Presentation on theme: "CANCER SCREENING TESTS: EVALUATING THE EVIDENCE"— Presentation transcript:
1 CANCER SCREENING TESTS: EVALUATING THE EVIDENCE Leah Karliner, MD, MASDepartment of MedicineUCSF
2 CASE56 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?”
3 OUTLINE Evaluating Tests Colon cancer screening: old tests and new Breast cancer screening: mammograms and MRIsProstate cancer screening: should we screen?Where to go for the evidence(extra slides on ovarian and lung cancer screening)
4 PRINCIPLES OF SCREENING Disease has high prevalenceDisease has serious consequencesDetectable preclinical phaseTreatment for presymptomatic disease is more effective than after symptoms developPositive impact on clinical health outcomes: early detection reduces cancer mortality
5 EFFECTIVENESS OF TESTTests should be simple, inexpensive and acceptable with a high sensitivity and specificityNumber of false positives is acceptably low
6 EFFECTIVENESS OF TESTQuestions 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?
7 SCREENING: OTHER CONSIDERATIONS Screening in high risk groupsSelective vs universal screeningRare diseases and false positive test resultsInvolving patients in the decisionWhat are the co-morbid conditions?Associated life expectancy, feasibility of treatment, effects of treatment on quality of life
9 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 – polypsTreatment for pre-symptomatic disease is more effective than after symptoms develop - yesScreening 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 mortalityHigh prevalence disease with serious consequences.Impact on health outcomes – reduces
10 HOW ARE WE DOING?Adults > age 50, National Data from the Center for Disease Control:FOBT in past 2 yearsWhiteBlackLatinoOtherMultiracialEver had a sig or colonoscopy27%28%24%17%20%53%54%49%39%41%BRFSS, 2004
11 COLON CANCER SCREENING RECOMMENDATIONS U.S. Preventive Services Task Force recommends screening all persons over 50Benefits of screening outweigh potential harmsQuality of evidence, magnitude of benefit and potential harms vary with each methodUnclear which is the best test: FOBT, FOBT plus sigmoidoscopy, colonoscopy
12 AVAILABLE TESTSTests should be simple, inexpensive and acceptable with a high sensitivity and specificity: ????Available/commonly used tests:Fecal occult blood testSigmoidoscopyColonoscopyNewer tests:Virtual Colonoscopy?Fecal DNA testing?Immunochemical FOBT?
13 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?
14 TEST ISSUES Sigmoidoscopy FOBT Fair evidence for reducing mortality Sigmoidoscopy alone can miss proximal neoplasia – a positive test needs to be followed by colonoscopyFOBTGood evidence for reducing mortalityTrials used 6 sample every 1-2 yearsPositive test needs to be followed by colonoscopyMany 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?
15 FOBT vs. IN-OFFICE SINGLE FOBT Sensitivity for advanced neoplasia was 24% for 6 sample FOBT vs 5% for digital FOBTSpecificity was 94% for 6 sample FOBT and 98% for digital FOBTDigital FOBT is a poor screening methodCollins, 2005
16 IS COLONOSCOPY “BETTER?” Two observational studies of patients undergoing colonoscopyGoal: Determine prevalence and location of colonic neoplasia in asymptomatic patients and the risk of proximal advanced neoplasia in patients with or without distal neoplasiaDid NOT assess morbidity and mortality
17 IS COLONOSCOPY “BETTER?” Colonoscopy showed some lesions that would have been missed by sigmoidoscopy alonedistal polyps were a predictor of proximal neoplasia,but some patients with proximal neoplasia did not have distal polypsIf sigmoidoscopy alone had been done and if every adenomatous polyp triggered colonoscopy, 80% of high risk lesions would have been detected
18 SCREENING COLONOSCOPY? Would proximal lesions have been detected by FOBT?No assessment of morbidity and mortality
19 SCREENING COLONOSCOPY? More sensitive than FOBT/sigmoidoscopyMore specific than FOBTHigher risk (diagnostic colonoscopies have 1/2000 perforation rate; with polypectomy 1/ )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
20 WHICH TEST?Most preventable cases of colon cancer are found in those who have never been screenedIf we screened with the currently available tests at the recommended intervals, we could make a big impact – particularly in ethnic minoritiesAny screening is better than no screening for reducing colorectal cancer mortality
22 VIRTUAL COLONOSCOPYNon-invasive colon imaging method using thin section CTTest characteristics in largest study to dateN=1,233 average risk individualsSensitivity94% for polyps ≥8 mm89% for polyps ≥6 mmSpecificity96% for polyps ≥10 mm80% for polyps ≥6 mmPickhardt, 2003
23 VIRTUAL COLONOSCOPYStudy used 3 D technology which is not available everywhereSingle center studyAre these results reproducible? Is this feasible in widespread practice?
