Transcript PREVENTION OF CORONARY ARTERY DISEASE IN WOMEN

CANCER SCREENING TESTS:
EVALUATING THE EVIDENCE
Leah Karliner, MD, MAS
Department of Medicine
UCSF
CASE
56 y.o. man, healthy, no family history of GI cancer,
no current symptoms of rectal bleeding, changes in
stool or weight loss.
“Doc, can I get one of those virtual
colonoscopies?”
OUTLINE
Evaluating Tests
 Colon cancer screening: old tests and new
 Breast cancer screening: mammograms and MRIs
 Prostate cancer screening: should we screen?
 Where to go for the evidence
(extra slides on ovarian and lung cancer screening)

PRINCIPLES OF SCREENING
Disease has high prevalence
 Disease has serious consequences
 Detectable preclinical phase
 Treatment for presymptomatic disease is more
effective than after symptoms develop
 Positive impact on clinical health outcomes: early
detection reduces cancer mortality

EFFECTIVENESS OF TEST

Tests should be simple, inexpensive and
acceptable with a high sensitivity and
specificity

Number of false positives is acceptably low
EFFECTIVENESS OF TEST
Questions to be answered when evaluating/comparing
tests:
 Who will be tested?
 What tests will it supplement or replace?
 Is the new test safer?
 Is the new test less costly?
 Is the test more specific (excluding cases of nondisease)?
 Is the new test more sensitive (detecting more cases of
disease)?
 Is wide-spread use of the test feasible in practice?
SCREENING:
OTHER CONSIDERATIONS

Screening in high risk groups
– Selective vs universal screening
– Rare diseases and false positive test results

Involving patients in the decision
– What are the co-morbid conditions?
– Associated life expectancy, feasibility of treatment,
effects of treatment on quality of life
COLON CANCER
COLORECTAL CANCER:
Principles of Screening
Disease has high prevalence: Second most common
form of cancer in the U.S.
 Disease has serious consequences: second highest
cancer mortality rate overall in U.S.
 Detectable preclinical phase – polyps
 Treatment for pre-symptomatic disease is more
effective than after symptoms develop - yes
 Screening reduces cancer mortality:

– Several studies have shown that screening with fecal occult
blood test (FOBT) or sigmoidoscopy is associated with a
reduction in colorectal cancer mortality
HOW ARE WE DOING?
Adults > age 50, National Data from the Center for Disease Control:
 FOBT in past 2 years
 27%
– 28%
– White
– 24%
– Black
– 17%
– Latino
– 20%
– Other
– 27%
– Multiracial
 Ever had a sig or colonoscopy  53%
– White
– 54%
– Black
– 49%
– Latino
– 39%
– Other
– 41%
– Multiracial
»BRFSS, 2004
– 54%
COLON CANCER SCREENING
RECOMMENDATIONS

U.S. Preventive Services Task Force recommends
screening all persons over 50
– Benefits of screening outweigh potential harms
– Quality of evidence, magnitude of benefit and potential
harms vary with each method
– Unclear which is the best test: FOBT, FOBT plus
sigmoidoscopy, colonoscopy
AVAILABLE TESTS
Tests should be simple, inexpensive and acceptable
with a high sensitivity and specificity: ????
 Available/commonly used tests:

– Fecal occult blood test
– Sigmoidoscopy
– Colonoscopy

Newer tests:
– Virtual Colonoscopy?
– Fecal DNA testing?
– Immunochemical FOBT?
WHICH TEST?
Are the tests equally safe?
 Are the tests equally costly?
 Are the tests equally specific?
 Are the tests equally sensitive?
 Is wide-spread use of the test feasible in practice?

