Cancer screening

1. Cancer screening Bindu Shah Senior Talk 2008

2. Case A 52 y.o woman presents to her primary care physician�s office for a routine visit. She has not been seen in 4 years and has no significant past medical history. She has no complaints at this time but would like to know if there are any tests she needs. What would you recommend at this time?

3. Objectives After attending this lecture, participants will be able to� Define a screening test and its uses/pitfalls in ambulatory practice Describe the United States Preventive Services Task Force and interpret its levels of�recommendations Discuss the current USPSTF recommendations regarding 5 common cancer screenings Discuss the cost-effectiveness data of common cancer screenings and their ultimate impact on cancer prevention Describe alternative recommendations by various agencies

4. What is the USPSTF? United States Preventive Services Task Force An independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services. Sponsored since 1998 by the Agency for Healthcare Research and Quality (AHRQ)

5. USPSTF

6. Screening tests A test for a particular disease given to patients who have no symptoms Should be an important, morbid health condition Generally cheap Highly sensitive Not too demanding or risky There should be a treatment Sensitive: identify almost all of the people who have the condition tested for) Sensitive: identify almost all of the people who have the condition tested for)

7. Screening tests Universal screening Screening all individuals of a certain category (e.g. PKU screening in kids) Case finding Screening a small group of individuals based on the presence of risk factors (e.g cancer clusters, family members diagnosed with hereditary disease)

8. Screening tests Adverse effects Stress and anxiety caused by false positive results Unnecessary radiation/chemical exposure and test discomfort Prolonged knowledge of a disease with no treatment False sense of security over false negative results Overuse of medical resources Unnecessary secondary investigations for false positives Unnecessary secondary investigations for false positives

9. Screening tests Biases Lead time bias Length time bias Selection bias Overdiagnosis bias Avoid bias by using Randomized Control Trials (RCTs) Lead time bias: Diagnosing the disease earlier however having the same mortality as without screening Length time bias: Slow growing tumors have the better prognoses than fast growing tumors, and screening tests more likely to detect these tumors that are more treatable anyway Selection bias: -If patients with higher risk of disease are more likely to be screened, screening test results will look worse than they are Overdiagnosis bias: Test may diagnose abnormalities that would never cause a problem in a person�s lifetime (i.e. prostate cancer) Lead time bias: Diagnosing the disease earlier however having the same mortality as without screening Length time bias: Slow growing tumors have the better prognoses than fast growing tumors, and screening tests more likely to detect these tumors that are more treatable anyway Selection bias: -If patients with higher risk of disease are more likely to be screened, screening test results will look worse than they are Overdiagnosis bias: Test may diagnose abnormalities that would never cause a problem in a person�s lifetime (i.e. prostate cancer)

10. Commonly screened diagnoses Cancer (Breast, lung, colorectal, prostate, pancreatic, cervical, ovarian, skin, testicular, thyroid) Cardiovascular (AAA, Blood pressure, Lipid disorders, carotid artery stenosis, PAD) Infectious disease (HIV, Hep B/C, STDs, Tuberculosis) Injury and violence (domestic violence, Youth violence/gang activity, seatbelt use) Mental health/substance abuse (Etoh, illicit drugs, tobacco, depression, suicide risk) Endocrine/Metabolism (Diabetes, IDA, obesity, physical activity) MSK �osteoporosis OB/Gyn (Pre-eclampsia, Rh incompatibility, neural tube defects, asymptomatic bacteruria, Down�s syndrome) Pediatrics (PKU, sickle cell disease, visual impairment, lead intoxication, hearing loss, dental caries)

11. Case A 52 year old is concerned about her risk of ovarian and breast cancer. She has 2 children that were born vaginally after uneventful pregnancies. Menarche was at age 15 and she entered menopause at age 50. Her mother was diagnosed with breast cancer at age 62 and her paternal grandmother was diagnosed with breast cancer at age 70. Her mother�s two sisters are both without cancer. At this time, the appropriate management is to A) advise her to have a bilateral salpingo-oophorectomy B) advise her to have genetic testing C) measure CA-125 levels D) order periodic transvaginal ultrasounds E) recommend annual or biannual mammography

