Principles and Concepts of Cancer Screening

1. Principles and Concepts of Cancer Screening Lorelei Mucci, ScD Epidemiology of Cancer – Lecture 3 February 1, 2011

2. Cancer screening - definition • The examination of asymptomatic individuals to classify them as likely or unlikely to have the disease of interest • Goal is to reduce the morbidity and mortality associated with a cancer by diagnosing the disease at an earlier stage • Early treatment is less intrusive, less prone to risk or complications, and more effective than delayed

3. Cancer screening in the US • US Preventive Services Task Forces: • Supports screening for: • Breast cancer (2009): biennial mammogram, women 50 – 74 years • Cervical cancer (2003): pap, women 18* – 64 years • Colorectal cancer (2008): colonoscopy/FOBT/sigmoidoscopy, men and women 50-74 years http://www.uspreventiveservicestaskforce.org/uspstopics.htm#Ctopics

4. Cancer screening in the US • US Preventive Services Task Forces: • Not enough evidence for: • Skin (2009) • Ovarian (2004) • Prostate (2011) • Lung (2004) http://www.uspreventiveservicestaskforce.org/uspstopics.htm#Ctopics

5. Success of cancer screening Effectiveness of screening for a specific cancer relies on a number of key attributes: • Suitability of the disease • Suitability of the screening test • Suitability of the screening program in the population selected for testing • Effectiveness of screening program

6. I. Suitable disease A’ A B C D biologic detectable by clinical diagnosis severe illness death from onset screening test due to symptoms develops (metastases) the disease |-------|------------------|-------------|----------------| Preclinical phaseClinical phase • Preclinical phase • Cancer is not symptomatic but is detectable • Screening is not useful if: • Cannot detect prior to onset of symptoms • Treatment during preclinical phase is no more effective • - Length of preclinical phase depends on screening tool (clinical exam vs. biomarkers)

7. I. Suitable disease • Cancer prevalence  preclinical phase • Prevalence ≈ Incidence * Duration • Cancer may not be suitable for screening if low incidence or short duration in preclinical phase • Heterogeneity in duration of preclinical phase • Incidence of disease may be low in general population, higher among subgroups • E.g. smokers, genetic susceptibility • Targeted screening

8. I. Suitable disease • Cancer mortality • Expected rates of death/metastases should be sufficiently high, AND • Earlier intervention during preclinical phase leads to substantial reductions in morbidity from the cancer and its treatment, and mortality

9. II. Suitable screening test • Relatively simple to administer and perform • Rapid, both in its conduct and in its turn-around time to obtain results • Inexpensive: low cost to benefit ratio • E.g. mammography $25000 USD per life year saved • Safe, and should cause as little discomfort or potential harm • Important since most screened will likely not have the cancer of interest • Acceptable to target population • E.g. Colonoscopy • Balance of benefit and harm from false positive

10. II. Suitable screening test • Correctly identify as positive individuals who have cancer and as negative those without cancer: reliability and validity • Reliability • Ability of test to give same result on repeated applications in the same person • Depends on the intrinsic variability of the factor being measured, the variability of the method used, the skill of performing the measurement, and the accuracy of interpretation of its value

11. Validity: The 2x2 Table II. Suitable screening test False positive False negative

12. Sensitivity Sensitivity is “positivity” of the test in the presence of disease; indicates % individuals with disease correctly classified by screening test as having disease • Drives number of false negatives • Estimate of sensitivity should be regarded as the sensitivity of the screening test relative to the diagnostic test

14. Specificity Specificity is the probabilitythat individuals without the disease will be correctly classified by the screening test as being disease-free  Drives number of false positives

15. Sensitivity and Specificity Receiver Operator Curve Disease-free Cancer (False positive)

16. Positive Predictive Value Positive Predictive Value (PPV) is proportion of individuals correctly classified as having cancer among total who test positive • Specificity drives false positives because number of non-diseased individuals greatly exceeds number with cancer. Small decreases in specificity may lead to large increase in false positives and a large decrease in the PPV • Many influence acceptability of test in population

17. Negative Predictive Value Negative Predictive Value (PPV) is proportion of individuals classified as being disease-free who do not have the disease • Sensitivity drives false negatives • If NPV < 1 is similar to prevalence of preclinical disease, then screen test may miss most of preclinical disease PPV and NPV are driven by sensitivity and specificity and prevalence of disease