24 VIRTUAL COLONOSCOPY Multicenter study of screening population 615 participants at 9 hospitalsTwo-dimensional scansSensitivity55% for lesions ≥10 mm39% for lesions ≥6 mmSpecificity96% for lesions ≥10 mm91% for lesions ≥6 mmCotton, 2004
25 VIRTUAL COLONOSCOPY Requires bowel prep and insufflation Patients do not necessarily prefer over colonoscopyTest interpretation is very time consumingCost effectivenessAssuming 100% sensitivity and specificityTo replace colonoscopy, it would have to be less than 50% the cost of colonoscopy and compliance would have to be 15-20% betterSonnenberg, 1999
26 FECAL DNA TESTINGDNA alterations in colorectal cancer can be detected in the stoolPotential advantagesNon-invasiveNo preparationDetection along entire length of the colon
27 FECAL DNA TESTINGRecently evaluated as a screening test in asymptomatic individuals aged 50 and olderFecal DNA test (21 mutations), Hemoccult II and colonoscopy4404/5486 completed all three aspects of the studySubgroup of 2507 patients were analyzedImperiale, 2004
28 FECAL DNA TESTING Fecal DNA Hemoccult II Sensitivity for invasive cancer51.6%12.9%Sensitivity for invasive cancer/adenoma with high grade dysplasia40.8%14.1%Sensitivity for advanced neoplasia18.2%10.8%Specificity
29 FECAL DNA TESTING20% of the subjects either did not provide samples or did not have colonoscopyMany were aged 65 and overBoth FOBT and fecal DNA had relatively low sensitivities compared with what was expected based on prior studies
30 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
31 IMMUNOCHEMICAL FOBT Potential advantages: Easier to use Improved specificityProbably small increase in sensitivity (may not need as many samples)Test characteristics in large average risk populations has not been studied
32 COLORECTAL CANCER SCREENING: CONCLUSIONS Any currently available screening is better than no screening for reducing colorectal cancer mortalityVirtual colonoscopy, immunochemical tests and fecal DNA testing may have a role in the future
34 BREAST CANCER SCREENING Disease has high prevalence: most commonly detected cancer in women in U.S.but lower prevelance for women in 40’sDisease has serious consequences: second highest cancer mortality rate for women in U.S.Detectable preclinical phase – microcalcificationsTreatment for pre-symptomatic disease is more effective than after symptoms develop – unclear in case of DCISScreening reduces cancer mortality: Several studies have shown that screening mammography can reduce mortalityRCTs have not shown a mortality reduction in women in their 40’s
35 USPSTF Data are most clear for women aged 50-69 United States Preventive Services Task Force recommends screening mammography with or without clinical breast examination every 1-2 years for women aged 40 and olderData are most clear for women aged 50-69For women in their forties the evidence is weakerBenefit to women aged 70 and older if life expectancy not compromised by co-morbid disease
36 USPSTFEvidence insufficient for or against clinical breast examination aloneEvidence insufficient for or against teaching or performing routine breast self-examination
37 TEST ISSUESTests should be simple, inexpensive and acceptable with a high sensitivity and specificity: Increased density of pre-menopausal breast tissue leads to decreased sensitivityNumber of false positives is acceptably low:Cumulative risk of false positive result: 49% after ten mammogramsFalse positive rates were higher for women in their forties than for women age 50-69(Elmore et al, 1998)
38 MAMMOGRAPHY IN WOMEN AGED 40-49 Increased density of premenopausal breast tissue leads to decreased sensitivityMore 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 unclearOnly 20% will progress to invasive cancer over 10 years and those that do progress will do so slowlyWho will benefit from DCIS treatment?
