BME 301

1
BME 301

• Lecture Thirteen

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Review of Lecture 12

• The burden of cancer
• Contrasts between developed/developing world
• How does cancer develop?
• Cell transformation ? Angiogenesis ? Motility ?
  Microinvasion ? Embolism ? Extravasation
• Why is early detection so important?
• Treat before cancer develops ? Prevention
• Accuracy of screening/detection tests
• Se, Sp, PPV, NPV

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Question 3 If a clinical test for a certain type
of cancer is found to have a specificity of 100,
is there any reason to worry about the
sensitivity of the test?
Question 4 If a clinical test for a certain type
of cancer is found to have a sensitivity of 100,
is there any reason to worry about the
specificity?
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Amniocentesis Example

• Amniocentesis
• Procedure to detect abnormal fetal chromosomes
• Efficacy
• 1,000 40-year-old women given the test
• 28 children born with chromosomal abnormalities
• 32 amniocentesis test were positive, and of those
  25 were truly positive
• Calculate
• Sensitivity Specificity
• PPV NPV

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Possible Test Results
Test Positive Test Negative
Disease Present 25 3 with Disease 28
Disease Absent 7 965 without Disease 972
Test Pos 32 Test Neg 968 Total Tested 1,000
Se 25/28 89 Sp 965/972 99.3 PPV
25/32 78 NPV 965/968 99.7
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Dependence on Prevalence

• Prevalence is a disease common or rare?
• p ( with disease)/total
• p (TPFN)/(TPFPTNFN)
• Does our test accuracy depend on p?
• Se/Sp do not depend on prevalence
• PPV/NPV are highly dependent on prevalence
• PPV pSe/pSe (1-p)(1-Sp)
• NPV (1-p)Sp/(1-p)Sp p(1-Se)

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Is it Hard to Screen for Rare Disease?

• Amniocentesis
• Procedure to detect abnormal fetal chromosomes
• Efficacy
• 1,000 40-year-old women given the test
• 28 children born with chromosomal abnormalities
• 32 amniocentesis test were positive, and of those
  25 were truly positive
• Calculate
• Prevalence of chromosomal abnormalities

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Is it Hard to Screen for Rare Disease?

• Amniocentesis
• Usually offered to women gt 35 yo
• Efficacy
• 1,000 20-year-old women given the test
• Prevalence of chromosomal abnormalities is
  expected to be 2.8/1000
• Calculate
• Sensitivity Specificity
• Positive Negative Predictive Value
• Suppose a 20 yo woman has a positive test. What
  is the likelihood that the fetus has a
  chromosomal abnormality?

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Possible Test Results
Test Positive Test Negative
Disease Present 2.5 .3 with Disease 2.8
Disease Absent 6.98 990.2 without Disease 997.2
Test Pos 9.48 Test Neg 990.5 Total Tested 1,000
Se 2.5/2.8 89.3 Sp 990.2/997.2 99.3 PPV
2.5/9.48 26.3 NPV 990.2/990.5 99.97
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Prostate Cancer

• Early Detection

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http//cwx.prenhall.com/bookbind/pubbooks/silverth
orn2/medialib/Image_Bank/CH24/FG24_09a.jpg
Prostate gland contributes enzymes, nutrients and
other secretions to semen.
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Prostate Cancer Statistics

• United States
• 230,110 new cases in US
• 29,900 deaths in US
• 2nd leading cause of cancer death in men
• Worldwide
• 543,000 new cases each year
• Third most common cancer in men
• Risk Factors
• Age
• Race (incidence 3X higher in African Americans)
• Family history of prostate cancer

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Global Incidence of Prostate Cancer

• Figure 5.45

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Development of Prostate Cancer

• Normal prostate
• 30-50 branched glands leading to urethra
• Covered by columnar epithelium
• Precancer of the prostate
• Figure 5.50

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Development of Prostate Cancer

• Prostate Cancer
• Slow, but continuously growing neoplasia
• Preclinical form develops at age 30
• Remains latent for up to 20 years
• Can progress to aggressive, malignant cancer
• Peak incidence 7th decade of life
• Signs and symptoms
• Often asymptomatic in early stages
• Weak or interrupted urine flow
• Inability to urinate
• These are symptoms of prostate enlargement

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Risk of Prostate Cancer in Next 5 Yrs
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http//www.prostatitis.org/1normalgland.gif
Normal Prostate
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te-01.jpg
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http//medlib.med.utah.edu/WebPath/jpeg1/MALE138.j
pg
Pre-cancerous Glands
Normal Gland
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pg
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Prostate Cancer
http//medgen.genetics.utah.edu/photographs/diseas
es/thumbnails/male074_small.
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Prostate Cancer

• Screening (American Cancer Society recs)
• Annual serum PSA test beginning at age 50
• Annual digital rectal exam at age 50
• Treatment
• Surgery, radiation therapy, hormone therapy,
  chemotherapy
• 5 year survival
• All stages 98
• Localized disease 100
• Distant metastases 31

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Screening Guidelines for the Early Detection of
Prostate Cancer, American Cancer Society 2003

• The prostate-specific antigen (PSA) test and the
  digital rectal examination (DRE) should be
  offered annually, beginning at age 50, to men who
  have a life expectancy of at least 10 years.
• Men at high risk (African-American men and men
  with a strong family history of one or more
  first-degree relatives diagnosed with prostate
  cancer at an early age) should begin testing at
  age 45.
• For men at average risk and high risk,
  information should be provided about what is
  known and what is uncertain about the benefits
  and limitations of early detection and treatment
  of prostate cancer so that they can make an
  informed decision about testing.

