1. Cancer Screening in Women… Update Jodi Friedman, MD David Geffen School of Medicine at UCLA

2. Principles of Prevention FIRST DO NO HARM! –asymptomatic, by definition –predominantly healthy population –evidence-based medicine

3. Principles of Prevention Where do Preventive Services recommendations come from?  USPSTF, CTFPHC extensive review of literature rigorous requirements of proof of efficacy  Various subspecialty organizations

4. What the USPSTF Grades Mean and Suggestions for Practice Ann Intern Med 2009;151:716-726 ©2009 by American College of Physicians

5. Principles of Screening Appropriateness of a screening test the d isease the test the population

6. Potential Adverse Effects of Screening –physical complications of the test –consequences of false positives anxiety complications from work-up labeling/insurability –over treating insignificant abnormalities –financial costs

7. Screening  Cervical Cancer  Breast Cancer  Colorectal Cancer  Lung Cancer  Ovarian Cancer

8. Cervical Cancer Screening  Since early 1970’s, mortality has decreased 74%  Largely attributable to screening with the Pap smear  Majority of disease now occurs in women with inadequate screening

9. Cervical Cancer  Progression: HPV infxn  high grade lesion  invasive disease  On average, initial HPV infxn to invasive cancer takes 10-20 years  Lifetime risk of acquiring at least 1 HPV infxn estimated as high as > 90%  Majority of these infections are transient

10. Cervical Cancer  Over 100 HPV types, 13 are associated with cervical intraepithelial neoplasia  Most HPV infxns never progress beyond low grade disease (CIN 1) Women 15-25 years of age ~ 80% of HPV infections are transient  80 -90% of low grade cervical abnormalities will regress spontaneously

11. HPV Testing  2 commercially available assays for the “oncogenic” HPV types  These 13 types account for ~ 90% of HPV types associated with HSIL and cervical cancer

12. HPV Testing  Most established role of testing is to “triage” ASCUS results HPV + : double the probability of HSIL (15%) HPV - : less than 1% chance of HSIL  Role in primary screening less well- established

13. Current Recommendations  USPSTF (2003) begin w/in 3 yrs of first sexual activity or 21 yo, whichever first after 2-3 normal annual Paps, screen every 3 yrs in women who have had adequate screening (3 Paps in preceding 10 years) stop at 65 no screening if hysterectomy for benign causes

14. Current Recommendations  ACS (2009) begin w/in 3 yrs of first sexual activity or 21 yo, whichever first annual Paps until age 30 (or q 2 yrs with liquid- based cytology) after 3 normal annual Paps may begin every 2-3 yr screening may opt for HPV and Pap testing every 3 years annual screening if HIV, DES exposure, or significant immunosuppression if adequate screening, stop at 70

15. Current Recommendations  ACOG (11/2009) begin at age 21 every 2 years Paps until age 30 Age 30 and older, after 3 consecutive normal Paps should be screened once every 3 years annual screening if HIV, DES exposure, or significant immunosuppression may stop at 65 – 70 if 3 negative cytology results in a row No abnormal test in the past 10 years

16. Breast Cancer  Most prevalent cancer in women  Second leading cause of cancer deaths  Average lifetime risk of developing breast cancer is 1 in 8 40’s: 1 in 69 50’s: 1 in 38 60’s: 1 in 27

17. Breast Cancer Screening  Breast Self Exam  Clinical Breast Exam  Mammography  MRI

18. Breast Self Exam (BSE)  2 RCT’s, 1 large non-RCT  F/U 5-13 yrs  No reductions in mortality  No significant improvement in # or stage of cancers detected  2-fold increase in biopsies (benign) in BSE grps

19. Clinical Breast Exam  No direct evidence comparing CBE alone to no screening  Reductions in mortality observed when used with mammography  Reductions in mortality in mammography trials alone similar to that using CBE with mammography

20. Mammography  Positive predictive value Aged 40-49: 1-4% Aged 50-59: 4-9% Aged 60-69: 10-19% 70 and over: 18-20%

21. Mammography  9 RCTs: 0-32% mortality reduction  Meta-analysis shows: 50 yo and over: RR = 0.78 (CI,.70-.87) 22% reduction in breast cancer mortality 40-49 yo: RR=0.85 (CI,.77-.97) 15% reduction in breast cancer mortality  Only 1 study included women up to 74 yo No statistically significant benefit in women 70-74 but numbers small

22. Pooled relative risk for breast cancer mortality from mammography screening trials compared with control for women aged 39 to 49 years.CNBSS-1 = Canadian National Breast Screening Study-1; CrI = credible interval; HIP = Health Insurance Plan of Greater New York.* Swedish Two-County trial. Nelson H D et al. Ann Intern Med 2009;151:727-737 ©2009 by American College of Physicians

