Beruflich Dokumente
Kultur Dokumente
Epidemiology and
Prevention of
Cancer
Otis W. Brawley, MD
LEARNING OBJECTIVES
After reviewing this chapter, the reader should be able to
for American men and women from 1996 to 2000 have been
compiled (Table 1-1).1
Survival is defined as the time from diagnosis to death.
A commonly used measure is the proportion of people
alive at five years after diagnosis (Table 1-2).
The American Cancer Society publishes an annual estimate of the absolute number of new cancer cases and
deaths. These numbers are widely quoted, especially by the
lay press. It should always be remembered that the numbers
are crude estimates based on rates measured in past years.2
Overview
Epidemiology is the study of disease in populations. It
is the analysis of trends over time, as well as the characteristics of individuals in whom a disease develops and in
whom it does not. Other aspects of epidemiology include
assessment of the effects of treatment, prevention, or
screening interventions on a group of people.
Descriptive epidemiology involves incidence and mortality rates, survival, and the number of cases of a disease diagnosed in a certain population. Incidence and mortality rates
are commonly expressed as the number of cases per 100,000
in the group at risk. These rates are frequently age adjusted,
meaning they are mathematically adjusted to a standard population to remove the effect of a populations age distribution
changing over time. Cancer is primarily a disease of older
people. With the extensive increase over the past 30 years in
the number of individuals in the United States who are 70
years and older, the absolute number and the crude rate per
100,000 of patients with cancer has also increased. Adjusting
disease rates for age removes the effects of aging of the population. Increases in age-adjusted incidence and mortality
rates are the result of causes other than the aging of the population. Average annual cancer incidence and mortality rates
Risk
Much of epidemiology involves assessment of cancer
risk. A person can be at increased risk of cancer due to
KEY POINT
Epidemiology is the study of disease in populations. It can include assessment of treatment
outcomes, disease prevention, and disease
screening.
Table 1-1. Cancer Incidence and Mortality, Annualized Per 100,000 Using Surveillance, Epidemiology, and End Results (SEER) Data from 1996 to 20001`
Women
Incidence
White
Non-Hispanic
Cancer
Oral cavity and pharynx
Esophagus
Stomach
Colon and rectum
Liver and intrahepatic
Pancreas
Lung and bronchus
Melanoma of the skin
Breast
Cervix uteri
Corpus and uterus
Ovary
Urinary bladder
Kidney and renal pelvis
Brain and other nervous system
Thyroid
Hodgkins lymphoma
Non-Hodgkins lymphoma
Myeloma
Leukemia
6.8
2.1
4.3
47.5
2.4
9.3
53.9
18.6
148.3
7.6
27.0
18.3
10.2
7.6
6.2
10.5
2.9
16.6
4.0
9.6
Men
Black
6.4
4.2
9.9
56.2
3.9
14.3
54.8
0.8
121.7
12.4
17.9
11.9
7.6
9.4
3.4
5.6
2.0
11.6
10.2
7.8
Hispanic
3.8
1.2
10.0
32.9
5.6
9.3
24.4
4.4
89.8
16.8
16.5
14.0
4.9
8.0
4.5
9.6
1.9
13.2
4.2
7.6
White
Non-Hispanic
Black
Hispanic
1.7
1.7
2.7
7.6
2.6
8.9
43.1
2.1
27.4
2.6
3.8
9.3
2.3
2.9
4.2
0.4
0.4
7.4
2.9
6.1
2.0
3.4
6.5
24.6
3.7
12.9
40.0
0.5
35.9
5.9
7.0
7.4
3.0
2.8
2.3
0.5
0.3
4.6
6.6
5.5
0.8
1.0
5.3
11.4
5.0
7.4
15.1
0.6
17.9
3.7
3.1
6.1
1.2
2.5
2.5
0.7
0.4
5.5
2.9
4.40
Incidence
White
Non-Hispanic
Cancer
Oral cavity and pharynx
Esophagus
Stomach
Colon and rectum
Liver and intrahepatic
Pancreas
Larynx
Lung and bronchus
Melanoma of the skin
Prostate
Testes
Urinary bladder
Kidney and renal pelvis
Brain and other nervous system
Thyroid
Hodgkins lymphoma
Non-Hodgkins lymphoma
Myeloma
Leukemia
16.6
7.6
10.0
64.6
6.2
12.4
6.8
80.5
27.5
163.3
6.8
40.9
15.6
9.0
4.0
3.5
25.1
6.7
16.7
Black
20.5
11.4
19.9
72.4
11.0
18.0
12.0
120.4
1.5
272.1
1.4
20.4
17.7
4.8
2.0
2.8
18.6
12.9
13.0
Mortality
Mortality
Hispanic
9.9
6.0
18.1
49.8
13.8
10.6
5.4
46.1
4.3
137.2
3.5
18.3
13.9
5.5
2.6
3.1
19.0
6.4
11.6
White
Non-Hispanic
4.1
7.5
5.7
25.4
5.7
12.0
2.4
80.8
4.7
30.5
0.3
8.1
