Carcinogenesis vol.31 no.1 pp.100–110, 2010
doi:10.1093/carcin/bgp263
Advance Access publication November 24, 2009
The global burden of cancer: priorities for prevention
Michael J.ThunÃ
, John Oliver DeLancey, Melissa
M.Center, Ahmedin Jemal and Elizabeth M.Ward
American Cancer Society, Research Department, 250 Williams Street,
Northwest, Atlanta, GA 30303-1002, USA
Ã
To whom correspondence should be addressed. Tel: þ1 404 329 5747;
Fax: þ1 404 327 6450;
Email: michael.thun@cancer.org
Despite decreases in the cancer death rates in high-resource
countries, such as the USA, the number of cancer cases and
deaths is projected to more than double worldwide over the next
20–40 years. Cancer is now the third leading cause of death, with
>12 million new cases and 7.6 million cancer deaths estimated to
have occurred globally in 2007 (1). By 2030, it is projected that
there will be $26 million new cancer cases and 17 million cancer
deaths per year. The projected increase will be driven largely by
growth and aging of populations and will be largest in low- and
medium-resource countries. Under current trends, increased
longevity in developing countries will nearly triple the number
of people who survive to age 65 by 2050. This demographic shift
is compounded by the entrenchment of modifiable risk factors
such as smoking and obesity in many low-and medium-resource
countries and by the slower decline in cancers related to chronic
infections (especially stomach, liver and uterine cervix) in economically
developing than in industrialized countries. This paper
identifies several preventive measures that offer the most
feasible approach to mitigate the anticipated global increase in
cancer in countries that can least afford it. Foremost among these
are the need to strengthen efforts in international tobacco control
and to increase the availability of vaccines against hepatitis B
and human papilloma virus in countries where they are most
needed.
Introduction
Cancer is now the third leading cause of death worldwide, with .12
million new cases and 7.6 million cancer deaths estimated to have
occurred in 2007 (1). By 2030, it is projected that there will be $26
million new cancer cases and 17 million cancer deaths per year (2).
Moreover, the global distribution of cancer and types of cancer that
predominate continues to change, especially in economically developing
countries. Low- and middle-income countries accounted for
about half (51%) of all cancers worldwide in 1975; this proportion
increased to 55% in 2007 and is projected to reach 61% by 2050 (3).
Cancers of the lung, breast, colon/rectum and prostate are no longer
largely confined to Western industrialized countries but are among the
most common cancers worldwide.
This global increase in the cancer burden and its disproportionate
impact on economically developing countries is being propelled by
both demographic changes in the populations at risk and by temporal
and geographic shifts in the distribution of major risk factors. The
three most important factors that contribute to these trends are:
1. Growth and aging of populations;
2. The entrenchment of modifiable risk factors (particularly cigarette
smoking, Western diet and physical inactivity) in developing
countries and
3. The slower decline in cancers related to infectious etiologies in
low-resource countries than in high-resource countries.
The first of these largely reflects progress in reducing death rates
from acute infectious conditions among children and young adults.
Unfortunately, this has not historically been matched by parallel
efforts to control the major modifiable risk factors that cause cancer
and other chronic diseases. Given the magnitude of the projected demographic
trends and their disproportionate impact on countries that
can least afford increased health care expenditures, preventive measures
offer the most feasible approach. This paper identifies several
preventive measures that could mitigate the expected increase in the
number of people affected by cancer over the next 20–40 years.
Foremost among these are the need to strengthen efforts in international
tobacco control and to increase the availability of vaccines
against hepatitis B virus (HBV) and human papilloma virus (HPV)
in countries where they are most needed. Both tobacco control and
universal childhood vaccination have been proven to be highly effective
and cost effective in countries across a wide range of economic
development. Both have the potential to provide the greatest benefit at
the lowest cost.
Global population changes
Population growth and aging are the largest contributors to the
increasing total number of cancer cases and the shift in the burden
of cancer and other chronic diseases toward economically developing
countries. The world population in 2008 was 6.7 billion. Barring
a catastrophe, this number is expected to increase to 8.3 billion
in 2030 (2) and to 8.9 billion by 2050 (3). Figure 1 illustrates that
the projected population growth will be much larger in low- and
medium-resource countries than in high-resource countries, even
in older age groups. For example, the number of people age
65 and above in low- and medium-resource countries is expected
to increase from 247 million to 982 million between the year
2000 and 2050. The corresponding increase in people age 65 and
above in high-resource countries will be from 171 million to 376
million. Aging of populations will disproportionately affect
the number of people who develop or die from cancer since almost
half (45%) of cancers diagnosed worldwide in 2002 occurred in
people .65 years of age (3).
Estimates of the future impact of population growth and aging on
the global cancer burden depend on assumptions about the anticipated
changes in cancer incidence rates as well as changes in the underlying
population at risk. However, it is more difficult to predict global trends
in incidence rates than to project demographic changes because the
information on cancer incidence rates is limited or non-existent for
large areas of the world and there is great variation among countries.
Hence, some projections of the future cancer burden assume that the
global cancer incidence rates will remain constant over time and that
the number of cancer cases and deaths will be affected only by growth
and aging of the population. For example, Figure 2 illustrates the
expected global increase in incident cancer cases from 2002 to
Abbreviations: EBV, Epstein Barr virus; FCTC, Framework Convention on
Tobacco Control; HBV, hepatitis B virus; HCC, hepatocellular carcinoma;
HCV, hepatitis C virus; HAART, highly active antiretroviral therapy; HHV-
8, human herpes virus 8; HIV, human immunodeficiency virus; HPV, human
papilloma virus; KS, Kaposi’s sarcoma; NHL, non-Hodgkin’s lymphoma;
WHO, World Health Organization.
Ó The Author 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2050 under this assumption. Even without any increase in the cancer
incidence rate, the number of cases anticipated in 2050 (24 million)
would be more than twice the number in 2002 (10.8 million). Most of
this increase would occur in low- and middle-resource countries (3).
By comparison, the number of cancers that the International Agency
for Research on Cancer projects by 2030 (26 million) is substantially
higher than the estimate in Figure 2 (18.9 million) because the International
Agency for Research on Cancer assumes a 1% annual
increase in the incidence rate as well as the anticipated demographic
changes in the population at risk (2).