TEST ISSUES

Sigmoidoscopy
– Fair evidence for reducing mortality
– Sigmoidoscopy alone can miss proximal neoplasia – a
positive test needs to be followed by colonoscopy

FOBT
– Good evidence for reducing mortality
– Trials used 6 sample every 1-2 years
– Positive test needs to be followed by colonoscopy
– Many providers use digital FOBT as a primary screening
test - this is different use from in the trials - is in office single
stool sample testing enough?
FOBT vs. IN-OFFICE SINGLE FOBT
Sensitivity for advanced neoplasia was 24% for 6
sample FOBT vs 5% for digital FOBT
 Specificity was 94% for 6 sample FOBT and 98% for
digital FOBT
 Digital FOBT is a poor screening method

• Collins, 2005
IS COLONOSCOPY “BETTER?”
Two observational studies of patients undergoing
colonoscopy
 Goal: Determine prevalence and location of
colonic neoplasia in asymptomatic patients and
the risk of proximal advanced neoplasia in
patients with or without distal neoplasia
 Did NOT assess morbidity and mortality

IS COLONOSCOPY “BETTER?”

Colonoscopy showed some lesions that would
have been missed by sigmoidoscopy alone
– distal polyps were a predictor of proximal neoplasia,
– but some patients with proximal neoplasia did not have
distal polyps

If sigmoidoscopy alone had been done and if
every adenomatous polyp triggered
colonoscopy, 80% of high risk lesions would have
been detected
SCREENING COLONOSCOPY?
Would proximal lesions have been detected by
FOBT?
 No assessment of morbidity and mortality

SCREENING COLONOSCOPY?
More sensitive than FOBT/sigmoidoscopy
 More specific than FOBT
 Higher risk (diagnostic colonoscopies have 1/2000
perforation rate; with polypectomy 1/500-1000)
 More costly? (USPSTF says all of these screening
methods are probably cost-effective)
 Presumed to save lives because used as diagnostic
test in FOBT studies, but at higher rate than FOBT?
 Feasibility in practice dependent on availability of
gastroenterologists and insurance coverage

WHICH TEST?

Most preventable cases of colon cancer are
found in those who have never been screened

If we screened with the currently available tests at
the recommended intervals, we could make a big
impact – particularly in ethnic minorities

Any screening is better than no screening for
reducing colorectal cancer mortality
NEWER TESTS
Virtual Colonoscopy
 Fecal DNA
 Immunochemical FOBT (iFOBT)

VIRTUAL COLONOSCOPY
Non-invasive colon imaging method using thin
section CT
 Test characteristics in largest study to date

– N=1,233 average risk individuals
– Sensitivity
» 94% for polyps ≥8 mm
» 89% for polyps ≥6 mm
– Specificity
» 96% for polyps ≥10 mm
» 80% for polyps ≥6 mm
• Pickhardt, 2003
VIRTUAL COLONOSCOPY
Study used 3 D technology which is not available
everywhere
 Single center study
 Are these results reproducible? Is this feasible in
widespread practice?

VIRTUAL COLONOSCOPY

Multicenter study of screening population
– 615 participants at 9 hospitals
Two-dimensional scans
 Sensitivity

– 55% for lesions ≥10 mm
– 39% for lesions ≥6 mm

Specificity
– 96% for lesions ≥10 mm
– 91% for lesions ≥6 mm
• Cotton, 2004
VIRTUAL COLONOSCOPY
Requires bowel prep and insufflation
 Patients do not necessarily prefer over colonoscopy
 Test interpretation is very time consuming
 Cost effectiveness

– Assuming 100% sensitivity and specificity
– To replace colonoscopy, it would have to be less than 50%
the cost of colonoscopy and compliance would have to be
15-20% better
• Sonnenberg, 1999
FECAL DNA TESTING

DNA alterations in colorectal cancer can be
detected in the stool

Potential advantages
– Non-invasive
– No preparation
– Detection along entire length of the colon
FECAL DNA TESTING
Recently evaluated as a screening test in
asymptomatic individuals aged 50 and older
 Fecal DNA test (21 mutations), Hemoccult II and
colonoscopy
 4404/5486 completed all three aspects of the
study
 Subgroup of 2507 patients were analyzed

• Imperiale, 2004
FECAL DNA TESTING
Fecal DNA
Sensitivity for invasive
cancer
Sensitivity for invasive
cancer/adenoma with
high grade dysplasia
Sensitivity for
advanced neoplasia
Specificity
51.6%
Hemoccult
II
12.9%
40.8%
14.1%
18.2%
10.8%
18.2%
10.8%
FECAL DNA TESTING
20% of the subjects either did not provide samples
or did not have colonoscopy
 Many were aged 65 and over
 Both FOBT and fecal DNA had relatively low
sensitivities compared with what was expected
based on prior studies

FECAL DNA:
REMAINING QUESTIONS

Are health outcomes improved?
– Even if we assume benefit based on FOBT trials, how
much?