6.3
6.3
0.4
0.6
11.2
4.5
10.7
Black
7.9
12.2
14.0
34.6
9.3
16.4
5.7
107.0
0.5
73.0
0.2
5.8
6.2
3.3
0.3
0.6
7.6
9.2
9.3
Hispanic
3.1
4.5
9.9
18.4
10.5
9.4
2.3
40.7
1.2
24.1
0.2
4.2
5.4
3.5
0.5
0.8
8.4
3.7
6.8
mortality rate for black women was 35.9 per 100,000, and
the rate for non-Hispanic white women was 27.4 per
100,000. During that period, the relative risk of death for
black women was 1.31 times that of white women (35.9
divided by 27.4).
A number of genes, polymorphisms, and genetic
mutations have been identified as predisposing a patient
for a disease. Many more will be discovered in the near
KEY POINTS
Risk can be increased due to extrinsic and
intrinsic influences.
A population risk is often reported relative to
another population.
KEY POINT
Most trials are designed to determine efficacy,
meaning how well the treatment works in a
selected environment. Some larger trials and
outcomes studies are designed to show effectiveness, meaning how well the treatment works in
the population as a whole.
Cancer Prevention
Primary cancer prevention is best defined as the use of
interventions to lower cancer risk. Important to prevention
is the fact that carcinogenesis is not a distinct event but
rather a process that occurs over time. It is a cumulative
continuum of discreet cellular changes resulting in uncontrolled growth. Primary prevention involves interventions
or manipulations of the genetic, biologic, and environmental factors in the causal pathway of carcinogenesis.
Smoking cessation, sun avoidance, diet modification, and
chemoprevention are primary-prevention activities.
Screening for asymptomatic cancers is considered secondary prevention. For some cancers, intraepithelial neoplasia
KEY POINTS
Avoidance of carcinogens is the easiest way to
prevent cancer. Smoking is the cause of nearly
one-third of all cancers in the United States.
Other environmental influences such as sun
overexposure, certain chemicals, and certain
viruses are associated with cancer causation.
Drugs and vitamins previously thought to be
harmless have been associated with increased
risk of harm, demonstrating the need to
rigorously assess a putative cancer preventative
agent before advocating its use.
Smoking Cessation
Tobacco use is the most avoidable risk factor for
cardiovascular disease, pulmonary disorders, and cancer.
Smoking cessation and avoidance have the potential to
save and extend more lives than any other public health
activity. A smoker has a one in three lifetime risk of dying
prematurely of a smoking-related disease. More human
lives are lost because of cardiovascular disease caused by
smoking than from smoking-related cancer. In addition to
lung cancer, cigarette smoking has been linked to cancer
of the larynx, oropharynx, esophagus, kidney, bladder, and
possibly the pancreas.
The risk from tobacco smoke is not necessarily limited
to the smoker. Epidemiologic studies strongly suggest that
environmental tobacco smoke, often called secondhand or
passive smoke, may cause lung cancer and other pulmonary diseases in nonsmokers. The amount of smoke
exposure, as well as the degree of inhalation of cigarette
smoke, is correlated with the risk of mortality associated
with lung cancer. The number of cigarettes smoked per day
is an approximate surrogate for cigarette exposure; however, socioeconomically disadvantaged people smoke cigarettes more efficiently, inhaling more smoke per cigarette
than middle-class individuals. Twenty pack-years (meaning one pack a day for 20 years or two packs a day for
10 years) means more smoke inhaled if the smoker is
poor.14
Light and low-tar cigarettes are not safer, as smokers
tend to inhale them more frequently and deeply.
Compared with nonfiltered cigarettes, filtered ones allow
smaller particles to get into the peripheral parts of the lung
and cause different histologic subtypes of cancer.15,16
Those who stop smoking almost immediately lower the
risk of cancer, despite the fact that some carcinogeninduced gene mutations persist for years.
