Principles of Cancer Screening
Robert Clark, MD
Radiology Service, H. Lee
Moffitt Cancer Center & Research Institute
Early detection of cancer,
prior to its clinical manifestations, appears to be a worthwhile and desirable
goal. Yet, the concept and acceptance of cancer screening remain controversial
and often confusing. While the benefits of screening are obvious to those whose
screening tests have resulted in successful interventions, attention also needs
to be given to the risks, economic costs, and psychological effects of screening
procedures. Specific governing principles that define the cancers to be screened,
the appropriate screening test, and the measurement of outcomes should be established
in order for a screening program to be deemed worthwhile. A beneficial screening
strategy detects cancer prior to its systemic spread, alters the natural history
of the disease, and defers the time of death.
Introduction
Cancer screening seems intuitively
beneficial. The concept of detecting cancer early, when tumor is manageable
and has not spread from its primary site, rather than late, when it has metastasized
to other vital organs, seems reasonable. Yet, despite being an intuitive or
reasonable concept, cancer screening remains controversial and often confusing.
Why not screen everyone in order to detect cancer early? Should screening be
recommended for the most common or most lethal cancers? Conversely, how can
cancer screening be considered useful when most screened individuals never get
the disease, yet incur the costs of screening and the anxiety of a possible
falsepositive test? Why is cancer screening so controversial, so debated, and
so rarely recognized as valuable?
Although the answers to
these questions often are different for specific cancers, many general principles
of cancer screening are common to the various cancers and screening strategies.
These principles should be considered ideals; few, if any, cancer screening
strategies will fulfill all degrees of proof. However, these principles should
be considered when reading the scientific literature and evaluating the rationale
for new screening tests or proposed strategies.
Definitions of Terms Relating
to Cancer Screening
Clinicians may define terms
used in cancer screening in different ways. The following summarizes current
usage.
Cancer Screening
Screening is the application of a test to detect a potential cancer where
no signs or symptoms of the cancer are present.[1,2] Testing for cancer screening
involves both the traditional tests and the newer tests for risk factors. The
traditional test detects cancer before it is clinically apparent, early in its
natural history, before it has become systemic, when treatment may be more effective,
less expensive, or both. An abnormal screening test in this situation leads
to further diagnostic evaluation to determine if cancer is present and leads
to subsequent treatment if cancer is detected. Another type of cancer screening,
which may become more prevalent in the future, involves screening for risk factors
or other markers (eg, genetic or molecular) that designate a high risk for developing
cancer. It is not yet clear what an abnormal screening test in this situation
means or what recommendations should follow.[3,4] Cancer screening is a secondary
form of cancer prevention, as distinguished from primary prevention, an example
of which would be avoidance of cigarette smoking to prevent lung cancer.
The term "cancer screening"
is synonymous with other terms, such as detection or early detection,[1] and
has been modified by some authors as "mass," "routine,"
"regular," or "selective" cancer screening. However, these
modifiers have no universally accepted definitions. Every cancer screening strategy
must identify its target population, the proposed screening test, and the frequency
of the screening test. Knowledge of these parameters for any screening strategy
makes other modifier terms moot.
Cancer Screening Test
The cancer screening test is the method used to detect a specific target cancer[1,2]
and may consist of a single modality or a combination of tests. Laboratory tests
of blood or body fluids, physical examinations, invasive procedures, and imaging
tests are examples of screening tests.
Asymptomatic The
goal of cancer screening is to detect cancer before it is clinically apparent.
Therefore, "asymptomatic" is defined in the perspective of the individual
who has no known signs or symptoms of cancer prior to the screening test. For
example, as a result of a digital rectal examination, a physician detects a
prostate nodule on the gland of a man with no previously known signs or symptoms.
The patient then has a sign of cancer detected by the physician and the screening
test; nevertheless, the man was asymptomatic prior to the screening and the
cancer was detected by screening. This example of asymptomatic status is appropriate
even if the man had symptoms related to another condition, such as benign prostate
hypertrophy. This concept is less clear in the skin cancer screening test involving
the inspection of a skin lesion visible to both the individual and the examiner.
Screened Individual
Screened individuals are often inappropriately referred to as patients. Screening
involves the testing of an asymptomatic person. A screened individual does not
become a "patient" until the screening test is abnormal. New concerns,
anxieties, costs, and discomforts begin when the individual becomes a "patient."