12. Breast cancer Epidemiology Most common cancer in women 180,000 new cases projected for 2008 Risk factors: prior breast cancer, age, early menarche, delayed childbearing, HRT) Second to lung cancer in cause of cancer death Prevalence: Caucasians >> African Americans Mortality: African Americans >> Caucasians Breast cancer in men (~2,000 cases/year with 400 deaths/year) (almost 1/3 of cancer diagnoses in women) Family history: in first degree relative (almost 1/3 of cancer diagnoses in women) Family history: in first degree relative

13. Breast cancer

14. Breast cancer USPSTF recommendations Screening mammography with or without clinical breast exam (CBE) every 1-2 years starting at age 40 Insufficient evidence for or against CBE alone Insufficient evidence for or against teaching or performing routine self breast exams Evidence strongest for women ages 50-69, weaker for those aged <50 Evidence strongest for women ages 50-69, weaker for those aged <50

15. Breast cancer

16. Breast cancer Cost effectiveness: Women aged 40-49: $105,000 per year of life saved10 Women aged 50-69: $21,400 per year of life saved Results: Reduction in total mortality as high as 65% Despite these reductions, data from 2000?2005 show decreasing rates of mammography16

19. Breast Cancer Other recommendations: AMA, ACOG, ACR, ACS: mammography and CBE Ages 40-49: Every 1-2 years Age 50 and above: Annually AAFP, ACPM: mammography Age 40: high risk women Age 50: all women ACR: (American College of Radiology), ACS: (American cancer society) AAFP: American Academy of Family Physicians ACPM: American College of Preventive Medicine ACR: (American College of Radiology), ACS: (American cancer society) AAFP: American Academy of Family Physicians ACPM: American College of Preventive Medicine

20. Case A 51 year old woman comes to the ED with fever, chills, and LLQ pain. CT scan diagnoses diverticulitis and the patient is treated with ciprofloxacin and metronidazole. She has no significant past medical history, has regular menstrual periods, and has smoked 1 ppd x 15 years. Since she has no regular physician, she is scheduled to follow-up for a new patient evaluation and monitoring of her diverticulitis in 3 days. During her new patient evaluation she should be scheduled for: A) a chest xray B) a mammogram every year for the first 2 years, then every 5 years C) a Pap smear D) serum FSH/LH levels E) yearly electrocardiogram

21. Cervical cancer Epidemiology 11,000 cases diagnosed annually 4,000 deaths Found in women mostly age 20-50 Hispanic>>Black>>Caucasian Overall 5-year survival rate 72% Risk factors: HPV, Smoking, STD�s 10th leading cause of cancer death 20% of diagnoses are women >6520% of diagnoses are women >65

22. Cervical cancer USPSTF recommendations Recommends screening in women who are sexually active and have a cervix Recommends against screening women > 65 years if they have negative screening history and no high risk behavior Recommends against screening women who have had hysterectomy for benign disease Insufficient evidence for new technologies to screen for cervical cancer Insufficient evidence for HPV testing as a primary screen for cervical cancer Recommends Screening: Start within 3 years of first sexual activity or turning age 21 Screen at least every three years after 3 normal exams New technologies: Liquid based cytology, computerized rescreening, algorithm based screening Recommends Screening: Start within 3 years of first sexual activity or turning age 21 Screen at least every three years after 3 normal exams New technologies: Liquid based cytology, computerized rescreening, algorithm based screening

23. Cervical cancer Screening tests Pap smear: 60-80% sensitivity, increases with repetitive screens HPV screening: Sensitivity 66%, Specificity 91% Combination HPV + Pap-sensitivity approaches 100%6 Mayrand trial: ~10,000 women screening with HPV vs PAP. Sensitivity of HPV 95.%, sensitivity of pap 55%. Together approached 100%. Part of the Canadian Cervical Cancer screening trial However, this trial was sponsered by Merck, who came up with the gardasil vaccine!!!!!Mayrand trial: ~10,000 women screening with HPV vs PAP. Sensitivity of HPV 95.%, sensitivity of pap 55%. Together approached 100%. Part of the Canadian Cervical Cancer screening trial However, this trial was sponsered by Merck, who came up with the gardasil vaccine!!!!!