More than 80% of adult American smokers begin
smoking before the age of 18.17 Communicating health
messages to the pediatric and adolescent population is
therefore a major public health challenge. Studies show
that a physicians simple advice to avoid or quit smoking
can positively influence patients.
Smoking is an addiction. It is easier for light smokers,
the less addicted, to quit. Experts believe heavy smokers
generally need an intensive, broad-based cessation program that includes counseling, behavioral strategies, and
drug therapy, such as nicotine-replacement therapy and
bupropion. Most Americans who successfully quit smoking
do so on their own without participation in an organized
Diet Modification
Rates of cancer of the breast, colon, endometrium, and
prostate are higher in the Western cultures than in cultures in the Far East or even in the old Eastern bloc. This
observation is the basis for the belief that dietary modification can significantly lower cancer risk for individuals in
the United States.19
Despite correlative data, the dietary fat-cancer hypothesis has not been definitively demonstrated. Case-control
and cohort epidemiologic studies yield conflicting results.
In addition, diet is a highly complex exposure to many
nutrients and chemicals. Low-fat diets may render some
protection through anticarcinogens found in vegetables,
fruits, legumes, nuts, and grains. Potentially protective
substances found in foods include phenols, sulfur-containing compounds, flavones, and fiber.
In epidemiologic (observational) studies, dietary fiber
intake is inversely associated with the risk of colonic
polyps and invasive cancer of the colon.20,21 Although
there is a correlation, the causal mechanism is unknown.
It has been suggested that fiber binds oxidized bile acids.
High-fiber diets may also protect against breast and
prostate cancers by absorbing and inactivating dietary
compounds that promote carcinogenesis through estrogenic and androgenic activity. In no prospective clinical
trial has it been demonstrated that cancer can be prevented through lowering dietary fat or increasing fiber
intake.
Sun Avoidance
Results of epidemiologic studies show a correlation
between the risk of nonmelanoma skin cancers (basal and
squamous cell) and cumulative exposure to ultraviolet radiation. Possible risk factors for melanoma include a propensity to sunburn, a large number of benign melanocytic nevi,
and atypical nevi. A history of severe sunburns, especially
in childhood and adolescence, is associated with increased
risk of melanoma in adulthood. Reduction of sun exposure
through the use of protective clothing and changing ones
pattern of outdoor activities to avoid the most intense and
direct sunlight have been advocated as ways to reduce the
risk of skin cancer. The use of sunscreens is controversial.
Whereas sunscreens decrease the risk of actinic keratoses,
the precursor to squamous cell skin cancer, findings from
epidemiologic studies indicate that an increased risk of
melanoma is associated with sunscreen use. Sunscreen use
may encourage prolonged exposure to the melanomainducing sun rays by protecting against sunburn.22
Chemoprevention
Cancers are prevented through chemoprevention or, in
certain cases, through surgical removal of the organ at risk.
Cancer chemoprevention is the use of natural or synthetic
chemical agents to reverse, suppress, or prevent carcinogenesis before the development of an invasive malignant
process.23 Although the concept that pharmacologic
agents can prevent a cancer is relatively new, the idea that
a compound can prevent chronic disease is not.
Antihypertensive agents are used to prevent heart disease,
kidney disease, and stroke. Lipid-lowering drugs are
prescribed to prevent coronary artery disease.
The initial genetic changes of carcinogenesis are
termed initiation. This alteration can be inherited or
acquired. Acquired genetic damage is the result of physical, infectious, or chemical carcinogens (Table 1-3). The
influences that cause the initiated cell to change phenotypically are called promoters. Known promoters include
androgens linked to prostate cancer and estrogen linked to
breast and endometrial cancers. The distinction between
the initiator and promoter can sometimes blur; some
Epidemiology and Prevention |
These agents are thought to act as cancer initiators or promoters for the
cancers with which they have been associated.
Gastric Cancers
Excessive salt intake, limited consumption of fresh
fruits and vegetables, and infection with Helicobacter pylori
are associated with an increased risk of gastric cancer.