Tobacco use and prevention of tobacco-related cancers
Tobacco use is the single largest preventable cause of cancer and
premature death worldwide. An estimated 1.3 billion people in the
world currently smoke tobacco; the vast majority of these smoke
manufactured cigarettes (4). If current trends in smoking and population
growth continue, the number of current smokers is expected to
reach 2 billion worldwide by 2030 (5). As shown in Figure 3, smoking
prevalence is highest among men in Eastern Europe, the former Soviet
Union, China and Indonesia. Cigarette smoking among women has
been decreasing in most high-resource countries but is stable or
increasing in several countries in Southern, Central and Eastern
Europe (4). With the decline of tobacco use in many industrialized
countries, the geography of smoking has shifted from the developed
to the developing world, especially for men. About 50% of men and
9% of women are current smokers in developing countries, compared
with 35% of men and 22% of women in high-resource countries
(4). Over 60% of all smokers in the world live in just 10
countries (in order): China, India, Indonesia, Russian Federation,
USA, Japan, Brazil, Bangladesh, Germany and Turkey (6). The
number of current smokers in China approximately equals the entire
population of the USA. While most of these smokers are currently
under age 40, the combination of continued smoking and aging will
vastly increase the future adverse effects of tobacco use on cancer
and other chronic diseases, unless effective campaigns can be
mounted to promote cessation.
The International Agency for Research on Cancer designates at
least 15 different types or subtypes of cancer as causally related to
smoking (7). These include cancers of the lung and bronchus (all
histological subtypes), larynx, oral cavity, pharynx, lip, nasopharynx,
nasal cavity and paranasal sinuses, esophagus (squamous and adenocarcinoma),
bladder, kidney (parenchyma and renal pelvis), pancreas,
uterine cervix, stomach, liver and acute myeloid leukemia (7).
Cancers attributed to cigarette smoking accounted for more than
one-fifth of the estimated 1.42 million cancer deaths that occurred
globally in the year 2000 (8). Lung cancer is the most common cancer
caused by smoking, even though it accounts for less than half of all
smoking-attributable deaths (9). Cigarette smoking accounts for
$80% of lung cancer cases in men and 50% in women worldwide
(5). Lung cancer has been the most common cancer in the world since
1985 (10).
300
0 - 4
5 - 9
10 - 14
15 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 44
45 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
75 - 79
80 - 84
85 - 89
90 - 94
95 - 99
100 +
Age
Men Women
World population, 2000 and 2050
Low and medium
resource countries
2000 2050
Source: U.S. Census Bureau, International Data Base, June 2009 data release
* Population is projected to decrease between 2000 and 2050 in age groups <55 yrs old in developed countries;
difference not shown
Population (Millions)
-200-300 -100 0 100 200 50
0 - 4
5 - 9
10 - 14
15 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 44
45 - 49
50 - 54
55 - 59
60 - 64
65 - 69
70 - 74
75 - 79
80 - 84
85 - 89
90 - 94
95 - 99
100 +
High Resource
Countries*
500
Fig. 1. Growth and aging of world population, 2000 and 2050 by gender and level of economic development.
2002 2010 2030 2050
10.8 12.8 18.9 24.0
High resource countries
Low and middle resource countries
Estimated cancers (millions):
Year:
Source: IARC, Globocan 2002
Fig. 2. Number and distribution of cancer cases by level of economic
development and year assuming no change in the annual incidence rate.
Global Priorities for Prevention
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In many countries, temporal trends in smoking, and more recently
in smoking cessation, have been so extreme that they have dominated
national trends in cancer mortality (9). For example, the downturn in
death rates from smoking-related cancers in men, ages 65–69 that
began in the UK in the early 1960s, in the USA in the mid-1980s
and in Poland in the early 1990s, has been the major driver in the
downturn in death rates from all cancers combined in these countries
(9). This has occurred despite the delay that occurs between reductions
in smoking prevalence and reductions in lung cancer mortality,
seen when comparing Figures 3 and 4 for men in North America and
Western Europe. Progress in reducing male lung cancer rates was
achieved principally by smoking cessation among adult men.
Unfortunately, cessation rates are much lower in large developing
countries like China than in the West. In China, many millions of
young cigarette smokers who began smoking in adolescence are
now aging. The future risks of cancer or other diseases caused by
smoking may eventually be greater among these younger generations
of Chinese men who began smoking in childhood than those now seen
among Chinese smokers who initiated smoking later in life (9).
Despite this bleak picture, much progress can and is being made to
reduce tobacco smoking, especially in high-resource countries. In the
USA, per capita cigarette consumption has decreased to levels not
seen since the start of World War II. Projections based on data from
the Food and Agriculture Organization of the United Nations indicate
that tobacco consumption will continue to fall in economically developed
countries but will rise in most low- and medium-resource
countries (11). A number of interventions have proven to be effective
in reducing the demand for tobacco products and in changing social
norms about smoking. Tax policies that raise the price of tobacco
products are the single most effective approach for reducing demand.
Price increases are an especially powerful deterrent against the initiation
of smoking in youth (12,13,14) and motivation for addicted
smokers to quit. Although the impact of price on cigarette demand
varies widely depending on the population studied and study design,
a 10% increase in cigarette prices result in a 2.5–5% reduction in
cigarette demand in high-resource countries. Estimates of price
responsiveness in low- and middle-income countries are at least as
large (15).
Smoke-free laws that prohibit smoking in public places substantially
reduce non-smokers’ exposures to secondhand smoke, change
social norms about smoking and motivate smokers to quit. Successful
smoke-free interventions by Ireland and other countries have greatly
broadened the protection of non-smokers. Public awareness about the
harmful effects of tobacco on health can be increased by requiring
prominent, graphical warnings on cigarette packaging (16) and by
educational campaigns aimed at health professionals. These are
Fig. 3. Prevalence of male and female smoking by geographic region.
M.J.Thun et al.
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especially important in low- and medium-resource countries, where
baseline levels of awareness about the extent of tobacco’s deleterious
effects are low and doctors still smoke. In China, 61.3% of
male physicians smoke, compared with 66.9% of the general male
population.
