Presentation on theme: "CANCER SCREENING 2008: Updates and Evidence"— Presentation transcript:
1 CANCER SCREENING 2008: Updates and Evidence Leah Karliner, MD, MCRAssistant Professor of MedicineDivision of General Internal MedicineUCSF
2 OUTLINE Evaluating Screening Tests: general principles Colon cancer screening: which test is best?Prostate cancer screening: to screen or not to screen?Ovarian cancer: to screen high risk?
3 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
4 EFFECTIVENESS OF TESTTests should be simple, inexpensive and acceptable with a high sensitivity and specificityNumber of false positives is acceptably low
5 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?
6 SCREENING: OTHER CONSIDERATIONS Involving patients in the decisionWhat are the patient’s co-morbid conditions?Associated life expectancy, feasibility of treatment, effects of treatment on quality of life?What will you do with the results?
7 OUTLINE Colon cancer screening: which test is best? Evaluating Screening Tests: general principlesColon cancer screening: which test is best?Prostate cancer screening: to screen or not to screen?Ovarian cancer: to screen high risk?
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 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
11 Changing Incidence Colon cancer incidence rates decreased for White and Asian-Pacific Islander men and women in U.S. from ;were stable for African American, Latino and Native American men and women;Decrease in incidence largely due to screening and removing pre-cancerous polypsDisparities in incidence rate decline also likely due to disparities in screening ratesEspey et al. Annual report to the nation on the status of cancer, , featuring cancer in American Indians and Alaska Natives. Cancer. Oct 15, 2007.
12 AVAILABLE TESTSTests should be simple, inexpensive and acceptable with a high sensitivity and specificity: ????Commonly used tests:Fecal occult blood testSigmoidoscopyColonoscopyNewer tests:CT ColonographyFecal DNA testing
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 GFOBT FIT (fecal immunochemical test) Fair evidence for reducing mortalitySigmoidoscopy alone can miss proximal neoplasia – a positive test needs to be followed by colonoscopyGFOBTGood evidence for reducing mortalityTrials used 6 sample every 1-2 yearsPositive test needs to be followed by colonoscopyFIT (fecal immunochemical test)More sensitive than GFOBT; somewhat less specificSpecific to human globin; no dietary restrictions; less direct stool handling
15 FIT compared to GFOBT Screening Populations: 3 cohort studies FIT appear to be more sensitive in detecting CRC and large ≥ 1cm adenomas than Hemoccult II;FIT appear to be somewhat less specific (higher false positive rates) than Hemoccut IIFIT GFOBT(Hemoccult II)Sensitivity 57% - 82% 32% - 50%Specificity 95% – 96% 98%
16 IS COLONOSCOPY “BETTER?” Two observational studies of patients undergoing colonoscopyGoals:prevalence and location of colonic neoplasia in asymptomatic patients, andAssess 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 CT COLONOGRAPHYNon-invasive colon imaging method using thin section CTTest characteristics in large 2003 study – 3-D scanN=1,233 average risk individuals, single siteSensitivity94% for polyps ≥8 mm89% for polyps ≥6 mmSpecificity96% for polyps ≥10 mm80% for polyps ≥6 mmPickhardt, 2003
21 CT COLONOGRAPHY 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
22 CT COLONOGRAPHY Kim et al NEJM Oct 4, 2007 Single site; 3-D scans Comparison of diagnostic findings in two parallel large case series of CT colonography (3,120) and optical colonoscopy (3,163)If CTC patient had polyp ≥6mm then offered same day therapeutic colonoscopy (7.9%)Foundsimilar rates of advanced neoplasia (3.2% vs 3.4%);a few more invasive cancers found on CTC (n=14 vs 4)5 times as many polypectomies done in colonoscopy group
23 CT COLONOGRAPHY Cornett et al Am J Gastroenterology; June 2008 159 patients with positive result on screening CTCSubsequent optical colonoscopyCTC overall miss rate 18.9% (25/132); but only 6.2% (4/65) for polyps >9mmOf the 4 large polyps missed, 2 had poor CTC colonic distention, 3 were sessileFalse positive CTC referral (no polyp seen on optical colonoscopy) = 5%
