue
• Expression per cell is less in neoplastic tissue than
normal tissue
• PSA normally produced as a prohormone
(proPSA) secreted into the prostate ductal lumen
• ProPSA acted on to generate active PSA
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Screening for Prostate Cancer: Measurement
of Prostate Specific Antigen (PSA)
• Active PSA undergoes proteolysis to form inactive
PSA
• Inactive PSA enters bloodstream and circulates
unbound (free PSA)
• Small amounts of active PSA enters bloodstream
and become bound by protease inhibitors
• Prostate cancer cells generate less PSA per cell
• Cancer disrupts basement membrane and normal
lumen architecture
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Screening for Prostate Cancer: Measurement
of Prostate Specific Antigen (PSA)
• In prostate CA, proPSA enters circulation and a
larger fraction of cancer cell generated PSA
escapes proteolysis.
• More PSA therefore is bound by serum protease
inhibitors, resulting in a lower percentage of free
or unbound PSA in the serum of men with prostate
cancer
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Screening for Prostate Cancer: Measurement
of PSA: Age specific references
• 40 to 49 years-old … 0 to 2.5 ng/ml
• 50 to 59 years-old … 0 to 3.5 ng/ml
• 60 to 69 years-old … 0 to 4.5 ng/ml
• 70 to 79 years-old … 0 to 6.5 ng/ml
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Screening for Prostate Cancer: Measurement
of PSA: Causes of elevated serum PSA
• BPH
• Prostate cancer
• Prostate inflammation
• Perineal trauma
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Measurement of PSA: Causes of elevated
serum PSA: BPH
• Most common reason for elevated PSA is BPH
• BPH tissue produces more PSA per gram than
normal prostate tissue
• Considerable overlap between men with BPH and
prostate cancer
• Medical treatment of BPH with finasteride reduces
PSA by nearly 50% during the first 3 months of
therapy
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Measurement of PSA: Causes of elevated
serum PSA: Prostate inflammation
• Prostatitis an important cause of elevated PSA
• One approach in elevated PSA with normal exam
is to treat with antibiotics and then repeat PSA
after six to eight weeks
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Measurement of PSA: Causes of elevated
serum PSA: Perineal trauma
• DRE may cause minor, insignificant elevations of
PSA in the 0.2 to 0.4 ng/ml range
• PSA may be measured immediately after DRE
• Ejaculation may increase levels up to 0.8 ng/ml,
returning to normal within 48 hrs.
• Vigorous biking may elevate the value
inconsistently
• TURP or prostate biopsy elevates values for six
weeks
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Measurement of PSA: Test Performance
• Determining accuracy difficult
• Most men with normal PSA do not undergo
biopsy unless DRE abnormal
• False negative rate of transrectal biopsies may
range from 10 to 20 %
– Levine MA; Ittman M; Melamed J; Lepor. J Urol 1998
Feb;159(2):471-5
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Measurement of PSA: Test Performance
• In one protocol using large numbers of samples
doing biopsies, it is estimated that upwards of
25% of cancers detected by PSA screening were
too small to have accounted for the PSA rise that
prompted the biopsy
– McNaughton Collins M; Ransohoff DF; Barry M.