Many of the adverse health effects of smoking can be averted by
cessation. Smoking cessation is the only effective way to reduce risk
for the 1.3 billion smokers in the world. As mentioned above, widespread
smoking cessation among men in high-income countries since
the 1950s is largely responsible for the significant decrease in death
rates from lung and other smoking-related cancers in these countries.
Although pharmacological treatment is less affordable in economically
developing than in high-resource countries, brief counseling
interventions by health care personnel are feasible. Counseling about
smoking cessation can be integrated into other public health and
health care delivery programs, such as tuberculosis, human immunodeficiency
virus (HIV)/AIDS, family planning and maternal health
programs.
No single country can successfully combat the resources of the
international tobacco companies. Thus, nations have united behind
the Framework Convention on Tobacco Control (FCTC), the first
health treaty negotiated under the auspices of the World Health
Organization (WHO). The FCTC provides a framework for national
legislation and enforcement of tobacco control measures. The FCTC
was promulgated in May 2003 in response to the global tobacco
pandemic with the objective of substantially reducing the worldwide
prevalence of tobacco use and exposure to tobacco smoke. As of
August 2009, 166 countries have ratified the treaty, representing
$80% of the world’s population. FCTC provisions establish international
standards for tobacco taxation, advertising and sponsorship,
regulation, trade, etc. Effective measures against smuggling are especially
important. Estimates suggest that 6–8% of cigarettes consumed
globally are contraband products, shipped to avoid taxes. Smuggling
can be deterred by prominent tax stamps that cannot be counterfeited
easily, local language warnings on cigarette packs and aggressive
enforcement of anti-smuggling measures and penalties.
Diet, obesity and physical inactivity
Like tobacco, obesity, physical inactivity and poor nutrition are established
causes of several types of cancer. Rapid increases in the prevalence
of obesity (defined by WHO as body mass index .30 in adults)
have occurred in the USA since the 1970s and more globally since the
1980s (17). The trend toward overweight and obesity is even greater in
Fig. 4. Lung cancer incidence in males and females.
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children than in adults and has occurred not only in high-resource
countries but also in urban and even rural areas of many low- and
middle-income countries (17). WHO estimates that the number of
overweight adults (age .15) in 2005 was $1.6 billion, of whom
300 million were obese. The number of overweight was projected
to increase to 2.3 billion by 2015 (18).
The global increase in overweight and obesity is attributed to increased
availability of calorie-dense foods and decreased physical
activity. Food supplies have become more plentiful and foods, especially
processed foods, have become more energy dense in fats and
sugars (17). Coinciding with this, humans have become more sedentary
as mechanization has eliminated much of the need for involuntary
physical activity. Excess adiposity, especially visceral adiposity, is
known to increase risk of a variety of cancers, including breast (postmenopausal),
endometrium, colon/rectum, esophagus (adenocarcinoma)
and kidney. Despite the negative health, social and economic
consequences of obesity, efforts are just beginning to develop solutions
to the problem. People who have gained weight generally have
great difficulty losing it and maintaining weight loss. There is great
interest in identifying policy measures to help people maintain
a healthy weight throughout life. However, research in this area is
currently at an early developmental stage and evaluation of these
methods is ongoing.
Cancers related to chronic infections
Persistent infection with various microbial organisms accounts for
$18% of cancers worldwide (19). The most common malignancies
caused by chronic infections are cancer of the uterine cervix, stomach
and liver, caused by HPV, Helicobacter pylori (H.pylori) and HBV
and Hepatitis C (HCV) virus, respectively (Table I). Several other
cancer sites related to infectious agents that occur mostly regionally
are also listed in Table I. These include Kaposi’s sarcoma (KS) caused
by human herpes virus 8 (HHV-8), nasopharyngeal cancer and certain
lymphomas from Epstein Barr virus (EBV), bladder cancer from
Schistosoma haematobium, leukemia from human t-cell lymphotropic
virus and biliary tract cancer from onchocerciasis.
In terms of global patterns, the incidence rates from cancers of
the stomach and liver have been falling in most countries worldwide,
although the decrease has been slower in low- and mediumresource
countries than in the West. The percentage of cancers
attributed to infections remains about three times higher in developing
(26%) than in developed (8%) countries (20). For most cancers
related to infectious organisms, chronic inflammation is an
important component of pathogenesis. Some viruses incorporate
their genetic material directly into host cell DNA (21). The remaining
sections of this paper will focus on the most common infectionrelated
cancers for which vaccines and other preventive approaches
are available.
HPV-related cancers
Cervical cancer is the second most common cancer among women
worldwide, with an estimated 555 000 new cases and 310 000 deaths
in 2007. About 80% of cervical cancer cases occur in developing
countries where, in many regions, it is the most common cancer
among women (2). Although the age-standardized incidence rate is
considerably lower in Asia than in Central America, Asia accounts for
more than half of the world’s cervical cancer cases and deaths because
of its immense population.
Incidence and mortality rates for cervical cancer in developed
countries have decreased dramatically in the past 25 years, due largely
to cervical cancer screening using Pap tests, which allows for detection
and treatment of precancerous lesions. The incidence and death
rates remain high in countries that cannot afford cytologic screening,
where oncogenic strains of HPV are still common. Worldwide, the
highest incidence rates are in South America and the Caribbean, SubSaharan
Africa and South and Southeastern Asia. The disproportionate
burden of cervical cancer on developing countries is due mainly to
lack of resources for cervical cancer screening.
Virtually, all cases of cervical cancer result from recurrent cervical
infections with HPV (22). About 40 HPV viral types have been found
to infect the anogenital tract (23). A recent pooled analysis of case–
control studies from nine countries identified 15 HPV types that are
associated with an increased risk of cervical cancer. Among these
types, HPV 16 and HPV 18 have the highest prevalence among
cervical cancer patients (50.5 and 13.1%, respectively) and are associated
with a .200-fold increased risk of cervical cancer (24). Although
infection with HPV (types 16 and 18 in particular) greatly
increase the risk of developing cervical cancer, such infection is common
and most infected women do not develop cervical cancer. The
prevalence of HPV infection among women as measured among
women without cervical cancer measured in a recent international
study was 15.5%, with 5% being positive for HPV types 16 or 18.