Colon Cancer
Findings from epidemiologic studies suggest that nonsteroidal anti-inflammatory agents, such as piroxicam,
sulindac, and aspirin, have protective effects against adenomatous polyps and invasive cancer. The results of
prospective intervention trials have demonstrated some
positive effects on the prevention of polyps but have yet to
show that these agents prevent colon cancer. In a placebocontrolled trial, high-dose celecoxib, a cyclo-oxygenase-2
(COX-2) inhibitor, was found to reduce the occurrence of
colorectal polyps in patients with familial adenomatous
polyposis. Trials to assess COX-2 inhibitors and other nonsteroidal anti-inflammatory agents for the prevention of
sporadic colorectal cancers are underway.20
The results of epidemiologic studies indicate that diets
high in calcium are associated with a lower risk of colon
cancer. Evidence from prospective randomized studies
shows that calcium supplementation decreases the risk of
recurrence of adenomatous polyps by about 20%. Calcium
binds bile and fatty acids, reducing intraluminal exposure
to compounds that cause hyperproliferation of the colonic
epithelium.
The Womens Health Initiative was a prospective, randomized study involving postmenopausal women randomly assigned to either combination therapy with
estrogen plus progestin or placebo. The rate of colorectal
cancer was lower for women taking the study drug compared with women taking placebo. The effect is, however,
offset by the life-threatening cardiovascular and breast
cancer risks associated with treatment with estrogen plus
progestin.35
Colectomy is used as a preventive measure for individuals at extremely high risk of colon cancer as a result of a
history of ulcerative colitis or a genetic predisposition to
the disease, such as familial adenomatous polyposis.36
Breast Cancer
Tamoxifen has mixed estrogenic and antiestrogen
activities. It acts as an estrogen agonist in the
endometrium and bone and as an estrogen antagonist
in breast tissue. It also upregulates transforming growth
factor-beta, which decreases breast cell proliferation. In
randomized, placebo-controlled trials to assess tamoxifen
as an adjuvant treatment for patients with early-stage
breast cancer, women receiving this drug were found to
have one-third fewer new cancers in the contralateral
breast than women receiving placebo. The Breast Cancer
Prevention Trial was a randomized, placebo-controlled
study of more than 13,000 women at high risk of breast
cancer. After a median treatment of 69 months, tamoxifen
was found to decrease the period risk of breast cancer by
49%. It was also associated with a reduction in bone fractures and a small increase in risk of endometrial cancer,
stroke, pulmonary emboli, and deep vein thrombosis.24
A trial to compare tamoxifen with another selective
estrogen-receptor modulator, raloxifene, is underway.
Raloxifene may have similar efficacy as a breast cancer
preventive agent with less risk of endometrial cancer.
Prophylactic bilateral mastectomy to prevent breast
cancer has not been well assessed. In a prospective series
of 139 women with BRCA1 and BRCA2 mutations, 76
chose prophylactic bilateral mastectomy and 63 chose
close surveillance. At three years, there was no breast cancer diagnosed in those who chose surgery; eight women in
the surveillance group had been diagnosed with breast
cancer. This study is small, of short duration, and, by
design, prone to selection biases. It is fair to say that the
short-term risk of breast cancer appears to be lower for
women with certain BRCA1 and BRCA2 mutations who
choose prophylactic mastectomy. Because this surgery
leaves some breast tissue behind, a patients risk is not
reduced to zero. Retrospective analysis of mastectomies
for women at high risk because of family history suggests
that prophylactic mastectomy can lead to a 90% reduction in risk. The impact of this procedure on mortality for
women at high risk of breast cancer is not completely
known.38
Prostate Cancer
Liver Cancer
Hepatitis B-induced hepatoma is one of the most common cancers diagnosed in Asia. The hepatitis B vaccine
has been advocated for its ability to prevent the disease.
Gynecologic Cancer
There are limited epidemiologic data to suggest that
the use of oral contraceptives by women in their 20s and
30s decreases the risk of ovarian cancer in later life.41
Laser ablation, conization, or hysterectomy are used to
treat cervical dysplasia or intraepithelial neoplasia, precursor to cervical cancer. In the future, vaccines for human
papillomavirus may prevent cervical cancer.
Cancer Screening
Screening is an attempt to detect disease early in
asymptomatic individuals, with the goal of intervening
and decreasing morbidity and mortality. A screening test
is not generally diagnostic for cancer. It is usually per8
KEY POINTS
Cancer screening is far more complicated than
just doing a test and finding a localized cancer.
The biases of screening are selection, lead time,
length, and overdiagnosis. These biases can make
a screening test appear beneficial when there is
actually net harm.
