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!!!!!