Screening stories: avoiding the hard sell

1. Screening stories: avoiding the hard sell Prof. dr. Elke Van Hoof Belgian Cancer Center

4. “The greatest need we have today in the human cancer problem, except for a universal cure, is a method of detecting the presence of cancer before there are any clinical signs of symptoms.” - Sidney Farber, letter to Etta Rosensohn, November 1962 - (The Emperor of All Maladies, Siddhartha Mukherjee) Sidney Farber (1903-1973) Paediatric pathologist and “father” of modern chemotherapy. The Dana-Farber Cancer Institute in Boston is partly named after him.

5. Overview • Historical background • Europe: Council recommendation on cancer screening (2003) • Current screening programmes • When to screen-which cancer sites to screen? • Controversy in breast cancer • Summary

6. 1. Historical background • George Papanicolaou (1883 – 1962), Greek cytologist • Studied the menstrual cycles of guinea pigs • Microscopical examination of cells of the cervix, removed by a cotton swab • Changes in morphology of the cells due to hormonal changes • Similar observations in women (he took a daily vaginal smear of his wife) • Importance of his work was not recognised (“ a useless invention”) • Focused on pathological smears • observed abnormal cells in smear of women with cervical cancer • still received lots of criticism: better methods of diagnosis already available • In 1950 (more than 20 years later!) it dawned on him that PAP smears might be useful to detect not cancer, but the precursor stages

7. Historical background • PAP smears as a means for early detection of cervical cancer? • 1952: Papanicolaou persuades the National Cancer Institute to set up a large clinical trial in secondary prevention • PAP smears were taken of 150 000 women + follow-up • detection of 555 invasive cervical cancer cases • ! detection of 557 cases of pre-invasive and pre-cancerous lesions • easily removable • mean age of these women: about 20 years younger than the mean age of women with cervical cancer • confirmed the prolonged development of cancer = opportunity to intervene early in the process

8. Historical background • Other attempts to visualise cancer • Albert Salomon (1883 – 1976), German surgeon • Executed lots of mastectomies • Tried to visualise the breast cancer tumours by use of X-rays on the amputated breasts • = foundation of mammography, but his work was interrupted by second world war and disinterest of surgeons in screening • Robert Egan, pioneer in radiology in Houston • Experimented with films, angles, positions and other settings • Succeeded in visualising tumours of a few millimetres

9. 2. Europe: Council Recommendation on cancer screening (2003) • Fundamental principles of best practice in early detection of cancer • Shared commitment by Member States to implement cancer screening programmes

10. Cancer screening • = early diagnosis of non-symptomatic cancer • aiming at the reduction of morbidity and mortality • Population-based screening: offered systematically to all individuals in the defined target group within a framework of agreed policy, protocols, quality management, monitoring and evaluation • Opportunistic screening: offered to an individual without symptoms of the disease when they present to a health care practitioner for reasons unrelated to that disease.

11. 3. Current screening programmes European recommendations • Breast cancer screening: • 2-yearly Mammography screening for women aged 50 to 69 in accordance with European guidelines on quality assurance in mammography. • minimum screening participation rate of 70% recommended • Current issues: • Allowed rate of overdiagnosis (5%? 10%? 50%?) • lower age limit? (40? 45?) • upper age limit? • dense breast tissue: mmx -> ultrasound? http://eu-cancer.iarc.fr/ (2007)

13. Current screening programmes European recommendations • Cervical cancer screening: • Pap smear screening for cervical cancer precursors starting not before the age of 20 and not later than the age of 30 with three to five-year intervals. • minimum screening participation rate of 85% recommended • Current issues: • HPV testing instead of pap smear (higher sensitivity) • HPV vaccination (primary prevention) http://eu-cancer.iarc.fr/ (2007)

16. Current screening programmes European recommendations • Colorectal cancer screening: • Faecal occult blood (FOB) screening for colorectal cancer in men and women aged 50 to 74. • 95% of the target group should be invited; A minimum of 45% of invitees should be examined, but it is recommended to aim for a rate of at least 65% • Current issues: • 3 tests: FOBT (guaiac and immunological), sigmoidoscopy, colonoscopy • Low participation http://eu-cancer.iarc.fr/ (2007)

17. 4. When to screen – which cancer sites to screen? • IMPORTANT DISEASE? • TEST AVAILABLE? • IMPACT ON DISEASE OUTCOME? • COST-EFFECTIVE? • CONSEQUENCES?