39 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 screeningIf mammography is offered, it should be performed annually
40 MAMMOGRAPHY IN ELDERLY WOMEN Age is the most important risk factor for breast cancerNearly half (47%) of breast cancer is diagnosed in women over the age of 65 and 52% of breast cancer mortality occurs in this age groupCompeting mortalityMandelblatt, JGIM 2005
41 SCREENING HIGH RISK WOMEN Women with BRCA1 and BRCA2 mutations or with a family history of breast cancer are often diagnosed at a young ageScreening is often offered to younger high risk women but efficacy is not knownLower sensitivity of mammography in younger womenHigh tumor growth rateAtypical mammography changes in women with BRCA mutations
42 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 cancerNot influenced by breast densitySpecificity is variableExpensive
43 MRI SCREENING236 Canadian women aged with BRCA1 and BRCA2 mutations had 1-3 annual screening examinationsMRI, ultrasound, mammography annuallyClinical breast examination every 6 monthsWarner et al JAMA 2004
44 MRI SCREENING 22 cancers detected 6 DCISAll four screening modalities combined had a sensitivity of 95% vs 45% for mammography plus clinical breast exam
45 SENSITIVITY AND SPECIFICITY TestSensitivitySpecificityMRI77%95%Mammography36%99.8%Ultrasound33%96%Clinical Breast Exam9%99%
46 IMPACT FOR CLINICAL PRACTICE MRI may be useful in screening high risk women, although the effect of MRI screening on mortality is not yet knownMRI is not currently recommended for screening average risk women
48 PROSTATE CANCER: SHOULD WE SCREEN? Disease has high prevalence: Most commonly diagnosed cancer in U.S. men10% lifetime risk30% of men have prostate cancer at autopsyDisease has serious consequences: variable; prostate cancer may be a benign disease for many menDetectable preclinical phase – ?PSATreatment 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 treatment8.4% incontinence60% impotenceProstate Cancer Outcomes Study 24 month follow upScreening reduces cancer mortality: ???
49 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 progressionAbsolute reduction in mortality is smallBill-Axelson, NEJM 2005
50 DOES SCREENING DECREASE MORTALITY? EPIDEMIOLOGIC EVIDENCE Prostate cancer mortality has decreased following the introduction of prostate cancer screeningReduction in mortality followed an initial increase in incidenceDue to PSA screening?Short time intervalChanges in treatmentIs the decline most in the areas with most screening?
51 RANDOMIZED CLINICAL TRIALS 46,000 men underwent DRE and PSA11 year follow-up23 % of invited group and 6.5% of non-invited group underwent screeningDecrease in prostate cancer mortality, but small numbers of deaths overallLabrie, Prostate 2004PLCO trial sponsored by the NCI is ongoingEuropean Randomized Study of Screening for Prostate Cancer
52 DIGITAL RECTAL EXAMINATION One-third of prostate cancers occur in areas which can be reachedHigher sensitivity performed by urologistsAn abnormal digital rectal examination increases the likelihood of prostate cancer somewhatA negative examination does not change the likelihood of a clinically significant prostate cancerLow sensitivity of the examination
53 PSA SCREENING: TEST ISSUES 15% of men over the age of 50 have an elevated PSAPSA >10 ng/ml:66% have prostate cancerPSA 4-10 ng/ml:22% have prostate cancer
54 PSA SCREENING: TEST ISSUES Levels of 4.0 ng/ml or less have typically been considered to be normalRecent results from the Prostate Cancer Prevention Trial show that prostate cancer is not rare even in these men27% cancer in those with PSA 3.1 to 4.024% in those with PSA 2.1 to 3.017% in those with PSA 1.1 to 2.010% in those with PSA 0.6 to 1.07% in those with PSA up to 0.5How many cancers would be clinically important?