Target Population
Certain characteristics identify an individual as a candidate for cancer screening.
For example, since prostate cancer is rare in teenage boys, screening is inappropriate
in this age group. The target population of a proposed screening strategy defines
the characteristics of an individual who would be appropriate to receive the
screening test. Typical defining characteristics of a target population include
sex, family history, specific known risk factors, geographic region of birth
or residence, race or ethnicity, and age.
Screening Practitioner
The screening practitioner is the health care professional who performs the
cancer screening test,[1] including primary care physicians, specialist physicians,
nurses, physician assistants, and technicians.
Diagnosis Screening
is not diagnosis.[1,2,5] The cancer screening test identifies asymptomatic individuals
with a high likelihood of having cancer. Screened individuals are divided between
two groups: those with normal test results and those with abnormal results.
In some individuals with normal results from a screening test (a falsenegative
screening test), cancer may be subsequently detected with diagnostic tests such
as biopsy. All individuals with abnormal screening test results require some
diagnostic evaluation. Some of those with abnormal results and further diagnostic
evaluation will not have cancer (a falsepositive screening test). Diagnosis
is the clinical problemsolving process applied to symptomatic individuals or
asymptomatic individuals with abnormal screening tests.
Symptomatic individuals
require diagnostic evaluation to determine the cause of symptoms. A screening
test applied to a symptomatic person is not be considered a cancer screening
event, since diagnostic evaluation is required regardless of the results of
the screening test. Moreover, the value of a screening strategy cannot be assessed
if symptomatic individuals are included in the target population, since these
people may already have advanced disease that needs diagnostic evaluation.
Screening Strategy or
Protocol A cancer screening strategy or protocol defines the operational
parameters of a cancer screening program: who, how, what, where, and when. The
screening strategy or protocol defines the population to be screened (the target
population) and the screening test to be used, as well as when and how often
the screening test should be applied. The screening strategy also may define
who should perform the screening test, the conditions under which it should
be applied, and the criteria for an abnormal test. A screening strategy or protocol
is useful in designing clinical trials and interpreting scientific data about
screening. Another function of screening strategies or protocols is to make
recommendations to individuals or groups about cancer screening.[1]
The screening protocol design
must be clearly understood when interpreting scientific evidence about cancer
screening. The protocol of a screening clinical trial often is limited. Therefore,
the results obtained by the trial are valid only for the conditions of that
protocol. For example, a cancer screening protocol that studies a target population
of white European women ages 50 to 69 years, applies a screening test every
two years for 10 years, and finds 40% fewer cancer deaths in screened women
than in unscreened women suggests strong evidence of the effectiveness of cancer
screening. However, it may not be applicable to women older than 69 years of
age, to women younger than 50 years, or to Japanese women, and the results of
this protocol may not be enough evidence alone to justify recommending cancer
screening annually for all black women older than 40 years of age. Alternatively,
a cancer screening test applied to men between ages 65 and 75 years showing
no benefit to the screened group when compared with unscreened men does not
signify a lack of potential benefit to screening men younger than age 65 years.
The results simply show that no information about screening younger men is available
from the screening test.
The scientific literature
focusing on cancer screening is replete with clinical trials that have different
screening strategies and protocols for the same target cancer. It is difficult
to compare or combine the data from these trials to answer scientific questions
that were not posed prior to the design of the clinical trial. However, cancer
screening strategies for clinical practice are not limited to those studied
by clinical trials; they may be recommended by individual practitioners, professional
medical societies, public health agencies, and health maintenance organizations.
Their recommendations are based on their best assessment of the available scientific
evidence, as well as their best estimate of applicability to individuals or
target populations not included in the original scientific protocols, which
varies among groups, practitioners, and policymakers. Therefore, it is not
surprising that "guidelines" for cancer screening may vary among various
organizations and among practitioners.
