Başak Oyan-Uluç, MD Yeditepe University Hospital Department of Medical Oncology

1. SCREENING AND EARLY DIAGNOSIS IN ONCOLOGY Başak Oyan-Uluç, MD Yeditepe University Hospital Department of Medical Oncology

2. Primary Elimination of risk factor Cessation of smoking Colonoscopy Vaccination Lifestyle modifications Prevention Onset of disease Clinical diagnosis Healthy Asymptomatic Clinical course Secondary Early diagnosis and treatment • Colonoscopy • Mamography • Pap smear Tertiary Reducing complications (rehabilitation)

3. Cancer Screening • Cancer screening: Early detection of asymptomatic or unrecognized disease by the application of inexpensive tests or examinations in a large number of people. • Main objective: To reduce morbidity and mortality from a particular cancer among people screened. • Screening procedure itself • Not diagnostic • Detects people with cancer risk • Positive or suspicious findings must be evaluated further to determine diagnosis and appropriate treatment.

4. Screening vs. Diagnosis

5. Patient features High impact: Morbidity, mortality, economy High incidance and high prevelance Predictable course and biology High prevelance of preclinic phase Effective treatment exists Requirements of screening test Diagnosing disease at preclinical phase Acceptable sensitivity and specificy Acceptable to people Simple anf cheap Safe Ideal screening program Quality of primary or secondary prevention (Cheap, effective, safe)

6. Cervical Cancer-Pap Smear • Long preinvasive period • Increased morbidity and mortality in invasive period • Treatable if early diagnosis • PAP smear: Sensitive, low cost, easy to apply, safe

7. Benefits of Screening • Improved prognosis for those with early-detected cancers • Less radical treatment • Reassurance for those with negative test results • Reduction of treatment costs

8. Cancers suitable for screening • Although there are more than 100 different cancers, most of them lack proven screening interventions • Cancers that have widely accepted screening interventions • Breast • Cervical cancer • Colorectal • Prostate ? • Hepatocellular cancer in patients with risk factor • Lung cancer in people with defined risk factors

9. Breast Cancer Screening • Most common cancer in females • Average risk • Increased risk • Prior thoracic RT (eg. Mantle) • Women who have a lifetime risk of >%20 • Strong family history of genetic predisposition • LCIS/atypical hyperplasia • Prior history of breast cancer

10. Breast Cancer ScreeningAverage risk women Widely accepted techniques for breast cancer screening includes: • Brest self-examination: Monthly after age 20 • Clinical breast examination: • Age 20-39: Every 3 years • Every year after age 40 • Mamography: Every 1-2 years after age 40-50 • In Turkey (KETEM): Every 2 years after age 40

11. Mamography TrialAgeDecrease in mortality(%) HIP 40-64 24 Malmö 45-69 19 2-kanton, İsveç 40-74 32 Edinburg 45-64 21 Stockholm 40-64 26 Kanada-1 40-49 -3 Kanada-2 50-59 -2 Gothenburg 39-59 16 Alltrials 39-74 24 CA Cancer J Clin 2003; 53:141

12. Mamography • Microcalcifications Spicular mass lesion

13. 0.4 cm komedo dkis 0.7 cm inv lob k

14. 1999 1993

15. Controversial points • Initiation of screening (age 40-49?) • Frequency (1 vs. 2 years) • Radiation dose • Side effects • Cost • High risk women

16. Age of initiation of screening • 40-49 years • Controversial • Long term follow-up results shows benefit • Decrease in mortality : 15% • Gothenburg trial: Decrease in mortality 45% • Metaanalyses: Decrease in mortality 15%

17. Frequency of screening • Decrease in distant metastases • Screening every year: 51% • Screening every 2 year: 22% Michaelson ve ark. Radiology 1999; 212:551

18. Radiation Dose • ACS guidelines:“many women are concerned about the exposure to x-rays but the level of radiation used in modern mammograms does not significantly increase the risk for breast cancer” • Mamography: Dose < 2 mGr (~ 1 mGr) • Ages 40-90 years, mamography every year: Total 20-40 rad • Dose of radiation exposure during a flight between New York and California : Equlas to 1 mamography