23. NNI to Prevent 1 Breast Cancer Death  39 – 49 yo 1904  50 – 59 yo1339  60 – 69 yo377

24. Frequency of Mammographic Screening  Trials range from 12-33 month intervals  Decision analysis study (USPSTF) Biennial screening produced 81% of the benefit of annual screening Half the number of false positives and unnecessary biopsies

25. MRI  14 prospective trials in hi-risk women (20- 80% lifetime risk)  No studies have demonstrated MRI reduces risk of death from breast cancer  Sensitivity 71-100% vs. 16-40% with mammo or utz  Specificity 81 – 97% vs. 93 -99% with mammo

26. USPSTF Breast Cancer Screening Recommendations (2009)  The USPSTF recommends biennial screening mammography for women aged 50 to 74 years. Grade: B recommendation.B recommendation  The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient's values regarding specific benefits and harms. Grade: C recommendation.C recommendation

27. USPSTF Breast Cancer Screening Recommendations (2009)  The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. Grade: I Statement.I Statement  The USPSTF recommends against teaching breast self-examination (BSE). Grade: D recommendation.D recommendation

28. USPSTF Breast Cancer Screening Recommendations (2009)  The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of clinical breast examination (CBE) beyond screening mammography in women 40 years or older. Grade: I Statement.I Statement  The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of either digital mammography or magnetic resonance imaging (MRI) instead of film mammography as screening modalities for breast cancer. Grade: I Statement.I Statement

29. Other Groups’ Recommendations  AAFP (2009) –  AAFP (2009) – all recommendations in agreement with new USPSTF guidelines  ACS Begin annual mammography at 40 CBE q 3 yr 20-40, yearly after 40 BSE option, beginning at 20

30. Screening Recommendations: MRI  ACS now recommends annual MRI (in addition to mammo) for women with lifetime risk estimate at least 20-25%  Also recommended for women with h/o chest irradiation for HD  ? When to begin  ? Personal h/o breast CA, LCIS, ADH

31. ASCO Screening Recommendations for High-Risk Women  Screening breast MRI appears to be more sensitive than mammography in high-risk women  BRCA 1/2 carriers should be screened with annual MRI, mammography and possibly ultrasound  The decision to use breast MRI in high-risk patients should be made on an individual basis

32. Colorectal Cancer (CRC)  Third leading cause of cancer deaths  Lifetime incidence is 5%, lifetime mortality is 2.5% 1 first-degree relative, RR=1.7 2 first-degree relatives, RR=2.7  Highest risk - familial polyposis syndromes and long-standing UC

33. Fecal occult blood testing (FOBT)  4 RCTs – all show mortality benefit Over 46,000 subjects ages 50-80 annual FOBT v. no screening 33% reduction in CRC mortality Biennial FOBT ages 45-74 15% - 18% reduction in mortality

34. Flexible Sigmoidoscopy  2 large case-control studies - 60% reduction in risk of death from CRC  1 RCT – showed increased detection rate of adv neoplasms and cancers compared to FOBT  Detects approx 50% of CRCs and adenomatous polyps up to 3% of pts screened will have advanced neoplasm that sigmoidoscopy will miss

35. Colonoscopy  No RCTs  Identification and removal of adenomas is the central element of reducing CRC incidence and mortality  One case-control study showed odds ratio for CRC mortality was 0.43  All other screening strategies include colonoscopy

36. Screening Recommendations (2008)  The USPSTF recommends screening for colorectal cancer (CRC) using fecal occult blood testing, sigmoidoscopy, or colonoscopy, in adults, beginning at age 50 years and continuing until age 75 years. The risks and benefits of these screening methods vary. Grade: A RecommendationA Recommendation  The USPSTF recommends against routine screening for colorectal cancer in adults age 76 to 85 years. There may be considerations that support colorectal cancer screening in an individual patient. Grade: C RecommendationC Recommendation

37. Screening Recommendations (2008)  The USPSTF recommends against screening for colorectal cancer in adults older than age 85 years. Grade: D RecommendationD Recommendation  The USPSTF concludes that the evidence is insufficient to assess the benefits and harms of computed tomographic colonography and fecal DNA testing as screening modalities for colorectal cancer. Grade: I Statement.I Statement

38. CRC Screening  Most groups agree that any strategy patient agrees to should be offered: annual FOBT sigmoidoscopy q 5 ys annual FOBT + flex sig q 5 yrs colonoscopy q 10 yrs  CRC screening is cost-effective at less than $30K per year saved regardless of strategy