The cumulative lifetime probability of acquiring a cervical infection
with at least one type of HPV is extremely high for sexually active
individuals. However, most HPV infections disappear spontaneously
within 2–4 years, and only a small percentage progress to low- and
high-grade squamous intraepithelial lesions. High-grade squamous
intraepithelial lesion, which includes carcinoma in situ, may progress
to invasive cancer if not detected and treated. Factors that may
influence progression include immunosupression, smoking, increasing
parity (number of children) and coinfection with herpes simplex
virus or chlamydia (25).
Table I. The burden of cancer caused by Infectious agents worldwide
Infectious agent IARC
classificationa
Cancer site/cancer Number of
cancer cases
Percentage of cancer
cases worldwide
Helicobacter pylori 1 Stomach 490 000 5.4
HPV 1, 2A Cervix and other sites 550 000 6.1
HBV, HCV 1 Liver 390 000 4.3
EBV 1 Lymphomas and nasopharyngeal carcinoma 99 000 1.1
HHV-8 2A KS 54 000 0.6
Schistosoma haematobium 1 Bladder 9000 0.1
HTLV-1 1 Leukemia 2700 0.1
Liver flukes Cholangiocarcinoma (biliary system) 800
Opisthorchis viverrini 1
Clonochis sinensis 2A
Total infection-related cancer 1 600 000 17.7
Total cancer in 1995 9 000 000 100
HTLV-1, human t-cell lymphotropic virus.
Source: World Cancer Report 2008 (2).
a
Group 1 5 carcinogenic to humans; Group 2A 5 probably carcinogenic to humans.
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In addition to cervical cancer, HPV infection is associated with
vulvar carcinoma, some oral carcinomas, penile carcinoma and anal
carcinoma. The anus is similar to the cervix in that both have a transformation
zone that is susceptible to HPV infection. The risk of anal
carcinoma is increased among men who have sex with men (26).
Primary prevention
Recently developed cervical cancer vaccines have the potential to
prevent HPV infection; however, effective vaccines against HPV infection
are too costly to be available in high-risk areas. Consequently,
negotiations for tiered pricing must reduce the cost from about $360
per woman and identify alternative sources of funding if the vaccine is
to be made available in the areas of greatest need in the next 10–20
years.
Although some HPV subtypes cause genital warts, most infections
with HPV cause no symptoms. Since HPV can be present in skin
throughout the anogenital area as well as in genital secretions, use of
condoms may be somewhat but not completely protective (26). Circumcision
apparently reduces the risk of transmission and acquisition of
HPV as well as the risk of cervical cancer among female partners (26).
Detection of high-grade squamous intraepithelial lesion and carcinoma
in situ by Pap testing, with effective treatment of precancerous
lesions, is currently the most effective way to prevent cervical cancer.
Pap testing is not available to most women in developing countries.
Barriers to Pap testing in developing countries are substantial and
include lack of public health and medical infrastructure to organize
population screening and follow-up, as well as the high level of expertize
and quality control needed to ensure accuracy of cytologic
diagnosis. In some countries, cultural taboos may also prevent women
from seeking or receiving appropriate screening from male health care
providers. Development and evaluation of alternative screening strategies
for use in developing countries has been a high priority for
international health agencies. Visual inspection of the cervix after
applying acetic acid is one cost-effective technique (27). Training
and employing midwives and other female health workers offers some
potential for overcoming cultural barriers.
Secondary prevention
In addition to preventing invasive cervical cancer, Pap testing can
detect cervical cancer at an early stage, when it is most readily treated.
Fig. 5. Liver cancer incidence in males and females.
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Liver cancer, HBV and hepatitis C virus
Liver cancer is the fifth most common cancer in men and the eighth
most common in women (1). An estimated 711 000 cases of primary
liver cancer occured worldwide in 2007; about three-quarters of these
are hepatocellular carcinoma (HCC). Liver cancer is the third leading
cause of cancer death worldwide with an estimated 680 000 deaths
occurring in 2007. More than 80% of cases occur in developing countries;
.55% occur in China alone. Figure 5 illustrates that liver cancer
incidence rates are highest in West and Central Africa and in Asia,
especially among men.
Globally, $75% of all liver cancer cases and 50% of all deaths are
caused by chronic infection with either HBVor HCV (1). The fraction
of cases attributable to HBV is greater in developing countries (59%)
than in developed countries (23%) The corresponding percentages for
HCV are 33 and 20%, respectively (1). Both HBV and HCV are directly
transmitted by person-to-person contact with blood or other
body fluids. Hepatitis A, another common agent of viral hepatitis, is
usually transmitted through contaminated food and does not cause
liver cancer.
A safe and effective vaccine against HBV has been available since
1982. No vaccine has yet been developed for HCV, which accounts for
$10% of liver cancer deaths worldwide. Vaccination for HBV is the
most cost-effective strategy to reduce liver cancer. Effective vaccination
programs could avert at least 300 000 liver cancer deaths per
year. The cost of the vaccine has been reduced from $100 to $1 (for
three doses of treatment) through the efforts of the Global Alliance
for Vaccines and Immunization. Over three-quarters of WHO member
states have introduced hepatitis B vaccine into routine infant immunization
schedules, although in many places it is difficult to deliver the
vaccine within 24 h of birth. Vaccine delivery is particularly challenging
in high risk, low-resource areas of Africa.
HBV
Approximately 54% of liver cancer worldwide is attributed to chronic
infection with HBV (20). Chronic (long term) infection with HBV is
indicated by persistence of hepatitis B surface antigen (a marker of
active Hepatitis B infection) in the blood after the acute infection has
passed. The probability of developing chronic infection is much higher
for infants and children than for adults. People with chronic infection
are also referred to as ‘chronic carriers’ because they are able
to infect others. Among people who have had HBV infection, only
those with chronic infection are at increased risk of developing
chronic liver disease, cirrhosis and liver cancer (28).
