cancer screening tests: evaluating the evidence leah karliner, md, mas department of medicine ucsf
TRANSCRIPT
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
non-disease)? 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?
FOBT in past 2 years– White – Black– Latino– Other– Multiracial
Ever had a sig or colonoscopy
– White – Black– Latino– Other– Multiracial
27%– 28%– 24%– 17%– 20%– 27%
53%– 54%– 49%– 39%– 41%– 54% »BRFSS, 2004
Adults > age 50, National Data from the Center for Disease Control:
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 Hemoccult II
Sensitivity for invasive cancer
51.6% 12.9%
Sensitivity for invasive cancer/adenoma with high grade dysplasia
40.8% 14.1%
Sensitivity for advanced neoplasia
18.2% 10.8%
Specificity 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 1-2 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 co-morbid 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 Forcehttp://www.ahrq.gov/clinic/uspstfix.htm Technology Evaluation Center / Blue Cross
- Blue Shield Associationhttp://www.bcbs.com/tec/whatistec.html California Technology Assessment Forum /
Blue Shield of California Foundationhttp://www.ctaf.org/
OVARIAN AND LUNG CANCER SCREENING
OVARIAN CANCER: SHOULD WE SCREEN?
Lifetime risk of ovarian cancer– No affected relatives 1.2%– One affected relative 5%– 2 affected relatives 7%– Hereditary syndrome 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!!!!!