A number of expert organizations have rigorously
accessed the scientific data supporting screening
methods and made recommendations.
Potential Biases
Screening is subject to several biases, including lead
time, length, and selection bias, the influences of which
are lessened in a randomized trial. All can lead one to
believe that there is a benefit to a screening test when, in
truth, there is none; there can even be a net harm.
Screening, whether beneficial or not, will increase the
number of specific cancers diagnosed. It can also produce
a shift in stage that will improve survival statistics without reducing mortality (i.e., the number of deaths of a
given cancer per number of people at risk of the disease).
In such a case, apparent duration of survival, measured
from the date of diagnosis, would increase without lives
being saved or life expectancy being changed.
When pure lead-time bias occurs, survivalthe time
from diagnosis to deathis increased, but treatment does
not prolong life. Patients do not live longer, they are
merely diagnosed at an earlier date. The screening test
only prolongs the time the individual is aware of the
disease and the time as a patient.
Length bias occurs when slow-growing, less aggressive
cancers are detected during screening. Cancers diagnosed
Accuracy
The accuracy of any medical test is described using
four indices: sensitivity, specificity, positive predictive
value, and negative predictive value, and the results of
screening tests can be classified into four categories
(Tables 1-4 and 1-5). Sensitivity and specificity are relatively independent of the underlying prevalence or risk of
the population being screened, but the positive and
Definition
Proportion of people with the disease who
have a positive result on a screening test
Proportion of people who do not have the disease and
who have a negative result on a screening test
Proportion of people with a positive result on a
screening test and actually have the disease
Proportion of people who have a negative results on
a screening test and truly do not have the disease
Ability of Test
Equation*
A / (A + C)
D / (B + D)
A / (A + B)
D / (C + D)
*A = true-positive result, B = false-positive result, C = false-negative result, D = true-negative result. Refer to Table 1-5 for definitions of these types of test results.
Test
Result
Disease
Present
Positive
Positive
Negative
Negative
Yes
No
Yes
No
negative predictive values are highly dependent on prevalence (Table 1-6). In other words, screening is most beneficial, efficient, and economical when targeting a cancer
common to the general population or groups with a high
prevalence (or high risk) of the specific disease being
screened. For a screening test to be valuable, high specificity is needed. Sensitivity need not be extremely high
(Table 1-6).46
(Sensitivity)(Prevalence)
(Sensitivity)(Prevalence) (1-Specificity)(1-Prevalence)
Sensitivity
0.8
Specificity
0.95
0.999
7%
80%
Sensitivity
0.95
9%
83%
Specificity
0.95
0.999
0.8
0.95
0.2%
7%
0.2%
9%
*The positive predictive value is expressed as a percentage. It is influenced by the sensitivity and specificity of the screening test and the prevalence of the
disease being screened for. The positive predictive value is particularly influenced by the specificity of the screening test at a given prevalence for relatively
uncommon diseases, such as cancer.
10
Table 1-7. Screening Recommendations for Asymptomatic Subjects with Normal Risk*
Test or Procedure
Sigmoidoscopy
Insufficient evidence
Insufficient evidence
Poor evidence to include or
exclude for men older than 50 years
Recommendation against
Fair evidence to include in the
examination of sexually active
women
Prostate-specific antigen
Pap test
Pelvic examination
Not considered
Breast self-examination
No recommendation
Mammography
Not considered
*These recommendations were made for the general population; that is, asymptomatic people who have no risk factors, other than age or gender, for the targeted
condition.
Cervical Cancer
No randomized clinical trial has been completed to
determine whether cervical cancer screening with the Pap
test reduces mortality, but findings from several cohort and
case-control studies have shown the utility of the Pap test.
Regular Pap testing is recommended for women who are
sexually active or over the age of 18. The recommended
interval for Pap screening ranges from one to three years.
An upper age limit at which screening ceases to be
effective is not known.
The American Cancer Society recently revised its
screening guidelines to recommend that screening start
about three years after a woman begins having vaginal
intercourse, but no later than age 21.52 The society recommends that cervical screening be performed annually in
the case of regular Pap tests or every two years in the case
of liquid-based cytologic tests. Women who have had normal results on three consecutive tests may be screened
every two to three years. Women with certain risk factors,
such as infection with the human immunodeficiency virus
(HIV) or a weakened immune system, might be screened
more frequently. Women 70 years and older who have had
normal results on three or more Pap tests and no abnormal
11
REFERENCES
1. Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER
Cancer Statistics Review, 1975-2000. Bethesda, Md:
National Cancer Institute; 2003. Available at: http://seer.
cancer.gov/csr/1975_2000. Accessed April 26, 2004.