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Recent Prostate-Specific Antigen (PSA) Test
Prevalence (), by Educational Attainment and
Health Insurance Status, Men 50 Years and Older,
US, 2001-2002
A prostate-specific antigen (PSA) test within
the past year. Note Data from participating
states and the District of Columbia were
aggregated to represent the United States.
Source Behavioral Risk Factor Surveillance
System Public Use Data Tape (2001, 2002),
National Center for Chronic Disease Prevention
and Health Promotion, Centers for Disease Control
and Prevention and Prevention,, 2002, 2003.
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Recent Digital Rectal Examination (DRE)
Prevalence (), by Educational Attainment and
Health Insurance Status, Men 50 Years and Older,
US, 2001-2002
A digital rectal examination (DRE) within the
past year. Note Data from participating states
and the District of Columbia were aggregated to
represent the United States. Source Behavioral
Risk Factor Surveillance System Public Use Data
Tape (2001, 2002), National Center for Chronic
Disease Prevention and Health Promotion, Centers
for Disease Control and Prevention and
Prevention,, 2002, 2003.
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What happens if DRE PSA are ?

• Biopsy of prostate (1500)
• Insert needle through wall of rectum into
  prostate
• Remove fragments of prostate
• Examine under microscope

http//my.webmd.com/NR/rdonlyres/0557C509-969D-444
1-A7BE-1236F9623C2F.jpeg
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Rx for Localized Prostate Cancer

• Radical prostatectomy (remove prostate)
• Usually curative
• Serious side effects
• Incontinence (2-30)
• Impotence (30-90)
• Infertility
• Conservative management
• Just watch until symptoms develop

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Does Early Detection Make a D?

• 10 Yr Survival Rates for Localized Prostate CA
• Grade I
• Surgery 94
• Conservative Rx 93
• Grade II
• Surgery 87
• Conservative Rx 77
• Grade III
• Surgery 67
• Conservative Rx 45
• Makes a difference only for high grade disease

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Challenges of Screening

• Prostate cancer is a slow-growing cancer
• Not symptomatic for an average of 10 years
• Most men with prostate cancer die of other causes
• Treatment has significant side effects
• 50 year old man
• 40 chance of developing microscopic prostate
  cancer
• 10 chance of having this cancer diagnosed
• 3 chance of dying of it

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Should we screen?

• Yes
• Localized prostate cancer is curable
• Advanced prostate cancer is fatal
• Some studies (not RCTs) show decreased mortality
  in screened patients
• No
• False-positives lead to unnecessary biopsies
• Over-detection of latent cancers
• We will detect many cancers that may never have
  produced symptoms before patients died of other
  causes (slow growing cancer of old age)
• No RCTs showing decreased mortality

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Clinical Evidence

• Tyrol, Austria
• Mortality from prostate cancer
• Constant from 1970-1993
• Screening with DRE serum PSA began in 1993
• Mortality decreased 42 since 1993 in Tyrol
• Mortality remained constant in other parts of
  Austria where screening not performed

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Clinical Evidence

• Three case-control studies of DRE
• Mixed results
• One completed RCT of DRE PSA
• Found no difference in of prostate cancer
  deaths between groups randomized to screening and
  usual care

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Why are RCTs so Important?Lead Time Bias
Survive 15 years post-diagnosis
Survive 25 years post-diagnosis
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Randomized Clinical Trials Underway

• Prostate Cancer vs. Intervention Trial (US)
• Prostate, Lung, Colorectal and Ovarian Cancer
  Screening Trial (US)
• European Randomized Study for Screening for
  Prostate Cancer
• 239,000 men
• 10 countries
• Will be complete in 2008

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Do All Countries Screen with PSA?

• United States
• Conflicting recommendations
• Europe
• No
• Not enough evidence that screening reduces
  mortality

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Conflicting Recommendations in US

• Guide to Clinical Preventive Services
• Do NOT screen using DRE or serum PSA
• American College of Preventive Medicine
• Men aged 50 or older with gt10 yr life expectance
  should be informed and make their own decision
• American Cancer Society (and others)
• Men aged 50 or older with gt 10 yr life expectancy
  should be screened with DRE and serum PSA

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USPSTF Recommendation

• The USPSTF found
• good evidence that PSA screening can detect
  early-stage prostate cancer but mixed and
  inconclusive evidence that early detection
  improves health outcomes.
• Screening is associated with important harms,
  including frequent false-positive results and
  unnecessary anxiety, biopsies and potential
  complications of treatment of some cancers that
  may never have affected a patients health.
• The USPSTF concludes
• that evidence is insufficient to determine
  whether the benefits outweigh the harms for a
  screened population.