About 350 million people in the world today (29), and 1.25 million
people in the USA (30), are chronic carriers of HBV. HBV may be
transmitted by mucous membrane or skin contact only when there are
breaks (even small and insignificant ones) in these barriers. It may be
transmitted by injection or sexual intercourse or pass from a mother to
her baby during birth. Because HBV is able to remain infectious for
about a week on any surface, minute exposures from sharing of toothbrushes,
razors and other items in household settings can result in
transmission (31). An important cause of HBVinfection in developing
countries is reuse of syringes or needles between patients without
sterilization. An estimated 20% of new HBV infections worldwide,
or 8–16 million infections per year, arise from unsafe injections in
medical care settings (32).
In high-prevalence areas of the world, HBV infection in $70% of
cases is acquired at birth or in early childhood. In industrialized
countries, infection more often occurs in adolescence and young
adulthood and is associated with high-risk behaviors such as injection
drug use and multiple sex partners. Health care workers and patients
with exposure to pooled blood products, such as hemophiliacs, are
also at increased risk.
The exact mechanism by which HBV infection causes HCC is unknown.
Tumor cells of patients with liver cancer often have DNA
from HBV inserted into cellular DNA. Inflammation and scarring of
the liver (cirrhosis) may contribute to malignant transformation.
Although 60–90% of patients with HCC due to chronic HBV have
cirrhosis, it is possible to develop HCC without cirrhosis (33). Exposure
to aflatoxins (toxic products of mold in grains and other foods
products) may be a significant cofactor in localized areas (34).
Primary prevention. Three doses of vaccine against HBV are needed
to achieve adequate long-term immunity. It is recommended that all
infants, unvaccinated adolescents and adults in high-risk groups receive
the vaccine. The first dose for infants should be administered
within 24 h. This is difficult in many parts of the worlds since about
half of all babies born worldwide are born at home. In countries such
as Indonesia, however, trained birth attendants have been taught to
administer the vaccine to babies at home. It is also recommended that
all pregnant women be tested for HBV carrier status; if positive, the
newborn infant receives Hepatitis B immune globulin as well as Hepatitis
B vaccine within 12 h after birth (35). This treatment is highly
effective in preventing infection in newborns.
In high-resource countries, vaccination of infants and children and
screening of blood donors for HBV surface antigen have greatly
decreased the incidence of acute HBV, especially among people under
the age of 20 (30,31). The burden of HBV infection and resulting liver
disease and HCC is much greater in the developing world than in
developed countries due to greater barriers to prevention. Although
the WHO recommends HBV vaccination for all infants, many poor
countries have been unable to implement this recommendation due to
the cost of obtaining and administering the vaccine. In 1999, a commitment
by the Bill and Melinda Gates Foundation of $750 million
over 5 years led to the development of the Global Alliance for
Vaccines and Immunization , an international partnership created to
improve access to sustainable immunization services.
Screening of blood products and sterilization of injection equipment
is essential to reduce HBV transmission in medical settings.
Another potential way to reduce the incidence of HCC in some developing
countries is to reduce consumption of foods contaminated
with aflatoxins, which may contribute to the development of HCC
among HBV carriers. Preventing aflatoxin contamination of the food
supply can be accomplished by implementing changes in pre-and
post-harvest agricultural practices and dietary patterns (34).
Secondary prevention. No treatment has been proven to be effective
in preventing progression to chronic liver disease and HCC among
HBV carriers. Treatment with a-interferon or lamivudine reduces
viral replication in some patients but the improvement is often transient
(31,36). A recent study of treatment with Vitamin K showed
some promise in reducing liver cancer rates among women with cirrhosis
(37).
There have been no randomized controlled trials to evaluate the
cost or efficacy of screening for liver cancer in chronic HBV carriers.
In the USA, many physicians screen healthy carriers yearly or twice
yearly for high levels of serum a-fetoprotein. Carriers with additional
risk factors, including active chronic hepatitis or cirrhosis, are
screened twice yearly with serum a-fetoprotein measurement and
ultrasound (38).
HCV
About 31% of liver cancer worldwide is attributed to HCV compared
with 8% in North America (20). First identified in 1988, HCV was
confirmed as the major cause of ‘non-A, non-B’ hepatitis in 1990 (39).
Although HCV infection can cause symptoms similar to HBV, the
majority of newly infected people have no symptoms. A person
infected with HCV has over an 80% probability of becoming a chronic
carrier. Worldwide, 170 million persons are infected with HCV, and
the global prevalence of HCV infection is 3.1%, ranging from 1.0% in
Europe to 5.3% in Africa (40).
Direct transmission by blood contamination, usually though a needle,
is the most important mode of HCV transmission. In the USA,
60% of chronic HCV infections are attributed to intravenous drug use,
15% to receipt of blood transfusions before 1989 (when a test to
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screen for HCV in donated blood became available) and 15% to
sexual transmission (41). The rate of acquisition of HCV infection
among intravenous drug users is very high, with a number of studies
showing 20–40% being infected within the first year of using needles
(42). HCV infection occurs in 3–8% of health care workers who
experience needlestick exposures to HCV-infected patients and in
2–8% of infants born to mothers with active HCV infection (31).
Approximately 50% of infants are able to eradicate the disease with
no intervention. Post-exposure prophylaxis with immunoglobulin has
not been proven effective in preventing HCV infection among infants
or adults (43).
A decline in the rate of HCV infection in developed countries has
been attributed to changes in the blood donor population and
transfusion practice, mandatory screening of donated blood and a
decline in injection drug use (44). Although liver cancer incidence
increased in some developed countries such as the USA during the
same time, this increase is thought to be due to the aging of the
population previously infected (45).
About 25% of people with chronic HCV infection will develop
hepatic fibrosis that evolves into cirrhosis. Among those who develop
cirrhosis, liver cancer develops at a rate of 1–4% per year. Cofactors
that may influence this progression are alcohol intake, age at infection
and coinfection with HBV or HIV (43).
In developing countries, use of unscreened blood and blood products
and reuse of injection equipment in medical settings are major
routes of HCV transmission (42).
Primary prevention. There is no vaccine available for HCV. In most
developed countries and in some developing countries, the main route
of transmission is intravenous drug use. Needle and syringe exchange
programs have been shown, in a limited number of studies, to reduce
rates of HCV infection (42). Universal precautions (a set of precautions
designed to prevent transmission of blood-borne pathogens
when providing first aid or health care) and safer needle design have
reduced risks of infection among health care workers.