2. Jemal A, Murray T, Samuels A, et al. Cancer statistics,
2003. CA Cancer J Clin. 2003;53:5-26.
3. Welcsh PL, King MC. BRCA1 and BRCA2 and the
genetics of breast and ovarian cancer. Hum Mol Genet.
2001;10:705-713.
4. Brawley OW. Population categorization and cancer
statistics. Cancer Metastasis Rev. 2003;22:11-19.
13
14
Questions
1. Which of the following describes the difference
between efficacy and effectiveness in the interpretation
of clinical trial results?
A. Efficacy considers the outcomes of a treatment under
carefully controlled conditions, whereas effectiveness
considers the outcomes when applying a treatment in the
routine (real-world) setting
B. Efficacy considers short-term and long-term effects,
whereas effectiveness considers long-term effects only
C. Efficacy considers only the effect of survival, whereas
effectiveness considers all outcomes
D. Efficacy is a clinical measure, whereas effectiveness is
statistical measure
Tamoxifen therapy
Raloxifene therapy
Annual mammography
Adoption of a low-fat diet
3. Which of the following provides the strongest evidence that a cancer screening test is beneficial?
A. Increased five-year survival of those screened compared
with historical controls
B. Earlier stage at time of diagnosis for those screened
compared with those not screened
C. Large numbers of so-called cured patients who die of
causes other than cancer
D. Decreased cause-specific mortality for those in the
screened arm compared with those in the control arm of a
randomized clinical trial
15
A.
B.
C.
D.
90 divided by (1 + 90)
8 divided by (90 + 1)
90 divided by (90 + 8)
8 divided by (8 + 1)
16
9. A postmenopausal woman is considering using estrogen and progesterone and asks you for information.
Which of the following do you tell you about the use of
these agents in postmenopausal women?
A. This use has been shown to lower the risk of cardiovascular
disease
B. This use has been shown to lower the risk of colorectal
cancer
C. This use has been shown to lower the risk of breast cancer
D. This use has been shown to improve cognition
Explanatory Answers
1. A
Educational Objective: To understand the concepts of
efficacy and effectiveness as they relate to the interpretation of clinical trials results.
Efficacy is the outcome of a clinical trial. The population
enrolled in the study will differ from the population at
large. Participants in clinical trials generally have less
comorbid disease and, in prevention studies, there is often
a healthy volunteer effect. Volunteers are often more
interested in health than the average member of the population at large. How well the intervention works in the
group as a whole in routine practice is termed effectiveness.
There are a few trials with effectiveness endpoints. Such
studies are generally large and long-term.
Suggested Reading
Kramer BS, Brawley OW. Cancer screening. Hematol
Oncol Clin North Am. 2000;14:831-848.
Suggested Reading
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen
for prevention of breast cancer: report of the National
Surgical Adjuvant Breast and Bowel Project P-1 Study. J
Natl Cancer Inst. 1998;90:1371-1388.
Greenwald P, Clifford CK, Milner JA. Diet and cancer
prevention. Eur J Cancer. 2001;37:948-965.
Thomas DB, Gao DL, Ray RM, et al. Randomized trial of
breast self-examination in Shanghai: final results. J Natl
Cancer Inst. 2002;94:1445-1457.
Wickerham, DL. Tamoxifen versus raloxifene in the prevention of breast cancer. Eur J Cancer. 2002;38:S20-S21.
2. A
3. D
In randomized, placebo-controlled trials to assess tamoxifen as an adjuvant treatment for patients with early stage
breast cancer, women taking the drug were found to have
one-third fewer new cancers in the contralateral breast
than women taking placebo. The Breast Cancer
Prevention Trial was a randomized, placebo-controlled
study of more than 13,000 women at high risk of breast
cancer. After a median treatment of 69 months, tamoxifen was found to decrease the period risk of breast cancer
by 49%. Tamoxifen was also associated with a reduction
in bone fractures and a small increase in the risk of
endometrial cancer, stroke, pulmonary emboli, and deepvein thrombosis. A trial to compare tamoxifen with
another selective estrogen-receptor modulator, raloxifene, is underway. Raloxifene may have similar efficacy
The major reason to screen for cancer is to decrease mortality. A second reason would be to decrease morbidity
associated with treatment. Assessment of survival outside
of a randomized control trial is subject to lead-time bias.