JAMA 1997 Nov 12;278(18):1516-9
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Measurement of PSA: Test Performance:
Sensitivity and Specificity
• Using traditional cutoff of 4.0 ng/ml;
– Sensitivity estimated at 70%
– Specificity estimated at 60-70%
• Aggressive high grade cancers produce less PSA
per unit volume, hence reduced sensitivity of PSA
• Lower sensitivity in men with symptomatic BPH
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Measurement of PSA: Test Performance:
Sensitivity and Specificity
• Physicians’ Health Study (early 1980s), before
PSA availability
– Gann PH; Hennekens CH; Stampfer MJ. JAMA 1995
Jan 25;273(4):289-94
• 366 men with prostate cancer detected clinically
• 1098 age matched controls
• PSA later measured from stored serum
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Measurement of PSA: Test Performance:
Sensitivity and Specificity
• Physicians’ Health Study (early 1980s), before PSA
availability
– Gann PH; Hennekens CH; Stampfer MJ. JAMA 1995 Jan
25;273(4):289-94
• PSA cutoff of 4.0 was 73% sensitive in detecting cancer
within four years of entering study (87% in detecting
aggressive cancers)
• PSA specificity 91%
• PSA over 4.0 preceded clinical detection by 5 yrs
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Measurement of PSA: Test Performance:
Positive predictive value (PPV)
• Positive predictive value = the proportion of men
with an abnormal value who have prostate cancer
• Overall PPV for PSA > 4.0 ng/ml approx. 30%
• PSA 4.0 to 10.0 ng/ml is 25%
• PSA > 10 ng/ml equates with PPV from 42 to 64%
• 75% cancers found in 4.0 to 10.0 ng/ml zone are
organ confined and potentially curable
• 50% organ confined if PSA > 10 ng/ml
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Measurement of PSA: Effect of lowering PSA
cutoffs
• Prostate Cancer Prevention Trial
– Prevalence of prostate cancer among men with a prostate specific
antigen level < or = 4.0 ng/ml. N Engl J Med 2004. May 27; 350
(22):2239-46. Thompson IM et al
• 18,882 men
• 9459 randomly assigned to placebo had annual PSA and
DRE
• 2950 of 9459 never had PSA > 4.0 or abnormal DRE
• After 7 years, all 2950 (ages 62 to 91 yrs) underwent
prostate biopsy
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Measurement of PSA: Effect of lowering PSA
cutoffs
• Prostate Cancer Prevention Trial:
– Prevalence of prostate cancer among men with a prostate specific
antigen level < or = 4.0 ng/ml
• Prostate cancer found in 449/2950 (15.2%)
• 67/449 (14.9%) = Gleason score 7 or higher
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Measurement of PSA: Effect of lowering PSA
cutoffs
• 6.6% prevalence with PSA < 0.5
• 10.1% prevalence with PSA 0.6 to 1.0
• 17.0% prevalence with PSA 1.1 to 2.0
• 23.9% prevalence with PSA 2.1 to 3.0
• 26.9% prevalence with PSA 3.1 to 4.0
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Measurement of PSA: Effect of lowering PSA
cutoffs
• Nevertheless, a study of 875 men undergoing
radical prostatectomy found limited association
between pre op PSA of 2 to 9 and cure rates
• Survival curves did not diverge until PSA > 7
• Most PSA elevations below 7.0 attributed to BPH
• Stamey TA; Johnstone IM; McNeal JE; Lu AY; Yemoto
CMSO - J Urol 2002 Jan;167(1):103-11.
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Measurement of PSA: Improving the accuracy
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PSA velocity
PSA density
Free PSA
Complexed PSA
Age-specific reference ranges
Race-specific reference ranges
None of above reduce the number of unnecessary
biopsies or improve clinical outcomes
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Screening for prostate cancer: Digital Rectal
Exam (DRE)
• Abnormal findings include
– Nodules
– Asymmetry
– Induration
• DRE can detect findings in the posterior and
lateral aspect of the gland …
• 85% of cancers arise peripherally where they can
be detected
• The majority of cancers detected by DRE alone are
clinically or pathologically advanced
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Screening for prostate cancer: Digital Rectal
Exam (DRE)
• No controlled studies have shown a reduction in
morbidity or mortality when detected by DRE at
any age
• Urologists have relatively low interrater agreement
for detecting prostate abnormalities. (84%
concordance in recommending findings for biopsy)
– Interexaminer variability of digital rectal examination in
detecting prostate cancer. Smith DS, Catalona WJ;
Urology 1995 Jan;45(1):70-4.
• Positive predictive value of DRE … 5 to 30%
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Screening for prostate cancer: Combining PSA
and DRE
• Combined use can increase the overall rate of
cancer detection
• Multicenter screening study
• 6630 men
• 15% PSA > 4.0; 15% DRE abnl; 26% either/or
both
• 1,167 biopsies
• 264 cancers
• PSA found 82% (216 of 264) and DRE 55% (146
of 264)
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Screening for prostate cancer: Combining PSA
and DRE
• 45% cancers detected by PSA alone; 18% detected by DRE
alone
• 160 (of the 264 pts with cancer) underwent radical
prostatectomy
• 114/160 (71%) had organ confined disease
• PSA detected 85/114 (75%) organ confined disease
• DRE detected 64/114 (56%) organ confined disease
• Both DRE and PSA positive detected 50 of 64 (78%) over
DRE alone
– Catalona, WJ; J Urol 1994 May;151(5): 1283-90
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Screening for prostate cancer: Effectiveness:
Evidence from randomized trials
• There are no convincing data from randomized,
controlled clinical trials of screening that show
benefits on morbidity and mortality.