The Centers for Disease Control and Prevention recommend that
routine HCV testing be offered to individuals in high-risk groups,
although this practice may not be feasible in developing countries.
Individuals who test positive are provided medical referral and counseling
to reduce the risk of HCV transmission to others (44).
Other important elements of primary prevention are screening of
donated blood and blood products for antibody to HCVand instituting
infection control practices during all medical, surgical and dental
procedures. While these measures are particularly important in parts
of the world with high prevalence of HBV and HCV, they have not
been implemented in many developing countries due to resource
constraints (42).
Secondary prevention. Patients with HCV should be evaluated to
determine the extent of their liver disease, and if appropriate, receive
counseling to limit their alcohol intake, receive anti-viral treatment,
immunization with hepatitis A, hepatitis B, pneumococcal and influenza
vaccines and treatment for drug or alcohol abuse. Treatment with
a-interferon and ribavirin produces sustained response rates (meaning
that HCV RNA is undetectable at 24 weeks after therapy) of 54–56%,
with a low probability of subsequent relapse (43), and reduces the
incidence of liver cancer among sustained responders (46). However,
there are numerous adverse effects and contraindications to this treatment
and the high cost makes it unaffordable for most HCV carriers in
developing countries (43).
Other infection-related cancers
A number of other chronic infections are known to cause various types
of cancer. Although these were not included among the top priorities
for prevention, they do contribute substantially to the cancer burden in
certain geographic areas and are discussed briefly below.
H.pylori and stomach cancer
Incidence and death rates from stomach cancer have steadily declined
over the last 50 years, even though stomach cancer remains the fourth
most common malignancy, and is second only to lung cancer as the
leading cause of cancer deaths (10). Stomach cancer accounted for
.1 million estimated cases and 800 230 deaths in 2007, with an
estimated 60% of new cases occur in developing countries (1, 2).
Despite falling incidence rates, the number of new cases and deaths
continues to increase globally because of population growth and aging
in high-risk countries. Risks are generally highest in Asia (Korea,
Japan and China) and parts of Central and South America (Costa Rica,
El Salvador and Columbia) and lowest in North America and most of
Africa.
Chronic or recurrent infection with H.pylori is the main cause of
chronic gastritis and peptic ulcers and increases risk for developing
gastric lymphoma and cancer of the distal stomach (47). H.pylori is
a spiral, gram-negative bacterium that colonizes the stomach. It is not
known with absolute certainty how H.pylori is transmitted, but the
most probable route of spread from person to person is through fecaloral
or oral-oral routes. Possible environmental reservoirs include
contaminated water sources. Based on prevalence surveys conducted
in the USA in 1988–1991, about one-third of adults had evidence of
H.pylori infection (48). Prevalence increased steadily with increasing
age, peaking at .50% among persons age !50. In developing countries,
the age at onset of infection is generally lower and peaks at
.90% among young adults (47).
The exact causes of the worldwide decline in gastric cancer incidence
in the past decades are not known but are thought to include
improvements in diet, food storage and a decline in H.pylori infection
due to a general improvement in sanitary conditions and increasing
use of antibiotics (49, 50). The eradication of H.pylori in asymptomatic
carriers has been proposed as a potential method to prevent stomach
cancer. Trials of the efficacy of this approach in preventing the
development of atrophic gastritis should be conducted in high-risk
areas. However, this approach does not preclude the existing practice
of screening for gastric cancer in high-risk populations.
Primary prevention. Since the source of H.pylori is not yet known,
recommendations for avoiding infection have not been made. In general,
it is always wise for persons to wash hands thoroughly, to eat
food that has been properly prepared and to drink water from a safe,
clean source. Trials of H.pylori eradication in high-risk populations
have been attempted. Treatment with bismuth salts, amoxicillin and
clarithromycin is currently the regimen of choice; however, suboptimal
results (clearance of infection in ,50% of persons treated) have
been observed in some studies. Eradication will also be ineffective in
preventing stomach cancer if people are rapidly reinfected (47). There
is concern that extensive use of antibiotics may lead to antibiotic
resistant strains of H.pylori or other pathogens (51). Chemoprevention
trials using vitamin supplements have shown some promise and additional
trials are underway (47).
Efforts are also underway to develop an H.pylori vaccine, but trials
have thus far been disappointing (51). Furthermore, it has been hypothesized
that the reduction in gastric acid secretion due to H.pylori
infection may protect against the adverse effects of gastroesophageal
reflux disease such as Barrett esophagus and adenocarcinoma of the
gastric cardia and esophagus. Efforts to eradicate H.pylori with antibiotic
treatment or vaccination should consider the potential risks as
well as benefits (50).
Secondary prevention. Screening for stomach cancer has been practiced
in Japan (where the incidence of stomach cancer is about six times
higher than the incidence in the USA) since 1963. The main screening
technique used in Japan is indirect X-ray examination by the double
contrast method. Record linkage between participants in the screening
and a population-based cancer registry indicate that the sensitivity
(ability to identify correctly those who have the disease) and specificity
(ability to identify correctly those who do not have the disease) of this
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method were 88.5 and 92.0%, respectively (52). As a result of population
screening and perhaps greater awareness of early symptoms
and a low threshold for diagnostic evaluation, 50% of stomach cancers
in Japan are diagnosed at a localized stage, and the overall 5 year
survival has increased from 20% in 1962 to 40% in 1992. Over the
same time period, the 5 year survival rate in the USA remained stable
at 20% (53). Although general population screening is not recommended
in low-incidence countries such as the USA, a low threshold for
testing symptomatic individuals may be warranted.
KS, HHV-8 and HIV
It is estimated that 77 600 new cases of KS occurred worldwide in
2005. KS has been common in central Africa since the early 20th
century, and was also found in some Mediterranean countries and the
Middle East, but was rare elsewhere. It was also observed in developed
countries among immigrants from endemic areas, recipients of
organ transplants and patients with immune suppression from chemotherapeutic
drugs. In 1981, an aggressive form of KS began to appear
in the USA among homosexual men, one of the first signals of the
AIDS epidemic (54).
