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Principles of Screening William C. Black, M.D. Dartmouth-Hitchcock Medical Center [email protected]cock.org www.dhmc.org/goto/chest-imaging 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 Screening vs Diagnosis Non-patients Patients Asymptomatic Symptomatic Test non-diagnostic Test diagnostic Low prevalence High prevalence Timeline of Disease PRECLINICAL CLINICAL DPCP Onset of Disease Detectable by Test Signs or Symptoms Death from Disease or Other causes Critical Point The point in the natural history of disease before which therapy is more effective. Screening Effective DPCP Onset of Disease Detectable by Test Critical Point Signs or Symptoms Death from Disease or Other causes Screening Ineffective DPCP Onset of Disease Detectable by Test Critical Point Signs or Symptoms Death from Disease or Other causes Screening Unnecessary DPCP Onset of Disease Detectable by Test Signs or Symptoms Death from Disease or Other causes Critical Point Survival vs Stage Mountain CF. Chest 1986;89(suppl):225-233. Mayo Clinic Project 1 Subjects Incident cases % resectable % five-year survival Lung cancer deaths Relative risk2 (95%CI) 1 Screened Control (CXR + SC) (Usual) 4,618 4,593 206 46 31 160 31 13 91 prevalent cases and 1631 others excluded before randomization 2 based on cumulative lung cancer mortality at eleven year Mayo Clinic Project 1 Subjects Incident cases % resectable % five-year survival Lung cancer deaths Relative risk2 (95%CI) 1 Screened Control (CXR + SC) (Usual) 4,618 4,593 206 160 46 31 31 13 122 115 1.06 (0.82-1.36) 91 prevalent cases and 1631 others excluded before randomization 2 based on cumulative lung cancer mortality at eleven year Knox PA • Hamartoma SPN 4-10mm • Scoble Screen Detected Cases ELCAP Henschke et al. Lancet 1999;354(9173):99-105. Stage I < 10 mm 11-20 mm 20+ mm 13 8 2 II 1 0 0 III 1 0 2 Screen Detected Cases ELCAP Henschke et al. Lancet 1999;354(9173):99-105. Stage I < 10 mm 11-20 mm 20+ mm 13 8 2 II 1 0 0 III 1 0 2 Estimated five-year survival 80% vs 13% in SEER Biases of Early Detection •Lead time bias •Length bias •Overdiagnosis bias Lead Time Bias Signs or symptoms WITHOUT TEST Death from Disease SURVIVAL WITH TEST Positive test SURVIVAL LEAD TIME Length Bias Rapidly progressive TEST Slowly progressive TIME Length Bias Rapidly progressive TEST Slowly progressive TIME Length Bias Rapidly progressive TEST Slowly progressive TIME 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. Overdiagnosis The diagnosis of a condition that would not have become clinically significant had it not been detected. 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 Lung Ca Screening in Japan Subjects Lung Rate cancers (1000) Smokers 6295 29 4.6 NonSmokers 7491 31 4.1 13786 60 4.4 Total Sone et al. Br J Cancer 2001; 84(1): 25-32. 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 Comparisons of Survival are Invalid and Biased Population-based Mortality Deaths from disease Person-years of observation Observational Studies •Correlation •Case-control •Cohort Selection Bias Those screened at different risk than those not screened. If higher, then bias against screening If lower, then bias in favor of screening Randomized Clinical Trial To ensure that observed differences in outcome depend only on the interventions under investigation and not on other factors that affect outcome. Enroll screen eligible subjects Screening RCT Randomize Screen Arm Control Arm Assess Endpoints Assess Endpoints Benefits from Screening • Anxiety about dz (TN) • Morb & mort from dz • Morb & mort from rx lobectomy vs pneumonectomy Harms from Screening • Direct effect of test (radiation) • Anxiety about dz (FP) • Morb & mort from work-up • Overdiagnosis 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 Endpoints • Deaths from target disease • Deaths from any cause • Stage of target disease at dx • Adverse events • Quality of life • Resource utilization Sample Size Determination • Death rate from disease • Duration of follow-up • Effectiveness of screening • Power and significance level • Compliance in each arm Sample Size a=0.05(one-sided), b=0.20 Smokers 60-69 All 40-69 Screen vs no screen RRR 50% Compliance 100% 2,072 12,669 Screen vs no screen RRR 20% Compliance 80% 44,807 274, 042 All Cause Mortality •Not affected by COD misclassification •Puts screening in perspective •Insensitive measure of efficacy Generalizability • Participants • Screening tests and radiologists • Treatment and supportive care RCT Limitations •Compliance •Statistical power •Ascertainment Bias •Generalizability 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 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. 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, Welch HG. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. New England Journal of Medicine 1993;328(17):1237-43. 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. Disclaimer This web site and contents is provided for informational and educational purposes only and is not intended as medical advice nor is it intended to create any physicianpatient relationship. Please remember that this information should not substitute for a visit or a consultation with a health care provider. The views or opinions expressed in the resources provided do not necessarily reflect those of Dartmouth-Hitchcock Medical Center or the Radiological Society of North America. 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.