Do the benefits outweigh the risks?
– Public expectations about accuracy of DNA testing?
Frequency of testing?
 Acceptability and availability?
 Cost

– $400 to $800 vs $3 to $40 for FOBT
IMMUNOCHEMICAL FOBT
Potential advantages:
 Easier to use
 Improved specificity
 Probably small increase in sensitivity (may not
need as many samples)
 Test characteristics in large average risk
populations has not been studied
COLORECTAL CANCER
SCREENING: CONCLUSIONS

Any currently available screening is better than no
screening for reducing colorectal cancer
mortality

Virtual colonoscopy, immunochemical tests and
fecal DNA testing may have a role in the future
Breast Cancer
BREAST CANCER SCREENING

Disease has high prevalence: most commonly detected
cancer in women in U.S.
– but lower prevelance for women in 40’s




Disease has serious consequences: second highest cancer
mortality rate for women in U.S.
Detectable preclinical phase – microcalcifications
Treatment for pre-symptomatic disease is more effective than
after symptoms develop – unclear in case of DCIS
Screening reduces cancer mortality: Several studies have
shown that screening mammography can reduce mortality
– RCTs have not shown a mortality reduction in women in their 40’s
USPSTF
 United
States Preventive Services Task Force
recommends screening mammography with
or without clinical breast examination every 12 years for women aged 40 and older
–Data are most clear for women aged 50-69
–For women in their forties the evidence is
weaker
–Benefit to women aged 70 and older if life
expectancy not compromised by comorbid disease
USPSTF
Evidence insufficient for or against clinical breast
examination alone
 Evidence insufficient for or against teaching or
performing routine breast self-examination

TEST ISSUES

Tests should be simple, inexpensive and
acceptable with a high sensitivity and specificity:
Increased density of pre-menopausal breast
tissue leads to decreased sensitivity

Number of false positives is acceptably low:
– Cumulative risk of false positive result: 49% after ten
mammograms
– False positive rates were higher for women in their
forties than for women age 50-69
» (Elmore et al, 1998)
MAMMOGRAPHY IN WOMEN
AGED 40-49
Increased density of premenopausal breast tissue
leads to decreased sensitivity
 More cases discovered by mammography in
women in their forties are ductal carcinoma in situ
(DCIS) than in women in their fifties (40-45% vs 20%)

– Clinical significance of DCIS is unclear
– Only 20% will progress to invasive cancer over 10 years
and those that do progress will do so slowly
– Who will benefit from DCIS treatment?
MAMMOGRAPHY IN WOMEN
AGED 40-49
Discuss the pros and cons of mammography
screening and should consider patient risk factors
in making a decision about screening
 If mammography is offered, it should be
performed annually

MAMMOGRAPHY IN
ELDERLY WOMEN
Age is the most important risk factor for breast cancer
 Nearly half (47%) of breast cancer is diagnosed in
women over the age of 65 and 52% of breast cancer
mortality occurs in this age group
 Competing mortality

» Mandelblatt, JGIM 2005
SCREENING HIGH RISK WOMEN
Women with BRCA1 and BRCA2 mutations or with
a family history of breast cancer are often
diagnosed at a young age
 Screening is often offered to younger high risk
women but efficacy is not known

– Lower sensitivity of mammography in younger women
– High tumor growth rate
– Atypical mammography changes in women with BRCA
mutations
MRI SCREENING
Does MRI have a role for screening in high risk
women?
 Sensitive method of breast imaging and has been
used as a diagnostic tool in women with breast
cancer

– Not influenced by breast density
Specificity is variable
 Expensive

MRI SCREENING
236 Canadian women aged 25-65 with BRCA1
and BRCA2 mutations had 1-3 annual screening
examinations
 MRI, ultrasound, mammography annually
 Clinical breast examination every 6 months

» Warner et al JAMA 2004
MRI SCREENING

22 cancers detected
– 6 DCIS

All four screening modalities combined had a
sensitivity of 95% vs 45% for mammography plus
clinical breast exam
SENSITIVITY AND SPECIFICITY
Test
Sensitivity
Specificity
MRI
77%
95%
Mammography
36%
99.8%
Ultrasound
33%
96%
Clinical Breast
Exam
9%
99%
IMPACT FOR
CLINICAL PRACTICE
MRI may be useful in screening high risk women,
although the effect of MRI screening on mortality
is not yet known
 MRI is not currently recommended for screening
average risk women

Prostate Cancer
PROSTATE CANCER:
SHOULD WE SCREEN?

