Principles of Screening

1. Principles of Screening William C. Black, M.D. Dartmouth-Hitchcock Medical Center William.Black@Hitchcock.org www.dhmc.org/goto/chest-imaging

2. Definition Screening can be defined as the systematic testing of individuals who are asymptomatic with respect to some target disease. The purpose of screening is to prevent, interrupt, or delay the development of advanced disease in the subset with a pre-clinical form of the target disease through early detection and treatment. Hillman et al. JACR 2004;1(11):861-864

3. Screening vs Diagnosis Non-patients Patients Asymptomatic Symptomatic Test non-diagnostic Test diagnostic Low prevalence High prevalence

4. PRECLINICAL CLINICAL DPCP Onset ofDisease Detectableby Test Signs orSymptoms Death fromDisease orOther causes Timeline of Disease

5. Critical Point The point in the natural history of disease before which therapy is more effective.

6. DPCP Critical Point Screening Effective Onset ofDisease Detectableby Test Signs orSymptoms Death fromDisease orOther causes

7. Critical Point Screening Ineffective DPCP Onset ofDisease Detectableby Test Signs orSymptoms Death fromDisease orOther causes

8. Critical Point Screening Unnecessary DPCP Onset ofDisease Detectableby Test Signs orSymptoms Death fromDisease orOther causes

9. Survival vs Stage Mountain CF. Chest 1986;89(suppl):225-233.

10. Mayo Clinic Project 1 91 prevalent cases and 1631 others excluded before randomization 2 based on cumulative lung cancer mortality at eleven year

11. Mayo Clinic Project 1 91 prevalent cases and 1631 others excluded before randomization 2 based on cumulative lung cancer mortality at eleven year

12. Knox PA • Hamartoma

13. SPN 4-10mm • Scoble

14. Screen Detected Cases ELCAP Henschke et al. Lancet 1999;354(9173):99-105.

15. Screen Detected Cases ELCAP Henschke et al. Lancet 1999;354(9173):99-105. Estimated five-year survival 80% vs 13% in SEER

16. Biases of Early Detection • Lead time bias • Length bias • Overdiagnosis bias

17. Signs or symptoms Death fromDisease WITHOUT TEST SURVIVAL WITH TEST Positive test SURVIVAL LEADTIME Lead Time Bias

18. Length Bias TEST • Rapidly progressive Slowly progressive TIME

19. Length Bias TEST • Rapidly progressive Slowly progressive TIME

20. Length Bias TEST • Rapidly progressive Slowly progressive TIME

21. Tumor Histology ELCAP 25 Prevalent Cases • Adenocarcinoma (18) • Bronchioloalveolar carcinoma (3) • Mixed squamous adenocarcinoma (3) • Squamous cell carcinoma (1) • Atypical carcinoid (1) Henschke et al. Lancet 1999;354(9173):99-105.

22. Overdiagnosis The diagnosis of a condition that would not have become clinically significant had it not been detected.

23. Growth Rate of Lung Cancer Winer-Muram. Radiology 2002;223(3):798-805. • Median DT 181 days • 22% DT >= 465 days • 94% >= 1 yr grow 0.5-3.0 cm

24. Lung Ca Screening in Japan Sone et al. Br J Cancer 2001; 84(1): 25-32.

25. Effects of Overdiagnosis • Falsely increases sensitivity of test • Falsely increases PPV of test • Falsely increases incidence • Falsely improves stage distribution • Falsely improves case survival • Does not decrease pop mortality

26. Comparisons of Survivalare Invalidand Biased

27. Population-based Mortality Deaths from disease Person-years of observation

28. Observational Studies • Correlation • Case-control • Cohort

29. Selection Bias If higher, then bias against screening If lower, then bias in favor of screening Those screened at different risk than those not screened.

30. Randomized Clinical Trial To ensure that observed differences in outcome depend only on the interven- tions under investigation and not on other factors that affect outcome.