18. Top 10 cancers in European men and women WSR When to screen – which cancer sites to screen? • IMPORTANT DISEASE?

19. When to screen – which cancer sites to screen? • IMPORTANT DISEASE? • Important health problem for the general population • Natural history well known • Accurate diagnostic assessment • Effective treatment options • Earlier treatment improves disease outcome/prognosis

20. When to screen – which cancer sites to screen? • SUITABLE TEST? • Acceptable to the population • Test characteristics • Cancer process: • initation – promotion – abnormal growth – invasion – metastases • symptoms • diagnosis and treatment •  long interim period: window for screening Schiffman. N Engl J Med. 2005

21. When to screen – which cancer sites to screen? • SUITABLE TEST? • Preclinical detectable period depends on: • cancer (site, tumour volume doubling time, morphology, agressivity) • age (slower growth – longer asymptomatic phase: length time bias) • test (characteristics, improvement) • Mean lead time • amount of time by which the diagnosis has been advanced by screening • longer lead time → higher risk on overdiagnosis

22. Lead time bias • a monozygotic twin “Hope” and “Prudence” 2000: • both sisters develop an identical type of cancer (without knowing it) • Hope: • Participates in screening • 2005: tumour detected by screening => surgery + CT • 2010: relapse + decease • Prudence: • Refuses to participate in screening • 2009: tumour detected (1st symptoms) => surgery + CT • 2010: relapse + decease • At first sight, it seems that Hope lived longer, but • In fact, both sisters had the same lifetime, but Hope had to live longer with the disease (The Emperor of All Maladies, Siddhartha Mukherjee)

23. Length time bias • more slowly growing tumors, with less capacity to prove fatal • longer presymptomatic screen-detectable period • more likely to be screen-detected. •  artificial survival advantage to screen-detected cases Duffy et al. Am J Epidemiol. 2008

24. Interval cancers • Definition: • Cancer diagnosed after a negative screening test and before the following screening round • Concerns tumours not detected during screening test OR tumour developped after the negative screening test Higher proportion of invasive tumours in group of interval cancers and non-screened patients

25. When to screen – which cancer sites to screen? • TEST CHARACTERISTICS • Sensitivity: • Ability of the test to identify positive results • Proportion of actual positives which are correctly identified as such (i.e. the percentage of people with cancer who are correctly identified as having cancer) • TRUE POSITIVE rate • Never 100% • Specificity • Ability of the test to identify negative results • Proportion of negatives which are correctly identified (i.e. the percentage of healthy people who are correctly identified as not having cancer) • TRUE NEGATIVE rate

26. When to screen – which cancer sites to screen? • TEST CHARACTERISTICS 2 x 2 table

27. When to screen – which cancer sites to screen? • TEST CHARACTERISTICS • Positive predictive value (PPV): • The probability to have cancer following a positive test result • Proportion of positive test results which are TRUE POSITIVE • Negative predictive value (NPV): • The probability to be healthy following a negative test result • Proportion of negative test results which are TRUE NEGATIVE • BUT: PPV and NPV vary with prevalence

28. When to screen – which cancer sites to screen? • TEST CHARACTERISTICS e.g. fecal occult blood (FOB) screen test in 2030 people to look for colorectal cancer

29. When to screen – which cancer sites to screen? • TEST CHARACTERISTICS • Likelihood ratio (+): • The ratio of the probability of a positive test result when having cancer over the probability of a positive test result when not having cancer • The higher LR (+), the higher the positive predictive power of the test • Likelihood ratio (-): • The ratio of the probability of a negative test result when having cancer over the probability of a negative test result when not having cancer • The lower LR (-), the higher the negative predictive power of the test • Odds ratio: • The overall power of a test to discriminate between an ill and healthy condition • Ratio of LR(+)/LR(-) • The higher the odds ratio the higher the predictive power of the test

