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? Adults > age 50, National Data from the Center for Disease Control: FOBT in past 2 years 27% – White – 28% – Black – 24% – Latino – 17% – Other – 20% – Multiracial – 27% Ever had a sig or colonoscopy 53% – White – 54% – Black – 49% – Latino – 39% – Other – 41% – Multiracial – 54% »BRFSS, 2004 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 51.6% 12.9% cancer Sensitivity for invasive 40.8% 14.1% cancer/adenoma with high grade dysplasia Sensitivity for 18.2% 10.8% advanced neoplasia 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 UnitedStates 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 9% 99% Exam 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 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!!!!!
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