24. Cervical cancer Cost-effectiveness: $50,000/year of life saved (with screening every 3 years) Results: Reduced cervical cancer rates by 60-90% 92% survival rate for early disease 13% survival rate for late disease

25. Cervical cancer Other recommendations: ACS: onset-first sexual activity to age 21 annual screening until age 30, then every 3 years ACOG, ACPM, AAFP, AMA, AAP: onset-age 18 discontinue after 65-70 with 3 negative screens

26. Case A 43 yo man comes to the office requesting �that little blue pill they show on tv.� Upon review of his medical records, you see he has not been in the office for more than 2 years. He has a history of HTN and osteoarthritis. Family history is positive for colon cancer in his father at age 53 and HTN in his mother. He smokes 1ppd for more than 20 years. He denies any chest pain, shortness of breath, bowel or bladder changes. Blood pressure measured today is 132/87, blood sugar is 103. What is the most appropriate current intervention? A) prescribe viagra and follow-up in 2 months B) Refer for screening CXR for possible lung cancer C) Check a Hemoglobin A1C D) Refer for screening colonoscopy E) Order renal artery scan for HTN

27. Colorectal cancer Epidemiology: 3rd most common cause of cancer in U.S. 3rd most common cause of cancer death 150,000 new cases/year, with 50,000 deaths Risk factors: family history of colorectal cancer (FAP, HNPCC) ulcerative colitis h/o adenomatous polyps Obesity low fiber diet At age 50, 5% chance developing colorectal cancer and 2.5% of dying from it, with average 13 years life lost At age 50, 5% chance developing colorectal cancer and 2.5% of dying from it, with average 13 years life lost

28. Colorectal cancer USPSTF recommendations Strongly recommends screening for men and women age 50 or older Colonoscopy every 10 years FOBT annually + flexible sigmoidoscopy every 5 years No further screening after age 75 if negative screens since age 50 Testing 10 years before first diagnosed family member

29. Colorectal Cancer Sigmoidoscopy: 77% of colorectal cancer cases diagnosed at stage 1/2Sigmoidoscopy: 77% of colorectal cancer cases diagnosed at stage 1/2

30. Colorectal Cancer FOBT screening trials:3 Minnesota trial 13-year follow-up 18 year follow-up Nottingham Funen trial Minnesota trial: 46,551 patients, randomized to annual, biennial or control group: 13 year : 33% mortality reduction annually, 6% biennial mortality reduction 18 year: 33% mortality reduction annually, 21% biennial mortality reduction, especially in Stage D cancer Nottingham trial: 152, 850 participants�15% mortality reduction with biennial screening (short f/u and low compliance with screening = limitations) Funen trial: 61,933 participants, biennial screening, 18% mortality reduction (follow up 10 years, 56% compliance)Minnesota trial: 46,551 patients, randomized to annual, biennial or control group: 13 year : 33% mortality reduction annually, 6% biennial mortality reduction 18 year: 33% mortality reduction annually, 21% biennial mortality reduction, especially in Stage D cancer Nottingham trial: 152, 850 participants�15% mortality reduction with biennial screening (short f/u and low compliance with screening = limitations) Funen trial: 61,933 participants, biennial screening, 18% mortality reduction (follow up 10 years, 56% compliance)

31. Colorectal cancer Cost-effectiveness: $30,000/year of life saved Varied studies which strategy is most cost-effective Results: Cure rate with early screening approaches 90% 271 years of life gained for every 1000 screens (colonoscopy) 199 years life gained for every 1000 screens (flex sig)

32. Colorectal cancer Other recommendations ACS, U.S. Multi-Task force on Colorectal Cancer, ACR: Screening at age 50 (annual FOBT vs. flex-sig/barium enema/CT colonography every 5 years vs. colonoscopy every 10 years ACOG: colonoscopy as preferred source

33. Case With respect to prostate cancer, which of the following is true? A) A serum PSA of 4ng/dl is diagnostic of prostate cancer B) Prostate cancer is the most common non-skin cancer in men C) African-Americans and Caucasians have the same incidence of prostate cancer D) Prostate is the most common cause of cancer death in men E) The American Cancer Society recommends all men begin prostate cancer screening at age 30