30. When to screen – which cancer sites to screen? • IMPACT OF EARLY DETECTION ON DISEASE OUTCOME? • Lower disease-specific mortality • Less morbidity • Lower cancer incidence • E.g.: cervical and colorectal cancer – Detection + removal of pre-cancerous lesions => progression towards cancer is stopped • Higher cancer incidence – but shift towards lower stages = smaller tumours, not metastasised • E.g.: breast, prostate and lung cancer • Remark: at the start-up of a screening programme, prevalent tumours will be detected • Programme should be evaluated when it’s active during several years. Otherwise mortality rates will be biased by “old” = prevalent cases.

31. When to screen – which cancer sites to screen? • COST-EFFECTIVENESS OF SCREENING PROGRAMMES Favourable versus unfavourable effects • Advantages • Decrease of cancer mortality • Healthy life-years gained (or Quality Adjusted LifeYears if in good quality (QUALY)) • Prevention of metastasis (more early stages, less advanced stages detected) • Disadvantages • Earlier and additional diagnoses • More years lived with disease and follow-up after treatment • People worry about the risk that they might have a cancer • Unpleasant test • False positives • False negatives => false reassurance • Financial costs, time loss

32. When to screen – which cancer sites to screen? • COST-EFFECTIVENESS OF SCREENING PROGRAMMES • A large benefit for a few and relatively small unfavourable effects for many • The main benefit, which is prevention of deaths, and the main harm, with is the over-detection, is not know to the individual participant • On the other hand, individual participants are confronted with less serious harms, false positive and false negative test results. • Screening programmes will always cause harm as well – but all efforts should be made to minimise them as much as possible! • Physical harm: e.g. invasive interventions • Psychological harm: e.g. anxiety, additional years of living with a disease,… • Social harm: e.g. family relations, employment, insurance, financial implications,…

33. When to screen – which cancer sites to screen? • COST-EFFECTIVENESS OF SCREENING PROGRAMMES • If a screening programme is well organised, with high quality and if participation is high  screening might be beneficial • Population • Lower cancer-specific mortality • Life-years saved • Less advanced disease stages • Individual • May be not dying from disease • May be life-years gained • Less severe diagnostics and treatment needed • May have a higher quality of life

34. When to screen – which cancer sites to screen? • CONSEQUENCES Screening programmes • People must be enabled to make a deliberated choice by informing them on all aspects: harms and benefits • => Informed choice • Whether people decide to participate or not in screening, providing sufficient and correct information will increase the awareness of the public (+) • Objective is to detect in an early stage to increase prognosis and decrease late effects of treatment (less agressive treatment)

35. When to screen – which cancer sites to screen? • CONSEQUENCES When becomes screening acceptable? • Correct test: proven effectivenes – preferably in several well set-up randomised clinical trials • Positive balance between fabourable and unfavourable effects • Correct frequency: periodical screening, but not too often (costs ↗) • Correct risk group: broad age range, but not too young and not too old (=> identification of target population) • Optimal quality of organisation and performance of screening • Continual evaluation is essential

36. 5. Controversy • Breast cancer screening: • Tabár et al. Radiology. 2011 • Swedish Two-county Trial: longest-follow-up (29 years) of any breast screening trial • a highly significant decrease in breast cancer-specific mortality • at 29 years of follow-up: 1 death prevented for every 414 or 519 women screened for a 7-year period 42 years of life saved per 1000 women ASP = active study population PSP = passive study population RR = relative risk • Autier et al. BMJ. 2011 • Comparison of breast cancer mortality within 3 pairs of neighbouring European countries with different levels of screening • Despite time differences in implementation of mammography screening between the country pairs → similar reductions in mortality  suggest that screening did not play a direct part in the reductions in breast cancer mortality

37. 6. Summary • Proven effectiveness and acceptable unfavourable side-effects • => population-based screening more efficient than ad hoc screening of individual patients • Screening always implicates negative effects • => balanced information on both advantages and disadvantages is indispensable • Population-based screening aims to improve public health. This can collide with interests of individual participants • Organising a screening programme is complex. Effects only visible after a long period.