Table 1. Outcome Measures
in Cancer Screening Programs ---------------------------------------------------------------------------
| Shortterm Measures |
Number of individuals in the target
population who were offered screening
Number and proportion of individuals in
the target population who received screening
Number and proportion of target population
who were examined by multiple screens
Number or prevalence of preclinical
cancers detected
Proportion of abnormal screened
individuals brought to definitive
diagnosis or followup
Monetary cost per cancer detected
Sensitivity and specificity of the
screening test
Positive and negative predictive values
of the screening test
|
| Longterm Measures |
Stage distribution of detected cancers
Case fatality rate of screened individuals
Sitespecific cancer mortality rate of
screened target population
Total monetary costs
|
---------------------------------------------------------------------------
Outcomes The scientific
evidence of the value of screening requires that outcomes of a screening protocol
be measured. Outcomes are the health and economic results that are related to
screening.[1,6,7] Outcomes include the benefits, harms, and costs of screening
as well as its incurred diagnostic evaluations. Outcomes are measured by tracking
the detailed clinical results of screened individuals (Table 1).
Effectiveness The
effectiveness of cancer screening is determined by comparing outcomes to ascertain
if the benefits outweigh the harms and whether the health outcomes (benefits
and harms) justify the costs.[1,6,7] Moreover, the outcomes and effectiveness
measures of the screened population must be compared to those of a similar unscreened
group. For example, for a screening program to be judged effective, the stage
distribution of detected cancers in screened individuals should be lower than
cancers detected in unscreened people. Similarly, the casefatality rate and,
more important, the sitespecific mortality rate for a screened group should
be significantly less than that of an unscreened group.
Costeffectiveness
Ideally, the cost of the screening program (the total of screening costs,
diagnostic evaluations, treatment costs of detected cancers, and value of years
of life lost to cancer deaths) should be less than the cost for the unscreened
group (the total of diagnostic evaluations, treatment costs of detected cancers,
and value of years of life lost to cancer deaths). Relevant costs to be considered
in this evaluation are listed in Table 2. However, cost savings that result
from screening programs have been difficult to determine.[8] Hence, other costassociated
measures are analyzed, such as cost determination, costminimization, costeffectiveness,
costbenefit, and costutility analyses.[1,913]
Table 2. -- Relevant
Costs of a Cancer Screening Program _______________________________________________________________________
- Costs of screening tests:
- direct costs or charges
- indirect costs (time,
anxiety)
- Costs incurred by abnormal
screening tests:
- direct costs or charges
of diagnostic evaluation or biopsy
- indirect costs of complications,
morbidity, anxiety, time, loss of work
- Costs related to false-positive
screening tests:
- direct costs or charges
of diagnostic evaluation or biopsy
- indirect costs of complications,
morbidity, anxiety, time, loss of work
- Costs related to false-negative
screening tests:
- false sense of security
- delay in diagnosis due
to disregard of clinical symptoms
- Costs related to treatment
and rehabilitation
- direct costs or charges
of treatment and rehabilitation
- indirect costs of complications,
morbidity, anxiety, time, loss of work
- Costs related to death:
- direct costs or charges
related to death
- indirect costs of years
of life lost
_______________________________________________________________________
Prevalence and Incidence
The prevalence rate of cancer denotes the number of cancers that exist in
a defined population at a specific time, whereas the incidence rate denotes
the number of new cancers that develop in a defined population during a specific
period of time.[1,2] Both are commonly expressed as the number of cancers per
100,000 individuals in the defined population. The ideal screening test would
detect all the prevalent cases of cancer in the first screen of a previously
unscreened population. Subsequent screening examinations would detect incidence
cases developing in the population since the prior screen.
The incidence rate for a
given cancer is lower than the prevalence rate. Theoretically, in a defined
population of individuals who received three cancer screenings at yearly intervals,
the first screen would detect all prevalence cases (developing for several years
prior to the first screening). The second and third screenings would detect
incidence cases, ie, only those cases that developed since the first screening.
Measures of Validity of
a Screening Test
Several issues govern the
validity of a screening test (Table 3).