31. Assess Endpoints Assess Endpoints Enroll screen eligible subjects Screening RCT Randomize Screen Arm Control Arm

32. Benefits from Screening • ¯ Anxiety about dz (TN) • ¯ Morb & mort from dz • ¯ Morb & mort from rx • lobectomy vs pneumonectomy

33. Harms from Screening • Direct effect of test (radiation) • ­ Anxiety about dz (FP) • ­ Morb & mort from work-up • ­ Overdiagnosis

34. Patient Population • High risk for preclinical disease • No clinical signs or symp of disease • Willing and able to undergo screening or not • Willing and able to undergo workup and rx • Willing and able to undergo follow-up

35. Screening Protocol • Screening frequency • Equipment specifications • Interpretation and work-up criteria • Treatment plan

36. Endpoints • Deaths from target disease • Deaths from any cause • Stage of target disease at dx • Adverse events • Quality of life • Resource utilization

37. Sample Size Determination • Death rate from disease • Duration of follow-up • Effectiveness of screening • Power and significance level • Compliance in each arm

38. Sample Size a = 0.05 (one-sided), b = 0.20

39. All Cause Mortality • Not affected by COD misclassification • Puts screening in perspective • Insensitive measure of efficacy

40. Generalizability • Participants • Screening tests and radiologists • Treatment and supportive care

41. RCT Limitations • Compliance • Statistical power • Ascertainment Bias • Generalizability

42. Cancer Screening Outcomes and Values True positive, effective Major benefit. Death postponed, morbidity decreased True positive, ineffective Knowledge vs longer dx & rx True negative Reassurance False positive Harm. Work up False negative Possibly delayed dx Overdiagnosis Moderate to major harm. False labeling and rx

43. Summary • Diseases are dynamic processes • The evaluation of screening is difficult • Survival statistics are inappropriate and biased • RCT is most valid design, but has limitations.

44. References 1. Bach PB, Niewoehner DE, Black WC. Screening for lung cancer: the guidelines. Chest 2003;123(1 Suppl):83S-88S. 2. Black WC. Overdiagnosis: An underrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst 2000;92(16):1280-2. 3. Black WC, Haggstrom DA, Welch HG. All-cause mortality in randomized trials of cancer screening. J Natl Cancer Inst 2002;94(3):167-73. 4. Black WC. Randomized clinical trials for cancer screening: rationale and design considerations for imaging tests. J Clin Oncol 2006;24:3252-3260. 5. Black WC, Welch HG. Screening for disease. AJR. American Journal of Roentgenology 1997;168(1):3-11. 6. Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhn JR, et al. Screening for lung cancer: a critique of the Mayo Lung Project. Cancer 1991;67(suppl):1155-1164. 7. Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening [see comments]. Lancet 1999;354(9173):99-105. 8. Hillman BJ, Black WC, D'Orsi C, Hauser B, Smith R. The Appropriateness of Employing Imaging Screening Technologies - Report of the Methods Committee of the ACR Task Force on Screening Technologies. JACR 2004;1(11):861-864. 9. Morrison AS. The natural history of disease in relation to measures of disease frequency. In: Screening in chronic disease. 2nd ed. New York: Oxford University Press; 1992. p. 21-42. 10. Mountain CF. A new international staging system for lung cancer. Chest 1986;89(suppl):225S-233. 11. Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: their application to multislice CT screening for pulmonary and colorectal cancers. AJR Am J Roentgenol 2001;176(6):1357-62. 12. Sone S, Li F, Yang ZG, Honda T, Maruyama Y, Takashima S, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer 2001;84(1):25-32. 13. Welch HG, Schwartz LM, Woloshin S. Are increasing 5-year survival rates evidence of success against cancer? JAMA 2000;283(22):2975-8. 14. Winer-Muram HT, Jennings SG, Tarver RD, Aisen AM, Tann M, Conces DJ, et al. Volumetric growth rate of stage I lung cancer prior to treatment: serial CT scanning. Radiology 2002;223(3):798-805.

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46. Financial Disclosure I do not have nor have I had during the previous 12 months a relationship with a company or organization whose products or services are directly related to the subject matter of this presentation. William C. Black, M.D.