19. Radiation Risk in Breast Screening • Risk of radiation induced cancer for screening is about1 in 20,000 per visit • ~170 cancers detected for every cancer induced • Mortality benefit of screening exceeds radiation induced detriment by ~ 100:1

20. Risk of mamography Similar risks • Traveling 4000 miles by air • Traveling 600 miles by car • 15 minutes of mountain climbing • Smoking 8 cigarettes

21. LIMITATIONS OF MAMMOGRAPHY • As many as 5 – 15% of breast cancersare not detected mammographically • A negative mammogram should notdeter work-up of a clinically suspiciousabnormality

22. Adverse events • False negative mamography and interval cancers • False reassurance related to false negative mamography • Overdiagnosis of tumors not causing mortality • False positive mamography (recall rate %8-9) and unnecessary additionla tests and biopsy • Anxiety

23. Cervical Cancer Screening • Second most common cancer in females worldwide particularly in the underdeveloped regions • The incidence has declined in many countries due to the improved standard of living throughout the world

24. Cervical Cancer Screening • Pap test: Introduced in 1930s by Dr. Papanicolaou • Screening should begin at age 21

25. Cervical Cytologic Screening Guidelines from the American College of Obstetricians and Gynecologists, 2009 Screening not discontinued in: • In-uterine DES exposure • Personal history of cervical cancer, CIN grade 2/3 • Immune insuffiency (eg. HIV) • HPV DNA (+)

26. Colorectal Cancer Screening • Causes morbidity and mortality in both men and women • Second leading cause of death due to cancer • The natural history of colon cancer with relatively long time from biologic onset to development of carcinoma makes it a good candidate for screening

27. Adenoma-carcinoma sequence

28. Risk groups for screening • Average risk • Age ≥ 50 y • No inflammatoy bowel disease • No history of adenoma or colorectal cancer • Negative family history • Increased risk • Personal history of • Adenoma/sessile serrated polyp • Inflammatoy bowel disease • Colorectal cancer • Positive family history • High risk syndromes • Lynch syndrome/Hereditary nonpolyposis colorectal cancer (HNPCC) • Polyposis syndromes (familial adenomatous polyposis, Peutz-Jeggers syndrome, Juvenile polyposis syndrome, hyperplastic polyposis syndrome)

29. Screening tests for colorectal cancerAverage risk Starts at age 50 1. Colonoscopy every 10 years • preferred if available • For every 1% increase in complete colonoscopy rate, the hazard of death decreased by 3%. 2. Annual FOBT+/-Flexible sigmoidoscopyevery 5 years Annual Fecal occult blood test (FOBT) • Testing of stool for occult blood to detect colorectal cancer at an early stage • Variation is observed in estimates of the sensitivity but its lower cost and increased specificity to detect right-isded colonic lesions make it a good screening test Flexible sigmoidoscopy every 5 years • In contrast to FOBT, has a high sensitivity and specificity • Involves the use of a 60 cm flexible sigmoidoscope • Detects left sided lesions

30. Colorectal Cancer Screening Guidelines*

31. Prostate Cancer Screening • Most commonly diagnosed cancer among men and is the second leading cause of male cancer deaths • Two main screening modalities • Serum prostate specific antigen (PSA) • Digital rectal examination (DRE)

32. Prostate Cancer Screening • Benefit of screening is controversial • Prostate cancer is common and potentially lethal; however, more patients die with, rather than from, the disease. • Incidence: 1/6 Mortality: 1/30 • Screening detects more cases of organ-confined disease, but there is no proof that this detection saves lives. • In more instances, prostate cancer is not the cause of elevated PSA level. NEJM 2009; 360:1310 NEJM 2009; 360:1320

33. Prostate Cancer Screening • Localized treatment of prostate cancer is effective but is associated with complications than can include impotence and incontinence (~ 50%). • It is likely that prostate cancer screening using the PSA level is beneficial in a subset of men; however, the characteristics of the subset have not been defined.

34. Prostate Cancer Screening • Discuss benefit and harms of screening with the patient • In men with a life expectancy of >10 years, start screening at age 40y with: • PSA • Digital rectal examination • In last years, it is recommended to offer a baseline DRE and PSA at age 40 y.