34. Prostate cancer Epidemiology: 1 in 6 men will be diagnosed 218,000 cases/year, with ~23,000 deaths annually Median age of death ~80 years African Americans >>Caucasians in terms of incidence and mortality Overdiagnosis as high as 45% by PSA screen

35. Prostate Cancer USPSTF recommendations Insufficient evidence to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 Recommends against screening for prostate cancer in men > 75

36. Prostate Cancer Screening tests: PSA Sensitivity: 40-60% vs 91% (aggressive cases) Can be falsely elevated by BPH/prostatitis 75% of men with PSA 4-10 do not have cancer DRE Largely unknown statistics with and without PSA

37. Prostate Cancer Cost-effectiveness: Limited studies May have increased benefit if PSA checked every 2 years rather than 1 year2 Screening q 2 years: (may reduce number of screens by 50% while retaining 93% of years of life saved (PSA >4)Screening q 2 years: (may reduce number of screens by 50% while retaining 93% of years of life saved (PSA >4)

38. Prostate cancer Other recommendations: AAFP, ACOP, ACPM, AMA: recommend screening men > age 50 with life expectancy of at least 10 years ACS, American Urological Association: Recommend annual PSA/DRE for men > age 50

39. Case A 56 yo woman with a history of smoking 1ppd for 32 years presents to her primary care physician for routine follow-up. She has no medical problems, and denies chest pain, shortness of breath, cough, hemoptysis, fever, and weight loss. Her husband who arrived with her asks you if it would be possible to get her tested for lung cancer given her extensive smoking history. At this point you would recommend�. A) 3 consecutive sputum samples for cytology B) A chest xray today, then every six months C) No current screening as she is asymptomatic D) A chest xray every year after she turns 40 E) A high resolution chest CT given her extensive smoking history

40. Lung Cancer Epidemiology: 2nd leading cause but highest cancer mortality for both men and women 2008 projections: 215,000 cases diagnosed, 161,000 deaths Survival: 60-70% for Stage 1 disease, 5-15% for Stage 4 disease Risk factors: active/passive tobacco exposure, asbestos exposure, IPF, COPD, family history, environmental exposures (i.e. radon)

41. Lung Cancer USPSTF recommendations: Evidence is insufficient to recommend for or against screening in asymptomatic persons for lung cancer with either CXR, CT chest or sputum cytology

42. Lung Cancer Screening tests: CXR: Sensitivity 26%, Specificity 93% LDCT (Low Dose Computerized Tomography): False positive rate approaches 41% Increased cost, higher radiation exposure I-ELCAP trial9 Sputum cytology: unknown, most trials done in the setting of concomitant CXR I-Elcap: The International Early Lung Cancer Action Program 31,567 asymptomatic patients screened with low dose CT. 1993-2005. 484 patients diagnosed with lung cancer (mostly stage 1) with 10 year survival 88%, increased to 92% after surgical resection within 1 month. 8 pts with clinical stage 1 cancer who did not receive screenigng died within 5 years Limitations include: no control group (of non-screened people), harms of screening not discussed. Lead time bias (tumors detected earlier). CT screening more sensitivye for periheral disease *which are usually adenocarcinomas and have a better prognosis anyway. Was an observational study. Criticisms: Although the trial improved survival in those 484 pts screened and treated, the overall mortality of the entire group did not decrease. Also an overdiagnosis bias, the harms of overdiagnosing clinically irrevelant tumors were not addressed.I-Elcap: The International Early Lung Cancer Action Program 31,567 asymptomatic patients screened with low dose CT. 1993-2005. 484 patients diagnosed with lung cancer (mostly stage 1) with 10 year survival 88%, increased to 92% after surgical resection within 1 month. 8 pts with clinical stage 1 cancer who did not receive screenigng died within 5 years Limitations include: no control group (of non-screened people), harms of screening not discussed. Lead time bias (tumors detected earlier). CT screening more sensitivye for periheral disease *which are usually adenocarcinomas and have a better prognosis anyway. Was an observational study. Criticisms: Although the trial improved survival in those 484 pts screened and treated, the overall mortality of the entire group did not decrease. Also an overdiagnosis bias, the harms of overdiagnosing clinically irrevelant tumors were not addressed.