Table 3. --Hypothetical
Example of Validity Measures of a Screening Test
_______________________________________________________________________
Results of
Screening Test
|
True Characteristics in the Population
|
|
Have the
disease |
Do not have
the disease |
Total |
| Positive test |
80 |
100 |
180 |
| Negative Test |
20 |
800 |
820 |
| Total |
100 |
900 |
1000 |
| True-positive tests = 80 |
Sensitivity = 80/(80 + 20) = 0.80 |
| True-negative tests = 800 |
Specificity = 800/(80 + 100) = 0.89 |
| False-positive tests = 100 |
Positive predictive value = 80/(80 + 100) = 0.44 |
| False/negative tests = 20 |
Negative predictive value = 800/(800 + 20) = 0.98 |
_______________________________________________________________________
Positive and Negative
Tests A truepositive screening test is an abnormal test for cancer
in an individual who subsequently is found to have cancer within a defined period
of time after the test, whereas a truenegative screening test is a normal
test for cancer in an individual who subsequently is found not to have cancer
within a defined period of time after the test.[14,15] Conversely, a falsepositive
screening test is an abnormal test for cancer in an individual who subsequently
is found not to have cancer within a defined period of time after the test,
and a falsenegative screening test is a normal test for cancer in an
individual who subsequently is found to have cancer within a defined period
of time after the test.[14,15]
Sensitivity The
sensitivity of a screening test represents its ability to detect those individuals
with cancer in the defined population[2,14,15] and is derived from the truepositive
ratio, ie, the proportion of positive tests in all individuals with disease.
Sensitivity is defined as the number of truepositive (TP) cases divided by
the total number of truepositive and falsenegative (FN) cases.
TP
Sensitivity = -----
TP + FN
Specificity The
specificity of a test represents its ability to identify those free of cancer
in the population[2,14,15] and is derived from the truenegative ratio, ie,
the proportion of negative tests in all individuals without disease. Specificity
is defined as the number of truenegative (TN) cases divided by the total number
of true negative and falsepositive (FP) cases.
TN
Specificity = -----
TN + FP
Table 4. -Hypothetical
Examples of Relationship of Predictive Value of the Screening Test to the Prevalence
of Cancer in the Population
_______________________________________________________________________
Sensitivity of Screening
Test = 0.99
Specificity of Screening Test = 0.95
Prevalence of Cancer
= 1%
Test
Results |
Have
Disease |
Do Not
Have Disease |
Totals |
Positive
Predictive Value |
| Positive |
99 |
495 |
594 |
| Negative |
1 |
9405 |
9406 |
99/594=0.17 |
| Total |
100 |
9900 |
10,000 |
| TP = 99 |
TN = 9405 |
Sensitivity = 99/(99 + 1 ) = 0.99 |
| FP = 495 |
FN = 1 |
Specificity = 9405/(9405 + 495) = 0.95 |
Prevalence of Cancer
= 5%
Test
Results |
Have
Disease |
Do Not
Have Disease |
Totals |
Positive
Predictive Value |
| Positive |
495 |
475 |
970 |
| Negative |
5 |
9025 |
9030 |
495/970=0.51 |
| Total |
500 |
9500 |
10,000 |
| TP = 495 |
TN = 9025 |
Sensitivity = 495/(495 + 5 ) = 0.99 |
| FP = 475 |
FN = 5 |
Specificity = 9025/(9025 + 475) = 0.95 |
_______________________________________________________________________
Positive Predictive Value
The positive predictive value is the measure of the validity of a positive
test, ie, the proportion of positive tests that are truepositive cases.
TP
Positive Predictive Value = -----
TP + FN
The predictive value of
a test is dependent on the disease prevalence (Table 4). As the prevalence of
cancer increases in the population, the positive predictive value of the screening
test increases, even though its sensitivity and specificity remain unchanged.[1618]
Therefore, for maximum efficiency and costeffectiveness, screening should be
focused on the populations with highest risk (highest prevalence).
Negative Predictive Value
The negative predictive value is the measure of the validity of a negative
test, ie, the proportion of negative tests that are true negative cases.
TN
Negative Predictive Value = -----
TN + FN
Governing Principles of
Cancer Screening
The principles that should
be followed for a cancer screening program to be worthwhile. These principles
define characteristics of the disease considered for screening, the screening
test, and the outcomes. (Table 5)[1,2,19]
Table 5. - Governing
Principles of a Worthwhile Cancer Screening Program
_______________________________________________________________________
| Characteristics of the Disease |
Characteristics of the Screening Test |
| High morbidity, mortality, costs |
Able to detect disease
in preclinical phase |
| High prevalence and incidence |
Effective (ie, sensitive and specific) |
| Known natural history and biology |
Safe |
| Preclinical phase with high prevalence |
Simple, inexpensive |
| Effective treatment of early stage disease |
Acceptable to individuals |
_______________________________________________________________________
The disease considered for
screening should have high prevalence and incidence rates and should have serious
clinical consequences measured in mortality, morbidity, and costs. The biology
and natural history of the disease should be known. Ideally, the cancer should
exist for a long time in a preclinical phase amenable to screening, and this
preclinical phase should have a high prevalence rate in the screened population.
