CANCER SCREENING TESTS: EVALUATING THE EVIDENCE Leah Karliner, MD, MAS Department of Medicine UCSF

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CANCER SCREENING TESTS: EVALUATING THE EVIDENCE Leah Karliner, MD, MAS Department of Medicine UCSF Slide 2 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? Slide 3 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) Slide 4 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 Slide 5 EFFECTIVENESS OF TEST Tests should be simple, inexpensive and acceptable with a high sensitivity and specificity Number of false positives is acceptably low Slide 6 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 ? Slide 7 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 Slide 8 COLON CANCER Slide 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 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 Slide 10 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: Slide 11 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 Slide 12 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? Slide 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 ? Slide 14 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? Slide 15 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 Slide 16 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 Slide 17 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 Slide 18 SCREENING COLONOSCOPY? Would proximal lesions have been detected by FOBT? No assessment of morbidity and mortality Slide 19 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 Slide 20 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 Slide 21 NEWER TESTS Virtual Colonoscopy Fecal DNA Immunochemical FOBT (iFOBT) Slide 22 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 Slide 23 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? Slide 24 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 Slide 25 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 Slide 26 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 Slide 27 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 Slide 28 FECAL DNA TESTING Fecal DNAHemoccult 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% Specificity18.2%10.8% Slide 29 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 Slide 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 Slide 31 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 Slide 32 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 Slide 33 Breast Cancer Slide 34 BREAST CANCER SCREENING Disease has high prevalence: most commonly detected cancer in women in U.S. but lower prevelance for women in 40s 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 40s Slide 35 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 Slide 36 USPSTF Evidence insufficient for or against clinical breast examination alone Evidence insufficient for or against teaching or performing routine breast self-examination Slide 37 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