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Screening stories:
avoiding the hard sell
Prof. dr. Elke Van Hoof
Belgian 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 background
2.Europe: Council recommendation on
cancer screening (2003)
3.Current screening programmes
4.When to screen-which cancer sites to
screen?
5.Controversy in breast cancer
6.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
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
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
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
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.
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)
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)
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)
4. When to screen – which cancer sites to screen?
 IMPORTANT DISEASE?
 TEST AVAILABLE?
 IMPACT ON DISEASE OUTCOME?
 COST-EFFECTIVE?
 CONSEQUENCES?
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 DISEASE?
• Important health problem for the general population
• Natural history well known
• Accurate diagnostic assessment
• Effective treatment options
• Earlier treatment improves disease outcome/prognosis
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
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
Lead time bias
• a monozygotic twin “Hope” and “Prudence” 2000:
• both sisters develop an identical type of cancer (without knowing it)
Hope:
Prudence:
• Participates in screening
•Refuses to participate in screening
• 2005: tumour detected by
screening => surgery + CT
•2009: tumour detected
(1st symptoms) => surgery + CT
• 2010: relapse + decease
• 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
Higher proportion of invasive tumours in group of interval cancers and non-screened
patients
Percentage of stages among
breast cancer detection groups
100%
90%
80%
IV
70%
60%
III
50%
II
40%
I
30%
In Situ
20%
10%
0%
n = 4,101
n = 1,732
n = 3,176
Screen Detected
cancers
Interval cancers
Non-screened
patients
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
When to screen – which cancer sites to screen?
 TEST CHARACTERISTICS
2 x 2 table
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
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
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
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.
When to screen – which cancer sites to screen?
 COST-EFFECTIVENESS OF SCREENING PROGRAMMES
Favourable versus unfavourable effects
Advantages
Disadvantages
• Decrease of cancer mortality
• Earlier and additional diagnoses
• Healthy life-years gained
(or Quality Adjusted LifeYears if in
good quality (QUALY))
• More years lived with disease and
follow-up after treatment
• Prevention of metastasis (more early
stages, less advanced stages
detected)
• 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,…
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
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)
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
5. Controversy
Breast cancer screening:
 Tabár et al. Radiology. 2011
•Swedish Two-county Trial: longest-followup (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
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.
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