24 CT COLONOGRAPHY Requires bowel prep and insufflation Patients do not necessarily prefer over colonoscopy (50-50 in Kim et al study)Test 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
25 FECAL DNA TESTINGDNA alterations in colorectal cancer can be detected in the stoolPotential advantagesNon-invasiveNo preparationDetection along entire length of the colon
26 FECAL DNA TESTINGEvaluated 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
27 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
28 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
29 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 testingFrequency of testing? Interval unclearCost$400 to $800 vs $3 to $40 for FOBT
30 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 minorities who have lower screening rates than whitesAny screening is better than no screening for reducing colorectal cancer mortality
31 SCREENING FOR HIGH RISK POPULATIONS Family History1st degree relative with colon CA or adenomatous polyp diagnosed at age <60, or 2 1st degree relatives with colon ca at any ageScreening colonoscopy age 40 or 10 years prior to earliest family diagnosisRepeat screen every 5 years1st degree relative colon CA/adenomatous polyp diagnosed at age ≥ 60, or two 2nd degree relative with colon ca at any ageScreened as average risk persons, starting age 40Familial Adenomatous Polyposis (FAP)Annual sigmoidoscopy starting age 10-12HNPCCColonoscopy q1-2 years beginning age or 10 years prior to earliest CA diagnosis in family
32 SCREENING FOR HIGH RISK POPULATIONS History of Adenomatous Polyps:surveillance based on pathology and number of adenomas at most recent prior colonoscopyAny adenoma w/high grade dysplasia or villous features, or multiple adenomas (≥3)Repeat colonoscopy in 3 years1-2 small (<1cm) tubular adenomas w/ low grade dysplasia onlyRepeat colonoscopy in 5 years-10 years
33 OUTLINE Prostate cancer screening: to screen or not to screen? Evaluating Screening Tests: general principlesColon cancer screening: which test is best?Prostate cancer screening: to screen or not to screen?Ovarian cancer: to screen high risk?
35 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: ???
37 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?Changes in treatment?Serendipitous effects of non-cancer-directed treatments?
38 IS TREATMENT OF EARLY DISEASE EFFECTIVE? Does treatment of early prostate cancer reduce morbidity and mortality?Radical prostatectomy vs. watchful waitingRCT of 695 menreduction in all-cause mortality, reduction in prostate cancer specific mortality, metastatic disease and local progressionAbsolute reduction in prostate ca specific mortality30 in prostatectomy group vs. 50 in watchful waiting group5-year follow-up 2% fewer deaths in prostatectomy group10 year follow-up 5.3% fewer deaths in prostatecomy groupBill-Axelson, NEJM 2005
39 RANDOMIZED CLINICAL TRIALS 46,000 men underwent DRE and PSA11 year follow-up23% of invited group and 6.5% of comparison group underwent screeningDecrease in prostate cancer mortality, but small numbers of deaths overall(10/7,348 screened vs. 74/14,231 unscreened: NNS=263)Labrie, Prostate 2004
40 ONGOING RCTs PLCO trial sponsored by the NCI : Intervention group (38,350) annual screens (PSA x 5 and DRE x 3) vs. usual care (38,355) in healthy men 55-74Enrolled ; following for 13 yearsEuropean Randomized Study of Screening for Prostate Cancer (ERSPC) – 8 countriesRandomizing close to 220,000 men to screening with PSA, DRE (and for positive tests transrectal ultrasound) vs usual careResults expected “between ”
41 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
42 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
43 PSA SCREENING: TEST ISSUES Levels of 4.0 ng/ml or less have typically been considered to be normalResults 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?Thompson IM et al, NEJM, 2004