• Two large randomized trials underway …
American Prostate, Lung, Colorectal and Ovarian
Cancer Screening Trial and the European
Randomized Study of Screening for Prostate
Cancer.
• Results will be pooled, not available for a few
years
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Screening for prostate cancer: Effectiveness:
Evidence from observational studies
• Surveillance Epidemiology and End Results
(SEER) tumor registry data have shown a
significant decline in the incidence of advanced
stage disease, potentially consistent with effective
screening
– Eisner, MP; Kosary, CL, et al. SEER Cancer Statistics
Review, 1973-1999. National Cancer Institute,
Bethesda, MD, 2002.
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Prostate cancer mortality rates, which initially
increased following the advent of PSA testing, have
now declined to pre-PSA levels
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Evidence from observational studies:
• Center for Prostate Disease Research Database at
Walter Reed Army Medical Center
– Paquette EL - Urology - 01-NOV-2002; 60(5): 756-9
• 2042 patients with prostate cancer were registered
between 1988 and 1998
• The 5-year disease-specific survival rate was
86.9% for year groups 1988 to 1991 and 93.7% for
patients diagnosed from 1992 to 1994
• Prostate cancer was the cause of death for 37.5%
of the patients in 1988 to 1989 versus 15.4% in
1999 to 2000.
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Screening for prostate cancer: Effectiveness:
Evidence from observational studies
• Marked stage migration has occurred; from 1988 to 1998,
the percentage of patients presenting with metastatic
disease decreased from 14.1% to 3.3%
• Conclusion: A statistically significant improved 5-year
disease-specific survival and a decreased chance of dying
from prostate cancer has occurred after the widespread
implementation of PSA.
• The authors suspected that PSA testing has resulted in
fewer patients presenting with metastatic disease and more
patients presenting with localized disease amenable to
curative treatment
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Screening for prostate cancer: Effectiveness:
Evidence from observational studies
• The authors felt this portends well for the use of
PSA screening to improve outcomes for prostate
cancer.
• However, randomized trials (currently underway)
are needed to confirm the improvements in
survival and mortality.
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Screening for prostate cancer: Harm from
screening
• Psychological effects of a suspicious prostate cancer
screening test followed by a benign biopsy result.
McNaughton-Collins M; Fowler FJ Jr; Caubet JF; Bates
DW; Lee JM; Hauser A; Barry MJ- Am J Med 2004 Nov
15;117(10):719-25.
• 167 men having undergone prostate biopsy with benign
results and 233 men with a normal PSA responded to a
questionaire
• Questions concerned demographic characteristics, medical
history, psychological effects, biopsy experience, and
prostate cancer knowledge
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Screening for prostate cancer: Harm from
screening
• Forty-nine percent (81/167) of men in the biopsy
group reported having thought about prostate
cancer either "a lot" or "some of the time",
compared with 18% (42/230) in the control group
(P < 0.001).
• 40% (67/167) in the biopsy group reported having
worried "a lot" or "some of the time" that they may
develop prostate cancer, compared with 8%
(18/231) in the control group (P < 0.001).
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Screening for prostate cancer: Harm from
screening
• Men who underwent prostate biopsy more often
reported having thought and worried about prostate
cancer, despite having received a benign result.
• This under-recognized human cost of screening
should be considered in the debate about the
benefits and harms of prostate cancer screening.
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Screening for prostate cancer: Harm from
screening
• Risk from prostate biopsy
– < 1% risk of hospitalization following procedure
– Pain common and most of my patients tell me they
would really have preferred some sedation
• Over-diagnosis: Refers to the detection of cancers
that would not have become clinically significant
• This is of particular concern since most men with
screening-detected prostate cancer have early stage
disease and will be offered aggressive treatment
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Screening for prostate cancer: Harm from
screening
• 17% risk of being diagnosed with prostate cancer
• 3% risk of death from prostate cancer
• Autopsy series reveal prostate cancer present in 1/3
men age 65- 80 and 2/3 men > age 80
• “Is cure possible in those for whom it is necessary,
and is cure necessary in those for whom it is
possible?