The disease should have an effective treatment at an early stage, and this treatment
should be more effective than treatment at late stage. When a disease has no
effective treatment or when treatment in its early stage is no more effective
than in its advanced stage, screening is problematic unless counseling is shown
to be useful.
An effective screening test
should have the ability to detect cancer in its preclinical phase with acceptable
sensitivity, specificity, and predictive values. The test should be safe; screened
individuals are asymptomatic and should not suffer complications of a screening
examination. To be applied efficiently in large populations, the screening test
should be simple, inexpensive, and accessible. Moreover, if compliance with
repeated screens is expected, the test must be acceptable to the screened individuals.
The most important outcome
measure of the effectiveness of a screening strategy is the demonstration that
the mortality rate from the disease is significantly lower in the total screened
population when compared with the cancer mortality rate in an equivalent population
of unscreened people, preferably demonstrated by a randomized, controlled, definedpopulation
clinical trial.
Expected Benefits and Potential
Harms
The expected benefits of
screening are a lower mortality rate from the target cancer, a reduction in
morbidity from the disease, and lower health care costs. Additional benefits
may include improved length and quality of life, as well as less pain, anxiety,
and disability. Expected benefits of screening are derived from the true positive
results of a screening test. While not a benefit that makes a screening program
effective, a truenegative screening test result provides reassurance that cancer
has not developed.
The potential harms of screening
are related to the test itself or to its results. Those related to the test
are costs, inconvenience, anxiety, and discomfort. Additional potential risks
(complications) may be related to invasive screening tests. The potential harms
related to the results are associated with falsepositive and false negative
tests. The potential benefits of screening must outweigh the potential risks,
since any harm to an asymptomatic person is not to be considered lightly. A
falsepositive test result causes anxiety and incurs a diagnostic evaluation,
with its attendant costs, potential risks, and side effects. A falsenegative
test result can lead to a false sense of security. Subsequent clinical signs
or symptoms of cancer may be dismissed because of a prior negative screening
test, resulting in further delay in detection.
Table 6. - Cancer Control
Phases: A Systematic Evaluation Process for Proposed Screening Strategies
_______________________________________________________________________
- Basic research and epidemiology
- Hypothesis development
- Methods development
- Controlled intervention
trials
- Defined population studies
- Demonstration and implementation
projects
- Nationwide dissemination
programs
_______________________________________________________________________
Evaluation of a Proposed
Screening Strategy
A systematic approach to
cancer control research has been developed that provides a framework for the
evaluation of a proposed screening strategy (Table 6).[20,21] The evaluation
begins with knowledge about the basic biology and epidemiology of the cancer
and incorporates information about characteristics of the populations at high
risk, cancer prevalence and incidence rates, tumor growth rates, mortality rates,
and costs of care and disability. The next step, hypothesis development, synthesizes
the available scientific information and proposes possible interventions to
be applied to the cancer problem. Cancer screening may not always be the appropriate
intervention; primary prevention, if possible, is the optimum prevention. Theproposed
intervention strategy should be expressed as a testable hypothesis that can
be evaluated in an objective, scientific fashion.
Next, methodological research
is necessary to characterize the variables to be controlled or monitored in
subsequent clinical trials. This phase might include pilot studies to identify
target populations or compliance rates of screened individuals, to evaluate
application or acceptability of screening tests, or to estimate the efficacy
of the screening test. Methods that have been tested adequately and proven may
be incorporated into clinical intervention trials. Initial trials may be uncontrolled
but, ideally, these interventions should be controlled. Cohort studies or casecontrol
trials may be used to estimate benefits from a screening intervention; however,
randomized, controlled trials are likely to provide the most convincing results.
Measures of the quantitative
impact of a screening intervention using a defined population study would identify
not only barriers to widespread adoption of the intervention, but also methods
for overcoming these barriers. The defined population must be comprised of a
large number of people in order to show a significant intervention benefit.
The screening strategy is beneficial if the defined population study demonstrates
a significant reduction in diseasespecific mortality rate when compared with
the unscreened group.