44 Risk CalculationBased on date from the Prostate Cancer Prevention TrialCan use for men≥ age 50without a h/o prostate cancer,who have undergone PSA and DRE for screening within the past yearAssesses risk for biopsy positive prostate cancer and risk for high grade diseaseTakes into account: age, ethnicity, PSA and DRE results, history of negative biopsyThompson IM & Ankert DP; CMAJ June 19, 2007
45 PROSTATE CANCER SCREENING: RECOMMENDATIONS USPSTF: insufficient evidence to recommend for or against routine screening for prostate cancer using PSA or DRE in men <75PSA can detect early prostate cancer, but inconclusive evidence about whether early detection improves health outcomesDiscussion age (or age 45 for high risk: African American; 1st degree relative with h/o prostate ca)Recommends against screening in men >75ACP: individualize the decision to screen after discussion with patient about potential benefits and harmsACS: offer PSA and DRE annually starting at age 50, or age for high risk (African American; strong family history); men asking their doctor to decide should be screened
46 OUTLINE Ovarian cancer: to screen high risk? Evaluating Screening Tests: general principlesColon cancer screening: which test is best?Prostate cancer screening: to screen or not to screen?Ovarian cancer: to screen high risk?
48 OVARIAN CANCER: SHOULD WE SCREEN? Disease has high prevalence: 8th most common cause of CA in womenDisease has serious consequences: Usually diagnosed late (>60% stage III or IV): 5th cause of CA death in womenHigh risk group: family historyLifetime risk of ovarian cancerNo affected relatives 1.2%One affected relative 5%2 affected relatives 7%Hereditary syndrome 40%Treatment for pre-symptomatic disease is more effective than after symptoms develop: Ovarian cancer limited to the ovaries is associated with a much higher survival rateOverall 50 year survival: 35%Early stage survival: 90%Does screening decrease mortality: ???
50 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
51 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
52 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 (family history; BRCA1 and BRCA2 carriers; HNPCC), experts recommend:annual screening with recto-vaginal pelvic examination, CA-125 and trans-vaginal ultrasoundBRCA1 and BRCA2 carriers can consider prophylactic oophorectomy
53 FUTURE TRIALS PLCO Trial 74,000 women aged 55-74CA-125 at entry and annually for 5 yearsAnnual transvaginal ultrasound13 year follow-upNovel biomarkers are being investigatedUnited Kingdom Trial of Ovarian Cancer ScreeningRCT 200,000 women with 7 year follow-up to complete in 2010CA-125Ultrasound if elevated CA-125Surgical evaluation if ultrasound abnormal
54 SUMMARY OF RECOMMENDATIONS Ovarian cancer:maybe in high risk women only; otherwise await PLCO trialwomen at high risk should consider oral contraceptives (37% reduction in incidence)
55 SUMMARY OF RECOMMENDATIONS Colon cancer: any screening is better than no screening, use commonly available testsConsider CT colonography if your center has 3-D technology, experienced radiologists, willing patient population, easy access to follow-up colonoscopyAwait further research on fecal DNAProstate cancer: discuss pros and cons of PSA with eligible men age 50-70; await PLCO trialConsider using risk calculation in discussion of screening and in discussion of biopsy
56 WHERE TO GO FOR THE EVIDENCE U.S. Preventive Services Task ForceAmerican Cancer Society Guidelines for Early Detection of CancerNational Cancer InstituteTechnology Evaluation Center / Blue Cross - Blue Shield AssociationCalifornia Technology Assessment Forum / Blue Shield of California Foundation
59 LUNG CANCER: Principles of Screening Disease has high prevalence: In US in 2007, there will be an estimated 213,380 new cases of lung cancerDisease has serious consequences: – #1 cause of cancer mortality for both men & women in USDetectable preclinical phase – ???Treatment for pre-symptomatic disease is more effective than after symptoms develop – when detected in Stage I, improves 5-year survival from 15% to 40-70%Screening reduces cancer mortality:Neither x-rays nor sputum cytology screening reduces mortality, what about CT scans?High prevalence disease with serious consequences.Impact on health outcomes – reduces