Only one of the four subtypes of KS is associated with AIDS. The
AIDS-related KS has identical histopathology to the other subtypes; it
is more probable to involve multiple lesions and worse prognosis. In
areas of Africa where KS was relatively common before the AIDS
epidemic, the incidence of KS has increased $20-fold. In several
African countries (Malawi, Swaziland, Uganda and Zimbawe), it is
now the most common cancer in men and the second most common
cancer in women (54).
It is now thought that infection with HHV-8 (also known as KSassociated
herpes virus), rather than the AIDS virus itself, is the
principal cause of KS. Sexual contact is thought to be the major mode
of transmission of HHV-8. HHV-8 prevalence increases steadily with
age among children in Africa, indicating that alternate modes of transmission
exist (54).
In the USA, the risk of KS among men having sex with men is
much greater than among other persons infected with HIV (55). The
incidence of KS peaked among men age 20–54 in 1989 and then
declined markedly. Since highly active antiretroviral therapy
(HAART) did not become widely available in the USA until 1996,
some of this decline is probably due to changes in sexual practices that
reduced transmission of both HIV and HHV-8 (55,56). KS rates
peaked somewhat later (1991–1996) among African-American men,
and when first reported in 1992, rates among Hispanics were higher
than among white and African-American men. Incidence rates among
all five racial and ethnic groups declined from 1992 to 2001 but show
some evidence of stabilizing in the past 3–4 years.
Primary prevention
The most effective methods for preventing KS are those that protect
against exposure to HIV and HHV-8. Preventive behaviors include
sexual abstinence, sex only with an uninfected partner, consistent
and correct condom use, abstinence from injection drug use and consistent
use of sterile equipment by those unable to cease injection drug
use (57). Similar precautions are recommended for those who are
already HIV positive, both to prevent infecting others and to avoid
infection with other sexually transmitted and blood-borne diseases.
There is some evidence that progression to KS might be accelerated
among persons who become infected with HHV-8 after being infected
with HIV (58).
Secondary prevention
HAART treatment reduces the risk of KS among patients infected
with HIV and may also be effective in treating the tumors (55). In
2003, the WHO estimated that 6 million people in developing countries
needed immediate HAART and ,8% would get it. On World
AIDS Day in 2003, the WHO launched ‘The 3 by 5 Initiative’, whose
goal is to provide antiretroviral treatment to 3 million people in
developing countries by 2005 (11).
HIV, EBV and non-Hodgkin’s lymphoma
It is estimated that there were 300 000 new cases of non-Hodgkin’s
lymphoma (NHL) worldwide in 2007. NHL is an extremely varied
group of neoplasms. Some forms of NHL, including Burkitt’s lymphoma,
are associated with EBV. Most people are infected with EBV
at sometime in their lives. When infection occurs during adolescence
or young adulthood, it causes infectious mononucleosis 35–50% of
the time. EBV infection is also associated with some AIDS-related
NHL and Hodgkin’s lymphoma.
AIDS-related NHL is generally aggressive, high-grade lymphomas
of B-cell origin. They include primary central nervous system
lymphomas, high-grade immunoblastic and Burkitt’s lymphoma,
and to a lesser extent, intermediate-grade large cell diffuse lymphomas.
Unlike KS, which occurs primarily in men who have sex with
men, all HIV risk groups, including intravenous drug users and
children of HIV-positive individuals have equivalent risks of AIDSrelated
NHL. The diagnosis of AIDS precedes the onset of NHL in
57% of patients, but in 30% of cases, the diagnosis of AIDS is made at
the same time as NHL and HIV positivity. In general, the clinical
course of patients with AIDS-related lymphoma is more aggressive,
and the disease is more extensive and less responsive to therapy than
that of non-HIV patients with non-Hodgkin’s lymphoma (59).
There has also been some evidence of an increased risk of Hodgkin’s
lymphoma among HIV-infected individuals, but the evidence is less
strong (59).
Primary prevention
Primary prevention of AIDS-related lymphomas rests on primary prevention
of HIV infection, as described under KS. Since EBV is transmitted
through contact with saliva, and may be present in saliva of
healthy people, there are no methods for primary prevention of EBV
infection.
Secondary prevention
Some AIDS-related lymphomas are associated with high levels of
immunosuppression, as reflected by very low CD4 counts. The incidence
of primary central nervous system lymphoma, which is associated
with very low CD4 counts, fell rapidly after introduction of
HAART therapy, whereas the incidence of intermediate type lymphoma
has remained stable since 1995. Overall, epidemiologic data
show that the risk of AIDS-related lymphoma has decreased $50%
with HAART therapy, but risk is unchanged within groups of patients
stratified by CD4 count. As the proportion of patients receiving
HAART therapy has increased, there has been a shift to higher CD4
strata, with a change in the distribution of lymphoma types. Those
lymphomas that do occur are more responsive to treatment, which
may account for recent trends of improved survival for AIDS-related
NHL (60).
Conclusions
In summary, preventive measures provide the only feasible approach
to slow and ultimately reverse the global increase in cancer and its
disproportionate impact on countries that can least afford it. We have
emphasized why national and international efforts to strengthen tobacco
control and to make childhood vaccination against HBV and
HPV universally available and affordable in countries where these
infections are prevalent should be among the highest priorities. Successful
implementation of these programs will require both national
leadership and international collaboration to overcome the economic
and political barriers that often impede public health. It will also
require action-oriented translational research to adapt programs that
have proven to be effective in high-income countries to every setting
in which they are needed.
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Acknowledgements
Conflict of Interest Statement: None declared.
References
1.American Cancer Society. (2007) Global Cancer Facts & Figures 2007.
American Cancer Society, Atlanta, GA.
2.IARC. (2008) World Cancer Report, 2008. Boyle,P. and Levin,B.E. (eds),
IARC Press, Lyon.
3.Bray,F. et al. (2006) Predicting the future burden of cancer. Nat. Rev.
Cancer, 6, 63–74.
4.Shafey,O. et al. (2009) The Tobacco Atlas, 3rd edn. American Cancer
Society, Atlanta, GA, P. 128.
5.Mackay,J. et al. (2006) The Tobacco Atlas, 2nd edn. American Cancer
Society, Atlanta, GA.