When screening is shown
to be beneficial in defined population studies, demonstration and implementation
programs are appropriate. The purpose of these programs is to apply the proven
intervention in a community at large with measurement of the public health impact.
A surveillance system should be in place to ensure that the application, accuracy,
and effectiveness of screening in the community are equal to that demonstrated
in clinical trials. Quality control processes may be developed during this phase,
as well as assessment of the adequacy of diagnostic evaluation and treatment
in the community.
Finally, when demonstration
and implementation programs ensure that community dissemination can be achieved,
nationwide screening programs and policy recommendations may be developed.
Potential Harms and Biases
in Evaluation
All the steps in the evaluation
process described above are not always adhered to. Pressures to circumvent them
include immediate clinical acceptance and dissemination of a new screening test,
expense of defined population studies, and preliminary recommendations for screening
from professional organizations. However, without the assurance of this process,
an incompletely evaluated screening strategy may deliver more harms and costs
than benefits. Moreover, without the demonstrated benefit of a screening intervention
in a defined population trial, the potential benefit of a screening strategy
may be overestimated and invalid.
Almost invariably, individuals
with cancer identified by screening will have longer survival times than those
diagnosed with usual clinical detection. However, these apparent increased survival
times are not always equivalent to reduction in mortality from cancer. Three
biases that contribute to this spurious survival increase and potentially mask
the lack of screening benefit are leadtime bias, length bias, and overdiagnosis
bias. Randomized, controlled clinical trials can control for these biases and
can identify and quantify more accurately the benefits of a screening strategy.
Fig 1. - Natural history
of a lethal neoplasm is depicted schematically. The time line extends from left
to right, depicting onset of cancer, its systemic spread, the subsequent clinical
diagnosis, and death. The diamonds represent examples of two possible screening
test applications. If a screening test is applied at Screen #1, the time of
diagnosis is advanced from the time of usual clinical diagnosis by Lead Time
#1. Survival time is apparently increased by this lead time, even though the
natural history of the disease is unchanged. If a screening test is applied
at Screen #2, the lead time is increased by Lead Time #2. If Screen #2 is applied
prior to the systemic spread of the cancer, thereby altering the natural history
of the disease, the time of death will be deferred, ie, moved to the right.
This alteration of the natural history of the disease, with prolongation of
life, cannot be recognized without comparison of the screened group to controls.
LeadTime Bias
Leadtime bias refers to
clinical outcome observations that are not adjusted for the timing of the diagnosis.
The length of time by which screening advances the diagnosis of cancer compared
with the usual clinical detection is the lead time. In an uncontrolled clinical
trial, this lead time appears to increase survival time, since survival is measured
from the time of diagnosis to the time of death. However, despite the apparent
increase in survival time, the natural history of the disease and the time of
death remain unchanged (Fig 1). This apparent increase in survival time without
reduction in mortality is leadtime bias.[1,18]
A beneficial screening strategy
detects cancer prior to its systemic spread, alters the natural history of the
disease, and defers the time of death. This alteration of the natural history
of the disease, with prolongation of life, cannot be recognized without a randomized,
controlled trial that prevents leadtime bias.
Fig 2. - Length bias
sampling is represented schematically. The time line extends from left to right.
Each X signifies a cancer death, and the horizontal dashed lines indicate the
duration the cancer's presence prior to death. All the dashed lines and Xs together
represent a heterogeneous population of cancers, with varied rates of progression.
Four screening test applications are represented by S1 through S4. The vertical
lines represent the screening examinations; if the vertical line intersects
a horizontal line, the cancer is detected by screening. The four screening examinations
tend to detect those cancers with the longest horizontal lines (ie, those with
the longest detectable phase) or the slowest progression. Those cancers with
the slowest progression, (ie, the longest horizontal lines) offer two opportunities
for screening detection prior to death. Note that at virtually any time, a "one-time"
screening is more likely to select patients who live with the disease for the
longest period of time. This represents length bias sampling.References
Length Bias
Length bias refers to clinical
outcome observations that are not adjusted for the rate of progression of disease.[1,18]
The probability that a cancer will be detected by screening is directly proportional
to the length of its detectable preclinical phase, which is inversely related
to its rate of progression. Individuals with rapidly progressive cancers (ie,
those with brief preclinical phases) are more likely to die of their disease
and are less likely to be identified by screening. Alternatively, individuals
with slowly progressive cancers (ie, those with long preclinical phases) are
less likely to die of their disease and are more likely to be identified by
screening (Fig 2). Therefore, screening tends to detect cancer subsets with
long preclinical phases, less aggressive progression, and perhaps better inherent
prognosis. If the outcomes of individuals with screeningdetected cancers in
an uncontrolled clinical screening trial are compared with a general population
of clinically detected cancers, the screened group may demonstrate an artificially
higher survival rate because of the length bias sampling effect. A randomized,
controlled trial obviates this bias.