60 LOW DOSE SPIRAL COMPUTERIZED TOMOGRAPHY (LDCT) Helical, volumetric studies (like conventional chest CT)Continuous data acquisitionScans entire lung in < 20 seconds (single breath hold)No IV contrastMore radiation exposure than CXR, less than conventional CT
61 Published English-language studies of LDCT screening for lung cancer 1 cross-sectional6 longitudinal cohort studies1 randomized control trial – feasibility pilot study comparing LDCT to CXR4 studies with high risk populations (smokers/former smokers)4 studies with mixed-risk populations (ranging from 46-86% smokers)
62 Published English-language studies of LDCT screening for lung cancer Overall the studies show that LDCT:can detect lung cancertends to detect early stage (Stage I) cancers (53%-93% of cancers found at baseline screen)The studies with high-risk only populations1.2-2% prevalence of lung cancer on LDCT0.6-2% incidence of lung cancer on follow-up/annual screensOne study compared mortality to historical controls and found no difference (Swenson et al)2.8/1000 person-years in CT screened population versus 2.0/1000 person years in Mayo Lung Project participants
63 LDCT screening for lung cancer Henschke et al Oct 2006 NEJM: results of the International- Early Lung Cancer Action Project(I-ELCAP)83% smokers; 12% second hand smoke; 5% occupational exposureN=31,567Extensive protocol for follow-up of abnormal scansFormal adjudication of all casesLongitudinal cohort studyBaseline screen by LDCTFollow-up screen for most participantsNo comparison group
64 LDCT screening for lung cancer Baseline Screen (n= 31,567)4,186 positive test405 (1.3%) lung cancersAnnual Screen (n=27,456)1,460 positive test74 (0.27%) lung cancers5 cases interim diagnoses of lung cancer412/484 (85%) Stage IEstimated 10-year lung cancer specific mortality (average follow-up 5 years)All cancers 20%For Stage I cancers 12%
65 Potential Biases Lead-time bias Screening identifies disease earlier, but does not increase actual survivalFalse increase in apparent survival time by diagnosing cases earlierFrom: Newman & Kohn, 2006
66 Potential Biases Length-time bias False increase in apparent survival time by diagnosing more indolent diseaseFrom: Newman & Kohn, 2006
67 Potential Biases Overdiagnosis bias (pseudo-disease bias) False increase in apparent survival time by misclassifying detected abnormality as disease which would never have presented clinicallyVolunteer biasPeople who participate in screening trials may be inherently different (healthier) than those who do not--healthier habits,--better access to health care, and--different education and income levels
68 LUNG CANCER SCREENING RECOMMENDATIONS The U.S. Preventive Services Task Force (USPSTF)evidence is insufficient to recommend for or against screening asymptomatic persons for lung cancer with either low dose computerized tomography (LDCT), chest x-ray (CXR), sputum cytology, or a combination of these tests.
69 LDCT screening for lung cancer: potential harm Up to 93% of the non-calcified nodules >4mm found in the studies have been false-positivesAll require follow-up: conventional CT to surgical biopsyAll follow-up carries some risk: increased radiation exposure to bleeding/infection/deathRisks of higher radiation exposure due to LDCT at regular intervals are unknown
70 LDCT screening for lung cancer LDCT promising modality to screen for lung cancer and find it earlyStudies to date have not been designed to account for potential biasesDo not yet have convincing data that LDCT screening for lung cancer leads to decreased mortality.Ongoing large NCI RCT: National Lung Screening TrialResults anticipated in 2009
71 Smoking Cessation!Lung cancer incidence rates have stabilized in women and are declining in men in the U.S.True across race-ethnicitiesEspey et al. Annual report to the nation on the status of cancer, , featuring cancer in American Indians and Alaska Natives. Cancer. Oct 15, 2007.