18. III. Suitable screening program • Organized application of screening, early diagnosis and treatment activities in large groups is mass screening or population screening • Free of discomfort and attendant risks • Convenient and attractive to the target population • Economical, both to the individual and to society • High PPV and NPV

19. III. Suitable screening program • Improve suitability even if test characteristics fixed: •  PPV by increasing prevalence • Limit screening to high risk population • Decrease frequency of screening interval •  False positives • Raise threshold for positivity • Screen with two sequential tests, and “positive” only if positive on both tests •  False negatives • lower the criteria for positivity • Screen at more frequent intervals • Screen with two different tests and consider “positive” if positive on at least one

20. III. Suitable screening program • Critical that there be follow-up for individuals who test positive on screening • Protocol for quick follow-up with diagnostic testing • Subsequent therapeutic intervention if the individual is indeed found to have the disease • For screening program to be successful at reducing mortality, cases must be detected during the preclinical phase with time for treatment to be more effective than if treatment had been given at a later time  availability and timeliness of effective treatment are critical components

21. III. Suitable screening program Optimal screening interval • During initial screen, cancer incidence will be high as prevalent pool is diagnosed • After one screen, incidence will drop to level lower than expected (without screening) After 2nd screen, incidence will again rise • Rate of increase will depend on the interval since 1st screen • If timing between tests too short, preclinical cases will not be replaced

22. III. Suitable screening program Pseudodisease A lesion that becomes known only as a result of screening; it would not be discovered otherwise • Cases that would never progress to a symptomatic state • Cases that would progress but are interrupted by death from an unrelated diseases before symptoms develop 25% of mammographically detected breast cancers, 50% of chest x-ray and/or sputum-detected lung cancers, and 60% of prostate-specific antigen–detected prostate cancers (Welch and Black, JNCI 2010)

23. Heterogeneity of cancer progression. Welch H G , Black W C JNCI J Natl Cancer Inst 2010;102:605-613 Published by Oxford University Press 2010.

24. III. Suitable screening program Pseudodisease • If screening is continued indefinitely, incidence rate may increase above baseline • Detection of non-progressive cancer that would not have otherwise come to light clinically and only arise as a result of additional screening

25. IV. Evaluation of screening effectiveness • Study design: Randomized trial • Outcomes: • Improvements in overall survival • Cancer-specific survival* • Quality of life • Length of observation period: must account for the natural history of the cancer, time by which most screen-detected cases would die of cancer if they were not treated early. • Random allocation can take place at the individual or community level • Intention to treat analysis

26. IV. Evaluation of screening effectiveness • Study design: Observational studies • Case – control study • Cases – Individuals who die of cancer of interest • Controls – represent source population that gave rise to cases: should they include only individuals with cancer? • Controls should be sampled independently of whether they have been screened • Exposure window can be defined to approximate the detectable preclinical period

27. IV. Evaluation of screening effectiveness • Number needed to screen (NNS): number need to be screened for a given duration to prevent one death • NNS for haemoccult screening to prevent a death from colon cancer is 1,374 • NNS for mammography to prevent a death from breast cancer is 2451 among women aged 50-59 (50).

28. IV. Evaluation of screening effectiveness • There are possible sources of bias when evaluating a screening program that may result in a false picture of its efficacy • Lead-time bias • Length-time bias

29. IV. Evaluation of screening effectiveness Lead time bias: interval from disease detection with screening to the time at which diagnosis would have been made without screening; e.g. the amount of time by which the diagnosis was advanced due to screening • Distribution of lead times in a screening program depends on: • --the sensitivity of the screening test • --the frequency of the screening test • --the incidence rate of disease • --the distribution of the duration of preclinical disease

30. IV. Evaluation of screening effectiveness Length bias: Phenomenon by which screen-detected cases may not be representative of all cases Screen-detected cases have longer preclinical phases, biologically slower progression, and better prognosis than cases detected through diagnostic evaluation Screening program may appear artificially good because cases detected by screening may be less aggressive and higher proportion of indolent tumors found in screened group. Less aggressive forms of a disease are more likely to be picked up in a screening program because they have a longer detectable preclinical phase. Less aggressive forms of disease usually have better survival