43. Lung Cancer Cost-effectiveness: $2,500 per person/year of life saved Additional health care costs of $116,300 per quality-adjusted life year gained Results: 78-82% Stage 1 detection for CT screening NO improvement in mortality Significant overdiagnosis of non-relevant tumors Future: National Lung Cancer Screening Trial Sponsored by National Cancer Institute from 2002-2004 enrolling 50,000 patients randomized to CXR or CT screening with results expected in 8-10 years Sponsored by National Cancer Institute from 2002-2004 enrolling 50,000 patients randomized to CXR or CT screening with results expected in 8-10 years

44. Lung Cancer Other recommendations: American College of Chest Physicians: recommends against screening other than in setting of a clinical trial ACS: Informed individual decision making. If testing is chosen, spiral CT only in centers with multidisciplinary teams AAFP: No screening for asymptomatic persons

45. What�s next? PLCO trial (Prostate, Lung, Colorectal and Ovarian cancer screening trial) 1992-2001 (13 years planned f/u) >150,000 subjects Checks: PSA, DRE, flex sig, CXR, CA-125, transvaginal u/s Most published data has been prostate

46. References 1 )Barry et al. Prostate Specific Antigen testing for early diagnosis of Prostate Cancer. New England Journal of Medicine. May 3, 2001. Volume 344. 1373-1377. 2) Etzioni et al. Serial Prostate Specific Antigen screening for Prostate Cancer: A computer model evaluates competing strategies. The Journal of Urology. Sept 1999. Volume 162. pg 748 3) Mandel, J. et al. Colorectal Cancer Mortality: Effectiveness of Biennial Screening for Fecal Occult Blood. Journal of the National Cancer Institute.1999. pgs 434-437. 4) Mandelblatt, J et al. The Cost-Effectiveness of Screening Mammography Beyond age 65. Annals of Internal Medicine. 2003. Vol. 139. pgs 835-842 5) Manser et al. Screening for lung cancer (Review). The Cochrane Collaboration. 2008. 6) Mayrand, M.H. et al. Human Pappilomavirus DNA versus Papanicolaou Screening Tests for Cervical Cancer. The New England Journal of Medicine. October 2007. Vol. 357. pgs 1579-1588. 7) Mulshine and Sullivan. Lung Cancer Screening. New England Journal of Medicine. 2005. Volue 352. pgs2714-2720. 8) Patz et al. Screening for lung cancer. New England Journal of Medicine. Nov. 30 2000. Volume 343. pgs 1627-1633. 9) Ross. K. S. et al. Comparative Efficiency of Prostate Specific Antigen screening strategies for prostate cancer detection. Journal of the American Medical Association. 2000. Vol. 284. pgs 1399-1405. 10) Salzmann et al. Cost-effectiveness of extending screening mammography guidelines to include women 40-49 years of age. Annals of Internal Medicine. Dec. 1 1997. pgs 955-965. 11)The International Early Lung Cancer Action Program Investigators. Survival of Patients with Stage 1 Lung Cancer Detected on CT screening. The New England Journal of Medicine. 2006. Vol 355. Pgs 1763-1771. 12) Thompson et al. Prevalence of prostate cancer among men with a Prostate specific antigen level of less than or equal to 4 ng/milliliter. New England Journal of Medicine. May 27, 2004. Vol. 350. 13) Whitlock et al. Screening for colorectal cancer: A targeted, updated systematic review for the U.S Preventiv Services Task Force. Annals of Internal Medicine. Nov. 4, 2008. Vol. 149. 14) Weissfeld, J. et al. Flexible Sigmoidoscopy in the PLCO Cancer Screening Trial: Results from the Baseline Screening Examination of a Randomized Trial. Journal of the National Cancer Institute. 2005. p 989-997 Websites: 15) USPSTF: http://www.ahrq.gov/clinic/USpstfix.htm 16) American Cancer Society: www.cancer.org 17) National Cancer institute: http://www.cancer.gov/ 18) Uptodate: http://www.utdol.com