– Whitmore WF Jr. Urol Clin North Am 1990
Nov;17(4):689-9
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Screening for prostate cancer: Harm from
screening: Risk of therapy
• In absence of therapy, most men found with
prostate cancer from screening will have a lengthy
period of time without clinical problems
• Operative mortality about 0.5% under age 75,
approaches 1% over age 75
• Radical prostatectomy leads to sexual dysfunction
in upwards of 70% of men and urinary problems in
15 to 50% of men
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Screening for prostate cancer: Harm from
screening: Risk of therapy
• External beam radiation may cause …
– erectile dysfunction in 20 to 45% of men with
previously normal erectile function
– urinary incontinence in 2-16% of previously continent
men
– bowel dysfunction in 6 to 25% of men with previously
• Brachytherapy may cause all of above and may
also lead to significant bladder outlet symptoms
– Not indicated in men with very large prostates
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Screening for prostate cancer: Harm from
screening: Risk of therapy
• Given the lack of data on whether screening
improves disease-free survival …
• Quality of life issues related to treatment selection
become increasingly important decision-making
factors.
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Approach to screening: Informed consent:
ACP summary of discussion points
• Prostate cancer is an important health problem.
• The benefits of one-time or repeated screening and
aggressive treatment of prostate cancer have not
yet been proven.
• Digital rectal examinations and PSA measurements
can have both false-positive and false-negative
results.
• The probability that further invasive evaluation
will be required as a result of testing is relatively
high.
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Approach to screening: Informed consent:
ACP summary of discussion points
• Aggressive therapy is necessary to realize any
benefit from the discovery of a tumor.
• A small but finite risk for early death and a
significant risk for chronic illness, particularly with
regard to sexual and urinary function, are
associated with these treatments.
• Early detection may save lives.
• Early detection and treatment may avert future
cancer-related illness.
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Approach to screening: Age, frequency and
method of screening
• Age 50 for men with life expectancy greater than
10 years
• Black men and men with a family history of
prostate cancer … discuss screening at age 40-45
• PSA and DRE
• While annual testing is recommended, screening
studies have shown that cancer detection rates and
the positive predictive value of PSA substantially
decrease after the initial screening
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Approach to screening: Referral to urology
• Men with abnormal prostate exams …
– Nodule
– Induration
– Marked asymmetry
• Abnormal PSA
– PSA > 7.0
– Value consistently between 4.0 and 7.0 on repeat several
weeks apart (refrain from sexual activity or biking for
48 hours, if prostatitis, treat it)
– PSA velocity over 0.75 ng/ml/year (3 serial tests/12 mo)
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Approach to screening: When to stop
• Actuarial tables suggest only men 75 and younger
have a 10-year life expectancy
• Observational study of Swedish men diagnosed
with localized prostate cancer at median age of 72
• Men choosing watchful waiting had an 11 percent
chance of dying from prostate cancer during 15
years of follow-up, compared with 10 percent
among men who received initial treatment
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Approach to screening: When to stop
• However, when follow-up of the men choosing watchful
waiting was extended to 21 years, the mortality rate from
prostate cancer increased approximately threefold for men
who survived beyond 15 years.
• The authors concluded that aggressive treatment might be
warranted for men with a life expectancy exceeding 15
years, corresponding to an age at diagnosis of 70 years.
– Natural history of early, localized prostate cancer. Johansson JE;
Andren O; Andersson SO; Dickman PW; Holmberg L; Magnuson
A; Adami H - JAMA 2004 Jun 9;291(22):2713-9.
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Screening for prostate cancer: Conclusions
• It is unclear whether screening for prostate cancer reduces
morbidity or mortality, and whether even if it does so, the
benefits of screening outweigh potential harms to quality of
life.
• Given the lack of conclusive evidence of benefits of
screening from randomized trials, some suggestive
evidence of benefits from observational trials, and the
potential harms associated with screening, we feel that
individual patient preferences are usually the deciding
factor in determining whether or not screening for prostate
cancer is appropriate in that patient
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Screening for prostate cancer: Conclusions
• Discussions of screening for prostate cancer should present
patients with information on the risks and benefits of
screening
– (See attachment at end of handout)
• For appropriate patients who desire screening, DRE and
PSA should be done every 1-2 years
• See guidelines discussed above for reasons for referral to a
urologist
• Hopefully we’ll have more definitive data soon concerning
morbidity and mortality benefits from screening
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December 26, 2004: Oil and acrylic on
canvas, 48” x 24”
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