Disease has high prevalence: Most commonly diagnosed
cancer in U.S. men
– 10% lifetime risk
– 30% of men have prostate cancer at autopsy



Disease has serious consequences: variable; prostate cancer
may be a benign disease for many men
Detectable preclinical phase – ?PSA
Treatment for pre-symptomatic disease is more effective than
after symptoms develop - Does early detection do more good
than harm or vice versa?
Complications of prostate cancer treatment
– 8.4% incontinence
– 60% impotence
• Prostate Cancer Outcomes Study 24 month follow up

Screening reduces cancer mortality: ???
IS TREATMENT OF EARLY DISEASE
EFFECTIVE?

Does treatment of early prostate cancer reduce
morbidity and mortality?
– RCT showed reduction in mortality, prostate cancer
mortality, metastatic disease and local progression
– Absolute reduction in mortality is small
» Bill-Axelson, NEJM 2005
DOES SCREENING DECREASE MORTALITY?
EPIDEMIOLOGIC EVIDENCE
Prostate cancer mortality has decreased following
the introduction of prostate cancer screening
 Reduction in mortality followed an initial increase
in incidence

– Due to PSA screening?
» Short time interval
– Changes in treatment
– Is the decline most in the areas with most screening?
RANDOMIZED CLINICAL TRIALS

46,000 men underwent DRE and PSA
– 11 year follow-up
– 23 % of invited group and 6.5% of non-invited group
underwent screening
– Decrease in prostate cancer mortality, but small
numbers of deaths overall
» Labrie, Prostate 2004
PLCO trial sponsored by the NCI is ongoing
 European Randomized Study of Screening for
Prostate Cancer

DIGITAL RECTAL EXAMINATION
One-third of prostate cancers occur in areas
which can be reached
 Higher sensitivity performed by urologists
 An abnormal digital rectal examination increases
the likelihood of prostate cancer somewhat
 A negative examination does not change the
likelihood of a clinically significant prostate
cancer

– Low sensitivity of the examination
PSA SCREENING: TEST ISSUES
15% of men over the age of 50 have an elevated
PSA
 PSA >10 ng/ml:

– 66% have prostate cancer

PSA 4-10 ng/ml:
– 22% have prostate cancer
PSA SCREENING: TEST ISSUES
Levels of 4.0 ng/ml or less have typically been
considered to be normal
 Recent results from the Prostate Cancer Prevention
Trial show that prostate cancer is not rare even in
these men

– 27% cancer in those with PSA 3.1 to 4.0
– 24% in those with PSA 2.1 to 3.0
– 17% in those with PSA 1.1 to 2.0
– 10% in those with PSA 0.6 to 1.0
– 7% in those with PSA up to 0.5

How many cancers would be clinically important?
PSA SCREENING:
MODIFICATIONS
PSA Density
 PSA Velocity
 Free and complexed PSA

So far, none of these modifications have proven
superior to PSA alone
PROSTATE CANCER SCREENING:
RECOMMENDATIONS

USPSTF: insufficient evidence to recommend for or
against routine screening for prostate cancer
using PSA or DRE
– PSA can detect early prostate cancer, but inconclusive
evidence about whether early detection improves
health outcomes

ACP: individualize the decision to screen after
discussion with patient about potential benefits
and harms
SUMMARY OF
RECOMMENDATIONS
Colon cancer: any screening is better than no
screening, use commonly available tests
Breast cancer:
– women aged 50 to 69 should undergo mammography
every 1-2 years
– discuss the pros and cons of mammography screening
with women aged 40-49 and over age 70
– MRI screening may be useful in high risk women
Prostate cancer: discuss pros and cons of PSA with
eligible men; await PLCO trial
SUMMARY OF
RECOMMENDATIONS