It is possible to have survival after screening increase
while mortality also increases.
A screening intervention is best assessed in a randomized,
controlled screening trial with cause-specific mortality as
the endpoint. Studies showing a reduction in the incidence of advanced stage disease, improved survival, or a
shift in stage of the disease are weaker and offer potentially misleading evidence of benefit. These latter criteria
by themselves are not sufficient to establish the value of a
screening test.
Epidemiology and Prevention |
17
Suggested Reading
Harris R, Lohr KN. Screening for prostate cancer: an
update of the evidence for the U.S. Preventive Services
Task Force. Ann Intern Med. 2002;137:917-929.
Kramer BS, Brawley OW. Cancer screening. Hematol
Oncol Clin North Am. 2000;14:831-848.
Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer
screening: what we know and what we need to know. Ann
Intern Med. 1993;119:914-923.
Mandel JS, Church TR, Bond JH, et al. The effect of fecal
occult-blood screening on the incidence of colorectal
cancer. N Engl J Med. 2000;343:1603-1607.
NIH consensus conference. Ovarian cancer. Screening,
treatment, and follow-up. NIH Consensus Development
Panel on Ovarian Cancer. JAMA. 1995;273:491-497.
5. C
Suggested Reading
Kramer BS, Brawley OW. Cancer screening. Hematol
Oncol Clin North Am. 2000;14:831-848.
Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer
screening: what we know and what we need to know. Ann
Intern Med. 1993;119:914-923.
Smith RA, Cokkinides V, Eyre HJ. American Cancer
Society guidelines for the early detection of cancer, 2003.
CA Cancer J Clin. 2003;53:27-43.
4.
Educational Objective: To understand the impact of screening on cancer and population statistics.
Screening, whether beneficial or not, will increase the
number of specific cancers diagnosed in a population. Any
benefit, be it improvement in survival beyond the leadtime bias of screening or a decrease in morbidity or mortality, will only be seen much later. Some of the additional
cancers may be more indolent and less aggressive and
would not have been clinically diagnosed later in life. This
is the concept of length bias and, more specifically, the
more extreme form of length bias known as overdiagnosis.
Length bias occurs when slow-growing, less aggressive
cancers are detected during screening. Cancers diagnosed
as a result of the onset of symptoms between scheduled
screenings are, on average, more aggressive, and treatment outcomes are not as favorable. An extreme form of
length bias is referred to as overdiagnosis, or detection
of pseudodisease. Some undetected slow-growing tumors
fulfill the histologic criteria of cancer but will never be
clinically significant or cause death.
18
7. D
Educational Objective: To calculate and understand the
concept of sensitivity, specificity, positive predictive
value, and negative predictive value.
When screening for a particular condition, the following
outcomes are possible:
Condition
Condition
Present
Absent
Positive results True positive (A) False-positive (B)
Negative results False negative (C) True negative (D)
Sensitivity is the proportion of people with the condition
who have a positive test result: A divided by (A plus C).
Specificity is the proportion of people without the
condition who have a negative test result: D divided by
(B plus D).
Positive predictive value is the proportion of people with
a positive test result who have the condition: A divided
by (A plus B).
Negative predictive value is the proportion of people with
a negative test result who do not have the condition: D
divided by (C plus D).
The Womens Health Initiative was a prospective, randomized study involving postmenopausal women who
were randomly assigned to either estrogen plus progestin
or placebo. A lower rate of colorectal cancer was seen in
women taking the combination therapy than in women
taking placebo. This positive effect is, unfortunately, offset by the increased life-threatening cardiovascular and
breast cancer risks associated with treatment with estrogen plus progestin. Among postmenopausal women 65
years or older, treatment with this combination did not
improve cognitive function when compared with placebo.
Although most women taking estrogen plus progestin did
not have clinically relevant adverse effects on cognition
compared with women taking placebo, a small increased
risk of clinically meaningful cognitive decline did occur
in the treated group.
Suggested Reading
Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review.
JAMA. 2002;288:872-881.
Rapp, SR, Espeland, MA, Shumaker, SA, et al. Effect of
estrogen plus progestin on global cognitive function in
postmenopausal women: the Womens Health Initiative
Memory Study: a randomized controlled trial. JAMA.
2003;289:2663-2672.
8. A
19