Overdiagnosis Bias
Length bias effect may be
magnified as the screening test threshold is lowered and the least aggressive
tumors are detected. Among this group of neoplasms may be cases that would regress,
remain stable, or progress too slowly to ever have become clinically apparent
during the individual's lifetime. This effect has been termed overdiagnosis
bias, or pseudodisease.[1,18] Overdiagnosis bias is compounded by the difficulty
in defining pathologically the distinct lines between benign hyperplasia, atypical
hyperplasia, dysplasia, and carcinoma. As a screening strategy detects less
aggressive tumors at earlier stages in the progression of disease, some cases
of benign conditions will be classified as cancers, artificially elevating the
apparent survival benefit. Randomized, controlled trials offset the effects
of this error by controlling for this bias.
Conclusions
While screening for cancer
has enormous intuitive appeal, the true benefits, harms and costs of this cancer
control approach can only be determined from appropriate clinical trials that
measure the relevant parameters. While there is clearcut evidence of benefit
in some programs, such as cervical cancer screening, for many common cancers
evidence of benefit is inconclusive or lacking.
References
1. Eddy DM, ed. Common Screening
Tests. Philadelphia, Pa: American College of Physicians; 1991:121.
2. Hulka BS. Cancer screening:
degrees of proof and practical application. Cancer. 1988;62:17761780.
3. Hoskins KF, Stopfer JE,
Calzone KA, et al. Assessment and counseling for women with a family history
of breast cancer: a guide for clinicians. JAMA. 1995;273:577585.
4. ShattuckEidens D, McClure
M, Simard J, et al. A collaborative survey of 80 mutations in the BRCA1 breast
and ovarian cancer susceptibility gene: implications for presymptomatic testing
and screening. JAMA. 1995;273:535541.
5. Moskowitz M. Screening
is not diagnosis. Radiology. 1979;133:265268.
6. Ellwood PM. Shattuck
lecture. Outcomes management: a technology of patient experience. N Engl J Med.
1988;318:15491556.
7. Wennberg JE. Outcomes
research, cost containment, and the fear of health care rationing. N Engl J
Med. 1990;323:12021204.8. Fries JF, Koop CE, Beadle CE, et al. Reducing health
care costs by reducing the need and demand for medical services. The Health
Project Consortium. N Engl J Med. 1993;329:321325.
9. Doubilet P, Weinstein
MC, McNeil BJ. Use and misuse of the term "cost effective" in medicine.
N Engl J Med. 1986;314:253256.
10. Doubilet PM. "Costeffective":
a trendy, often misused term. AJR Am J Roentgenol. 1987;148:827828.
11. Eisenberg JM. Clinical
economics: a guide to the economic analysis of clinical practices. JAMA. 1989;262:28792886.
12. Detsky AS, Naglie IG.
A clinician's guide to costeffectiveness analysis. Ann Intern Med. 1990;113:147154.
13. Goodwin PJ. Economic
evaluations of cancer care incorporating qualityof life issues. In: Osoba
D, ed. Effect of Cancer on Quality of Life. Boca Raton, Fla: CRC Press; 1991:125136.
14. McNeil BJ, Keeler E,
Adelstein SJ. Primer on certain elements of medical decision making. N Engl
J Med. 1975;293:211215.
15. McNeil BJ, Adelstein
SJ. Determining the value of diagnostic and screening tests. J Nucl Med. 1976;17:439448.
16. Moskowitz M. Impact
of a priori medical decisions on screening for breast cancer. Radiology. 1989;171605608.
17. Moskowitz M. Predictive
value, sensitivity, and specificity in breast cancer screening. Radiology. 1988;167:576578.