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Question 5 A new blood test to screen for lung
cancer has a sensitivity of 99 and a specificity
of 50. If the test is positive, your physician
will recommend that you have a bronchoscopy to
confirm the diagnosis. Would you take the test?
Question 6 Would you take the test described in
question 5 if you had a history of smoking 2
packs of cigarettes per day for the last 30 years?
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PSA Test

• Details

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The PSA Test

• What is PSA?
• Prostate-specific antigen
• A glycoprotein responsible for liquefaction of
  semen
• Highly specific for prostate (only made by the
  prostate)
• PSA test is a blood test to measure PSA levels
• Why measure PSA to screen for cancer?
• PSA levels are closely (but not definitively)
  associated with prostate cancer
• May be elevated in benign conditions (BPH,
  Prostatitis)
• Not always high in cancer
• Cost
• 30-100

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PSA Levels

• Normal PSA Levels
• lt 4 ng/ml
• Can vary by age
• 40-49 yo lt 2.5 ng/ml
• 50-59 yo lt 3.5 ng/ml
• 60-69 yo lt 4.5 ng/ml
• 70-80 yo lt 6.5 ng/ml
• Cancer Patients
• 20-25 have PSA lt 4 ng/ml
• 20-25 have 4 ng/ml lt PSA lt 10 ng/ml
• 50-60 have PSA gt 10 ng/ml

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Sensitivity and Specificity of PSA

• How to determine
• Trial Serum PSA ? Biopsy (Gold standard)
• If BX is positive and PSA is positive get TP
• If BX is positive and PSA is negative get FN
• If BX is negative and PSA is negative get TN
• If BX is negative and PSA is positive get FP
• BUT if BX is negative
• Did BX just fail to sample area with cancer?
• Hard to calculate Specificity - TN/(TNFP)
• Cutpoint of 4 ng/ml
• Sensitivity 63-83
• Specificity 90

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Predictive Value Calculation

• Screening Performance
• Se 73 Sp 90
• Number Tested
• N1,000,000 Prevalence 2
• Costs
• Screening 30 Follow up biopsy 1500
• What are PPV NPV?
• What is screening cost?
• What is biopsy cost?
• What is cost/cancer found?

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PSA Example Predictive Value
Test Positive Test Negative
Disease Present 14,600 5,400 with Disease 20,000
Disease Absent 98,000 882,000 without Disease 980,000
Test Pos 112,600 Test Neg 887,400 Total Tested 1,000,000
PPV 14,600/112,600 13 NPV 882,000/887,400
99
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PSA Example Cost
Test Positive Test Negative
Disease Present 14,600 5,400 with Disease 20,000
Disease Absent 98,000 882,000 without Disease 980,000
Test Pos 112,600 Test Neg 887,400 Total Tested 1,000,000
Cost to Screen 301,000,0001500112,600
168,900,000 Cost/Cancer 168,900,000/14,600
13,623
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Question 5 A new blood test to screen for lung
cancer has a sensitivity of 99 and a specificity
of 50. If the test is positive, your physician
will recommend that you have a bronchoscopy to
confirm the diagnosis. Would you take the test?
Question 6 Would you take the test described in
question 5 if you had a history of smoking 2
packs of cigarettes per day for the last 30 years?
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Health Policy Space
Health
Improves Health Costs Money
Improves Health Saves Money
Most Interventions
Vaccines

Worsens Health Saves Money
Worsens Health Costs Money
??????????????????
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Richard J. Babaian, MD
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New Technologies Improved Screening

• Additional serum markers? Improve Sp
• Free PSA
• PSA density
• PSA velocity
• Predict those cancers which will progress to
  advanced disease
• Gene chips

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Review of Lecture 13

• Prostate cancer
• Leading cause of cancer in men in USA
• 2nd leading cause of cancer death in men in USA
• Slow growing cancer of old age
• Precancer?cancer sequence
• Precancer is very common
• PSA
• Serum antigen closely (but not exclusively)
  associated with prostate cancer
• Should we screen with PSA?
• Early prostate cancer is curable
• No RCTs showing decreased mortality yet
• Screening can lead to unnecessary biopsies and
  over-treatment of latent cancer

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Assignments Due Next Time

• WA8
• CPS 119-129
• http//www.bccancer.bc.ca/NR/rdonlyres/el4cwwvk5dn
  o63vawc6b4utxl6mpmi456q7crjryhd3wrsaaemzc4myftydgn
  5dlwgu42ilcxu6nfc/PSAwebBrochure1.pdf