55 PSA SCREENING: MODIFICATIONS PSA DensityPSA VelocityFree and complexed PSASo far, none of these modifications have proven superior to PSA alone
56 PROSTATE CANCER SCREENING: RECOMMENDATIONS USPSTF: insufficient evidence to recommend for or against routine screening for prostate cancer using PSA or DREPSA can detect early prostate cancer, but inconclusive evidence about whether early detection improves health outcomesACP: individualize the decision to screen after discussion with patient about potential benefits and harms
57 SUMMARY OF RECOMMENDATIONS Colon cancer: any screening is better than no screening, use commonly available testsBreast cancer:women aged 50 to 69 should undergo mammography every 1-2 yearsdiscuss the pros and cons of mammography screening with women aged and over age 70MRI screening may be useful in high risk womenProstate cancer: discuss pros and cons of PSA with eligible men; await PLCO trial
58 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 trialwomen at high risk should consider oral contraceptives (37% reduction in incidence)Lung cancer: do not screen; await PLCO trialSmoking Cessation!
59 WHERE TO GO FOR THE EVIDENCE U.S. Preventive Services Task ForceTechnology Evaluation Center / Blue Cross - Blue Shield AssociationCalifornia Technology Assessment Forum / Blue Shield of California Foundation
61 OVARIAN CANCER: SHOULD WE SCREEN? Lifetime risk of ovarian cancerNo 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
63 OVARIAN CANCER SCREENING: CLINICAL TRIAL 22,000 U.K. womenAnnual screening vs no screening for 3 years with 7 year follow-upScreeningCA-125Ultrasound if elevated CA-125Surgical evaluation if ultrasound abnormalSlight increase in mean survivalNo difference in mortalityJacobs et al, Lancet 1999
64 OVARIAN CANCER SCREENING: CONCLUSIONS Many women must be screened to detect a few casesSmall increase in survival:Is it worth it?Low disease prevalence limits utility of the tests despite high sensitivity and specificity
65 SCREENING RECOMMENDATIONS USPSTF: potential harms outweigh potential benefitsNIH Consensus Conference: Insufficient evidenceMany organizations recommend annual pelvic examinationNo evidenceAlthough there are no data regarding screening in high risk women, experts recommend:annual screening with rectovaginal pelvic examination, CA-125 and transvaginal ultrasound
66 FUTURE DIRECTIONS PLCO Trial 74,000 women aged 55-74CA-125 at entry and annually for 5 yearsAnnual transvaginal ultrasound13 year follow-upUnited Kingdom Trial of Ovarian Cancer Screening200,000 women with 7 year follow-upLysophosphatidic Acid (LPA)Tumor marker which shows promise
67 LUNG CANCER: SHOULD WE SCREEN? Lung cancer is the number one cause of cancer mortality in both men and womenIf screening works for so many other cancers, why don’t we screen for lung cancer?
68 LUNG CANCER SCREENING: SYSTEMATIC REVIEW Does screening for lung cancer reduce lung cancer mortalityIncluded 7 trials of lung cancer screeningFrequent screening with chest x-rays was associated with an increase in mortalityRR 1.11 (95% C.I )No difference in chest X-ray plus cytology vs chest X-ray alone
69 ROLE OF CT No evidence that screening CT reduces mortality Lung Cancer Screening StudyNCI sponsoredHigh risk patientsCT or chest X-rayResults available soonAt this time, spiral CT should not be routinely used in clinical practice
70 USPSTF RECOMMENDATIONS Evidence is insufficientScreening 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.
71 PRIMARY PREVENTION OF LUNG CANCER Smoking cessationSmoking cessation!!!!!