CANCER SCREENING 2008: Updates and Evidence

1. CANCER SCREENING 2008: Updates and Evidence Leah Karliner, MD, MCR Assistant Professor of Medicine Division of General Internal Medicine UCSF

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 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

4. EFFECTIVENESS OF TEST • Tests should be simple, inexpensive and acceptable with a high sensitivity and specificity • Number of false positives is acceptably low

5. 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?

6. SCREENING:OTHER CONSIDERATIONS • Involving patients in the decision • What 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 • 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?

8. COLON CANCER

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

10. 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

11. Changing Incidence • Colon cancer incidence rates • decreased for White and Asian-Pacific Islander men and women in U.S. from 1995-2004; • were stable for African American, Latino and Native American men and women; • Decrease in incidence largely due to screening and removing pre-cancerous polyps • Disparities in incidence rate decline also likely due to disparities in screening rates • Espey et al. Annual report to the nation on the status of cancer, 1975-2004, featuring cancer in American Indians and Alaska Natives. Cancer. Oct 15, 2007.

12. AVAILABLE TESTS • Tests should be simple, inexpensive and acceptable with a high sensitivity and specificity: ???? • Commonly used tests: • Fecal occult blood test • Sigmoidoscopy • Colonoscopy • Newer tests: • CT Colonography • Fecal DNA testing

13. WHICH TEST? • Are the tests equally safe? • Are the tests equally costly? • Are the tests equallyspecific? • Are the tests equallysensitive? • Is wide-spread use of the test feasible in practice?

14. TEST ISSUES • Sigmoidoscopy • Fair evidence for reducing mortality • Sigmoidoscopy alone can miss proximal neoplasia – a positive test needs to be followed by colonoscopy • GFOBT • Good evidence for reducing mortality • Trials used 6 sample every 1-2 years • Positive test needs to be followed by colonoscopy • FIT (fecal immunochemical test) • More sensitive than GFOBT; somewhat less specific • Specific 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 II FIT GFOBT (Hemoccult II) Sensitivity 57% - 82% 32% - 50% Specificity 95% – 96% 98%

16. IS COLONOSCOPY “BETTER?” • Two observational studies of patients undergoing colonoscopy • Goals: • prevalence and location of colonic neoplasia in asymptomatic patients, and • Assess risk of proximal advanced neoplasia in patients with or without distal neoplasia • Did NOT assess morbidity and mortality

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

18. SCREENING COLONOSCOPY? • Would proximal lesions have been detected by FOBT? • No assessment of morbidity and mortality

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

20. CT COLONOGRAPHY • Non-invasive colon imaging method using thin section CT • Test characteristics in large 2003 study – 3-D scan • N=1,233 average risk individuals, single site • Sensitivity • 94% for polyps ≥8 mm • 89% for polyps ≥6 mm • Specificity • 96% for polyps ≥10 mm • 80% for polyps ≥6 mm • Pickhardt, 2003

21. CT COLONOGRAPHY • 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

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%) • Found • similar 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 CTC • Subsequent optical colonoscopy • CTC overall miss rate 18.9% (25/132); but only 6.2% (4/65) for polyps >9mm • Of the 4 large polyps missed, 2 had poor CTC colonic distention, 3 were sessile • False 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 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

25. 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

26. FECAL DNA TESTING • 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

27. FECAL DNA TESTING

28. 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

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 testing • Frequency of testing? Interval unclear • Cost • $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 screened • If 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 whites • Any screening is better than no screening for reducing colorectal cancer mortality

31. SCREENING FOR HIGH RISK POPULATIONS Family History • 1st degree relative with colon CA or adenomatous polyp diagnosed at age <60, or 2 1st degree relatives with colon ca at any age • Screening colonoscopy age 40 or 10 years prior to earliest family diagnosis • Repeat screen every 5 years • 1st degree relative colon CA/adenomatous polyp diagnosed at age ≥ 60, or two 2nd degree relative with colon ca at any age • Screened as average risk persons, starting age 40 • Familial Adenomatous Polyposis (FAP) • Annual sigmoidoscopy starting age 10-12 • HNPCC • Colonoscopy q1-2 years beginning age 20-25 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 colonoscopy • Any adenoma w/high grade dysplasia or villous features, or multiple adenomas (≥3) • Repeat colonoscopy in 3 years • 1-2 small (<1cm) tubular adenomas w/ low grade dysplasia only • Repeat colonoscopy in 5 years-10 years

33. 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?

34. Prostate Cancer

35. 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: ???

37. 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? • 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 waiting • RCT of 695 men • reduction in all-cause mortality, reduction in prostate cancer specific mortality, metastatic disease and local progression • Absolute reduction in prostate ca specific mortality 30 in prostatectomy group vs. 50 in watchful waiting group • 5-year follow-up 2% fewer deaths in prostatectomy group • 10 year follow-up 5.3% fewer deaths in prostatecomy group • Bill-Axelson, NEJM 2005

39. RANDOMIZED CLINICAL TRIALS • 46,000 men underwent DRE and PSA • 11 year follow-up • 23% of invited group and 6.5% of comparison group underwent screening • Decrease 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 55-74 • Enrolled 1992-2001; following for 13 years • European Randomized Study of Screening for Prostate Cancer (ERSPC) – 8 countries • Randomizing close to 220,000 men to screening with PSA, DRE (and for positive tests transrectal ultrasound) vs usual care • Results expected “between 2008-2010”

41. 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

42. 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

43. PSA SCREENING: TEST ISSUES • Levels of 4.0 ng/ml or less have typically been considered to be normal • 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? • Thompson IM et al, NEJM, 2004

44. Risk Calculation • Based on date from the Prostate Cancer Prevention Trial • Can use for men • ≥ age 50 • without a h/o prostate cancer, • who have undergone PSA and DRE for screening within the past year • Assesses risk for biopsy positive prostate cancer and risk for high grade disease • Takes into account: age, ethnicity, PSA and DRE results, history of negative biopsy Thompson IM & Ankert DP; CMAJ June 19, 2007 www.compass.fhcrc.org/edrnnci/bin/calculator/main.asp

45. PROSTATE CANCER SCREENING: RECOMMENDATIONS • USPSTF: insufficient evidence to recommend for or against routine screening for prostate cancer using PSA or DRE in men <75 • PSA can detect early prostate cancer, but inconclusive evidence about whether early detection improves health outcomes • Discussion age 50-75 (or age 45 for high risk: African American; 1st degree relative with h/o prostate ca) Recommends against screening in men >75 • ACP: individualize the decision to screen after discussion with patient about potential benefits and harms • ACS: offer PSA and DRE annually starting at age 50, or age 40-45 for high risk (African American; strong family history); men asking their doctor to decide should be screened

46. 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?

47. OVARIAN CANCER

48. OVARIAN CANCER: SHOULD WE SCREEN? • Disease has high prevalence: 8th most common cause of CA in women • Disease has serious consequences: Usually diagnosed late (>60% stage III or IV): 5th cause of CA death in women • High risk group: family history Lifetime risk of ovarian cancer • No 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 rate • Overall 50 year survival: 35% • Early stage survival: 90% • Does screening decrease mortality: ???

49. OVARIAN CANCER: SCREENING TECHNIQUES • Serum CA-125 assay • Trans-vaginal ultrasound • Serum CA-125 plus ultrasound

50. 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