39. Lung Cancer  Leading cause of cancer-related death among women and men in the US.  Average 5-yr survival rates < 15% 70% for stage I < 5% for stage IV  USPSTF 1996 recommended against screening based on RCT data of CXR and sputum cytology screening

40. CXR +/- Sputum Cytology  6 RCTs (men only) varying screening intervals no benefit to those screened all studies limited by some level of screening in control groups

41. Mortality in randomized, controlled trials of lung cancer screening with chest radiography with or without sputum cytologic examination. Humphrey L L et al. Ann Intern Med 2004;140:740-753 ©2004 by American College of Physicians

42. Low Dose CT (LDCT)  Sensitivity 4 times greater than CXR  8 cohort studies using LDCT lung cancer diagnosed at earlier stage high rate of FPs cannot evaluate mortality outcomes without control groups

43. Low Dose CT (LDCT)  RCTs National Lung Screening Trial (NCI) LDCT vs. CXR NELSON Trial (Dutch study) LDCT vs. no screening

44. National Lung Screening Trial  RCT >53,000 current or former heavy smokers Age 55 – 74 3 annual screenings with LDCT vs. CXR 90% statistical power to detect 20% mortality reduction

45. National Lung Screening Trial  On October 28, 2010 the DSMB stopped the trial  A 20% reduction in lung cancer deaths was found in the LDCT screened group  6.9% reduction in all-cause mortality (secondary endpoint)  Await full publication of the results

46. USPSTF May, 2004  I Recommendation  fair evidence that screening with LDCT, CXR, or sputum cytology can detect lung cancer at an earlier stage than lung cancer would be detected in an unscreened population  poor evidence that any screening strategy for lung cancer decreases mortality  because of the invasive nature of diagnostic testing and the possibility of a high number of false-positive tests in certain populations, there is potential for significant harms from screening

47. Ovarian Cancer  Fifth leading cause of cancer-related death in women  Low incidence in general population overall incidence is 17 per 100,000 in women over 50, 44 per 100,000  for average risk women, an abnormal screening test will have a 1-4% positive predictive value

48. Ovarian Cancer Screening  Screening is Problematic Low PPV (low prevalence) High mortality No well-defined precursor lesion FPs lead to serious morbidity

49. Ovarian Cancer Screening  CA-125  Transvaginal Ultrasound  16 Fair-poor quality cohort studies: Sensitivities 80-100% False positives.6-2.5%

50. Ovarian Cancer Screening  1 RCT of multimodal screening non-statistically signif improvement in stage 1 detection (50% vs. 5%)  2 large cohort studies of UTZ 59-65% diagnosed in stage 1  No evidence that detecting early stage cancer through screening decreases mortality  3 RCTs in progress to evaluate mortality

51. Ovarian Cancer Screening  USPSTF (2004): D recommendation  There is no existing evidence that any screening test, including CA-125, ultrasound, or pelvic examination, reduces mortality from ovarian cancer  existing evidence that screening can detect early-stage ovarian cancer is insufficient to indicate that this earlier diagnosis will reduce mortality  Because of the low prevalence of ovarian cancer and the invasive nature of diagnostic testing after a positive screening test, there is fair evidence that screening could likely lead to important harms

52. Ovarian Cancer Screening  Routine screening NOT recommended by any professional organization  ACS hi-risk women may benefit from screening with CA-125 and UTZ  ACOG stay vigilant for early sxs and w/u when present

53. Bibliography  Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423–8.  Mark E. Sherman, et.al. Baseline Cytology, Human Papillomavirus Testing, and Risk for Cervical Neoplasia: A 10-Year Cohort Analysis JNCI Journal of the National Cancer Institute 2003 95(1):46-52  Screening for Cervical Cancer, Topic Page. January 2003. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspscerv.htm

54. Bibliography  HD Nelson et al. Screening for Breast Cancer: An Update for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151:727  USPSTF. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;151:716  Screening for Breast Cancer, Topic Page. November 2009. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspsbrca.htm

55. Bibliography  Screening for Colorectal Cancer, Topic Page. March 2009. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspscolo.ht m

56. Bibliography  The International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763-1771  Computed Tomography Screening and Lung Cancer Outcomes Peter B. Bach; James R. Jett; Ugo Pastorino; Melvyn S. Tockman; Stephen J. Swensen; Colin B. Begg JAMA. 2007;297:953-961.

57. Bibliography  Lung Cancer Screening, Topic Page. May 2004. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspslung.htm  Screening for Ovarian Cancer, Topic Page. May 2004. U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf/uspsovar.htm