Cervical cancer:
– Begin screening w/in 3 years of onset of sexual activity or at age 21;
– Screen at least every 3 years;
– Stop screening at age 65 in low risk women with adequate screening
history
(USPSTF 2003)
– ‘reflex’ HPV testing on pap smears read as ASCUS (ACOG 2003)

Ovarian cancer:
– maybe in high risk women only; await PLCO trial
– women at high risk should consider oral contraceptives (37%
reduction in incidence)

Lung cancer: do not screen; await PLCO trial
– Smoking Cessation!
WHERE TO GO FOR THE
EVIDENCE
U.S. Preventive Services Task Force
http://www.ahrq.gov/clinic/uspstfix.htm
 Technology Evaluation Center / Blue Cross - Blue
Shield Association
http://www.bcbs.com/tec/whatistec.html
 California Technology Assessment Forum / Blue
Shield of California Foundation
http://www.ctaf.org/

OVARIAN AND LUNG CANCER
SCREENING
OVARIAN CANCER:
SHOULD WE SCREEN?

Lifetime risk of ovarian cancer
– No affected relatives
– One affected relative
– 2 affected relatives
– Hereditary syndrome

1.2%
5%
7%
40%
Ovarian cancer limited to the ovaries is
associated with a much higher survival rate
OVARIAN CANCER:
SCREENING TECHNIQUES
Serum CA-125 assay
 Trans-vaginal ultrasound
 Serum CA-125 plus ultrasound

OVARIAN CANCER SCREENING:
CLINICAL TRIAL
22,000 U.K. women
 Annual screening vs no screening for 3 years with
7 year follow-up
 Screening

– CA-125
– Ultrasound if elevated CA-125
– Surgical evaluation if ultrasound abnormal
Slight increase in mean survival
 No difference in mortality

» Jacobs et al, Lancet 1999
OVARIAN CANCER SCREENING:
CONCLUSIONS
Many women must be screened to detect a few
cases
 Small increase in survival:

– Is it worth it?

Low disease prevalence limits utility of the tests
despite high sensitivity and specificity
SCREENING
RECOMMENDATIONS
USPSTF: potential harms outweigh potential benefits
 NIH Consensus Conference: Insufficient evidence
 Many organizations recommend annual pelvic
examination

– No evidence

Although there are no data regarding screening in
high risk women, experts recommend:
– annual screening with rectovaginal pelvic examination,
CA-125 and transvaginal ultrasound
FUTURE DIRECTIONS

PLCO Trial
– 74,000 women aged 55-74
– CA-125 at entry and annually for 5 years
– Annual transvaginal ultrasound
– 13 year follow-up

United Kingdom Trial of Ovarian Cancer Screening
– 200,000 women with 7 year follow-up

Lysophosphatidic Acid (LPA)
– Tumor marker which shows promise
LUNG CANCER: SHOULD WE
SCREEN?
Lung cancer is the number one cause of cancer
mortality in both men and women
 If screening works for so many other cancers, why
don’t we screen for lung cancer?

LUNG CANCER SCREENING:
SYSTEMATIC REVIEW
Does screening for lung cancer reduce lung
cancer mortality
 Included 7 trials of lung cancer screening
 Frequent screening with chest x-rays was
associated with an increase in mortality

– RR 1.11 (95% C.I. 1.00-1.23)

No difference in chest X-ray plus cytology vs
chest X-ray alone
ROLE OF CT
No evidence that screening CT reduces mortality
 Lung Cancer Screening Study

– NCI sponsored
– High risk patients
– CT or chest X-ray
– Results available soon

At this time, spiral CT should not be routinely used
in clinical practice
USPSTF RECOMMENDATIONS
Evidence is insufficient
 Screening with x-ray, low dose CT, sputum
cytology or combination can detect lung cancer
early, but there is no evidence that any screening
strategy reduces lung cancer mortality.

PRIMARY PREVENTION OF
LUNG CANCER
Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation
 Smoking cessation!!!!!
