screening stories: avoiding the hard sell prof. dr. elke van hoof belgian cancer center

Screening stories: avoiding the hard sell

Prof. dr. Elke Van HoofBelgian Cancer Center

“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.

Overview

1.Historical background2.Europe: Council recommendation on

cancer screening (2003)3.Current screening programmes4.When to screen-which cancer sites to

screen?5.Controversy in breast cancer6.Summary

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

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

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

Historical background

• Fundamental principles of best practice in early detection of cancer

• Shared commitment by Member States to implement cancer screening programmes

2. Europe: Council Recommendation on cancer screening (2003)

• = 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.

Cancer screening

European recommendations

3. Current screening programmes

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)


Current screening programmes

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)



Current screening programmes

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


IMPORTANT DISEASE?

TEST AVAILABLE?

IMPACT ON DISEASE OUTCOME?

COST-EFFECTIVE?

CONSEQUENCES?

4. When to screen – which cancer sites to screen?

When to screen – which cancer sites to screen? IMPORTANT DISEASE?

Top 10 cancers in European men and women

WSR

When to screen – which cancer sites to screen?

• Important health problem for the general population

• Natural history well known

• Accurate diagnostic assessment

• Effective treatment options

• Earlier treatment improves disease outcome/prognosis

IMPORTANT DISEASE?


• Acceptable to the population • Test characteristics• Cancer process:

• initation – promotion – abnormal growth – invasion – metastases• symptoms• diagnosis and treatment long interim period: window for screening

SUITABLE TEST?

Schiffman. N Engl J Med. 2005


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

SUITABLE TEST?

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)

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

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

0%

10%

20%

30%

40%

50%

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70%

80%

90%

100%

n = 4,101 n = 1,732 n = 3,176

Screen Detectedcancers

Interval cancers Non-screenedpatients

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Higher proportion of invasive tumours in group of interval cancers and non-screened patients


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

TEST CHARACTERISTICS

When to screen – which cancer sites to screen? TEST CHARACTERISTICS

2 x 2 table


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


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


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


• 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.

When to screen – which cancer sites to screen? IMPACT OF EARLY DETECTION ON DISEASE OUTCOME?

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

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,…


• 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


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)

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

When to screen – which cancer sites to screen? CONSEQUENCES

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 populationPSP = 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

• 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.

6. Summary

screening stories: avoiding the hard sell prof. dr. elke van hoof belgian cancer center

Documents

cancer sites

presence of cancer

cancer screening programmes

breast cancer tumours

national cancer institute

cancer albert salomon

human cancer problem

invasive cervical cancer