35. Prostate Cancer Screening • Serum PSA level • Allows earlier detection of prostate cancer • Normal PSA values are found in 1/3 of localized tumors (false negative) • Often elevated in men with noncancerous conditions such as benign prostatic hyperplasia (false positive)

36. Prostate Cancer Screening • NCCN recommendation • DRE yearly starting at age 40 • PSA yearly starting at age 40

37. Lung Cancer Screening Targetpopulation: • Age: 55-74 years + • Smoked ≥ 30 pack/year + • Continuetosmokeorhavequittedsmokingwithin 15 years Screeninigmethod: Lowdosethorax CT %20 reduction in lung-cancerrelatedmortality

38. Cirrhosis Hepatitis B, C Alcohol Genetic hemocromatosis Non-alcoholic steatohepatitis Autoimmune hepatitis Primary biliary cirrhosis No cirrhosis Hepatitis B carrier Non-alcoholic steatohepatitis Hepatocellular Carcinoma Diagnosis rate: %92 False (+): %7.5 Ultrasonography Alpha-feto protein (AFP) Every 6-12 months

39. People not to be screened • Life expectancy <5 years • People who do not wish to undergo additional diagnostic tests or who do not want any treatment

40. Future of Screening • Compliance: Encourage people to adhere the proven cancer screening modalities • New and better methods: With the discovery of cancer susceptibility genes (e.g. BRCA-1 susceptibility gene for breast cancer), lifetime risk for an individual to develop a specific cancer could be estimated.

41. ROLE OF TUMOR MARKERS IN SCREENING, DIAGNOSIS AND FOLLOW-UP

42. Tumor Markers • Secreted by the tumor or secreted in response to tumor • Also secreted by normal cells and found in low concentrations in serum • Some increase in inflammatory disease, hepatic and renal disorders

43. Ideal tumor marker • Detect small sized tumor while asymptomatic • Elevated only in malignancy • Can be used for screening and early diagnosis • (-) test result in healthy people and patients with benign diseases (Specificity 100%) • (+) test result in cancer patients(sensitivity 100%) • NO IDEAL TUMOR MARKER EXISTS

44. Application of Tumor Markers in Clinical Practice • Screening • Diagnosis • Prognosis and tumor load • Evaluation of treatment response and follow-up Also: Radioactive labelled markers to detect metastatic regions

45. Classification • Oncofetal proteins • CEA • AFP • Enzymes • PAP • LDH • NSE • PLAP • Hormones • Calcitonin • B-HCG • Thyroglobulin • Antigens • CA15-3 • Ca 19-9 • CA125 • B2-microglobulin • Others • 5-HIAA • VMA • Ferritin

46. Carcinoembryonic Antigen (CEA) • Surface glycoprotein of fetal colon epithelium • Not detected in normal adult tissues • Normal level: <5 ng/ml in non-smoker • Higher levels in smokers • Elevation • Liver, colorectal, breast, gastric,pancreas cancer • Liver diseases (cirrhosis, hepatitis) • Pancreatitis • Inflamatory bowel disease • Chronic renal failure • Chronic lung disease • Rectal polyps

47. CEA • Clinical use: • Prognosis (colon cancer) • Response evaluation and follow-up (detection of relapses) • Not used for screening and early diagnosis

48. Human Chorionic Gonadotropin (HCG) • Elevation in males and non pregnant females->Cancer • Half life: 14-24 hour • Elevation: • Gestational trophoblastic tm • Ovarian and testicular germ cell tm

49. Alpha-fetoprotein (AFP) • Secreted from fetal yolk sac, liver, intestines • Max. level.: Gestational 12-15. week • Not detected in healthy patients > age 1 • Elevation • Liver diseases • Hepatocellular carcinoma (HCC) • Testicular and ovarian germ cell tm • Teratocarcinoma

50. AFP • Clinical use: • Screening of HCC in patients with chronic active hepatitis, cirrhosis, hepatitis B antigen carriers (every 6 month) • >350 ng/ml • Diagnosis • Prognosis • Response evaluation and follow-up