6.Jha,P. (2009) Avoiding global cancer deaths and total deaths from smoking.
Nat. Rev. Cancer, 9, 655–664.
7.IARC. (2004) Tobacco smoke and involuntary smoking. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol.
83. International Agency for Research on Cancer, Lyon, P. 1452.
8.Ezzati,M. et al. (2005) Role of smoking in global and regional cancer
epidemiology: current patterns and data needs. Int. J. Cancer, 116, 963–971.
9.IARC. (2007) IARC Handbooks of Cancer Prevention, Tobacco Control.
Reversal of Risk After Quitting Smoking, Vol. 11, IARC, Lyon.
10.Parkin,D.M. et al. (2005) Global cancer statistics, 2002. CA Cancer J.
Clin., 55, 74–108.
11.Food and Agriculture Organization of the United Nations. (2003) Projections
of tobacco production, consumption and trade to the year 2010. FAO,
Rome.
12.Ranson,M.K. et al. (2002) Global and regional estimates of the effectiveness
and cost-effectiveness of price increases and other tobacco control
policies. Nicotine Tob. Res., 4, 311–319.
13.Chaloupka,F.J. et al. (2002) Tax, price and cigarette smoking: evidence
from the tobacco documents and implications for tobacco company marketing
strategies. Tob. Control, 11 (suppl. 1), s62–s72.
14.Guindon,G.E. et al. (2002) Trends and affordability of cigarette prices:
ample room for tax increases and related health gains. Tob. Control, 11,
35–43.
15.Ross,H. et al. (2006) Economic policies to tobacco control in developing
countries. Salud Publica Mex., 48 (suppl. 1), s113–s120.
16.Hammond,D. et al. (2006) Effectiveness of cigarette warning labels in informing
smokers about the risks of smoking: findings from the International
Tobacco Control (ITC) Four Country Survey. Tob. Control, 15 (suppl. 3),
iii19–iii25.
17.World Cancer Research Fund/American Institute for Cancer Research.
(2007) Food, Nutrition, Physical Activity, and the Prevention of Cancer:
A Global Perspective. AICR, Washington, DC.
18.World Health Organization. (2006) Preparing for the Introduction of HPV
Vaccines: policy and Programme Guidance for Countries. World Health
Organization, Geneva, Switzerland.
19.Mackay,J. et al. (2006) The Cancer Atlas. American Cancer Society,
Atlanta, GA, p. 128.
20.Parkin,D.M. (2006) The global health burden of infection-associated
cancers in the year 2002. Int. J. Cancer, 118, 3030–3044.
21.Mueller,N.B. et al. (2006) The best practices use of the guidelines by ten
state tobacco control programs. Am. J. Prev. Med., 31, 300–306.
22.IARC. (1995) Human papillomaviruses. In: IARC Monographs on the Evaluation
of Carcinogenic Risks to Humans. IARC Press, Lyon, Vol. 64. pp.
35–378.
23.World Health Organization. (2003) The World Health Report 2003. WHO,
Geneva.
24.Munoz,N. et al. (2003) Epidemiologic classification of human papillomavirus
types associated with cervical cancer. N. Engl. J. Med., 348, 518–527.
25.Schiffman,M.H. et al. (1995) The epidemiology of cervical carcinogenesis.
Cancer, 76, 1888–1901.
26.Schiffman,M. et al. (2003) Human papillomavirus: epidemiology and public
health. Arch. Pathol. Lab. Med., 127, 930–934.
27.IARC. (2003) Screening for cervical cancer. In: Stewart,B. and Kliehues,P.
(eds.), World Cancer Report, IARC Press, Lyon, 167–171.
28.WHO. (2002) Hepatitis B. http://www.who.int/csr/resources/publications/
hepatitis/WHO_CDS_CSR_LYO_2002_2/en (8 July 2009, date last accessed).
29.IARC. (2003) Chronic infections. In: Kliehues,B.SaP. (ed.) World Cancer
Report. International Agency for Research on Cancer, Lyon, pp. 56–61.
30.CDC. (2004) Incidence of acute hepatitis B—United States, 1990–2002.
MMWR Morb. Mortal. Wkly. Rep., 52, 1252–1254.
31.Nelson,K. et al. (2001) Viral hepatitis. In: Nelson,K., Williams,C. and
Grahm,N. (eds.), Infectious Disease Epidemiology: theory and Practise.
Aspen Publishers, Inc., Gaithersburg, MD.
32.Kane,A. et al. (1999) Transmission of hepatitis B, hepaptitis C and human
immunodeficiency viruses through unsafe injections in the developing
world: model-based regional estimates. Bull. World Health Organ., 77,
801–807.
33.Bailey,M.A. et al. (2002) Hepatocellular carcinoma: predisposing conditions
and precursor lesions. Gastroenterol. Clin. North Am., 31, 641–662.
34.Wild,C.P. et al. (2000) Primary prevention of hepatocellular carcinoma in
developing countries. Mutat. Res., 462, 381–393.
35.CDC. (2002) Achievements in public health: hepatitis B vaccination—
United States, 1982–2002. MMWR Morb. Mortal. Wkly. Rep., 51, 549–552.
36.Camma,C. et al. (2001) Interferon and prevention of hepatocellular carcinoma
in viral cirrhosis: an evidence-based approach. J. Hepatol., 34,
593–602.
37.Habu,D. et al. (2004) Role of vitamin K2 in the development of hepatocellular
carcinoma in women with viral cirrhosis of the liver. JAMA, 292,
358–360.
38.Nguyen,M.H. et al. (2002) Screening for hepatocellular carcinoma. J. Clin.
Gastroenterol., 35 (5 suppl. 2), S86–S91.
39.Alter,M.J. et al. (1990) Risk factors for acute non-A, non-B hepatitis in the
United States and association with hepatitis C virus infection. JAMA, 264,
2231–2235.
40.WHO. (2000) Hepatitis C. http://www.who.int/mediacentre/factsheets/fs164/
en/ (8 July 2009, date last accessed).
41.CDC. (2004) Viral hepatitis C. http://www.cdc.gov/ncidod/diseases/he[patitis/c/plan/HCV_infection.htm
(24 August 2004, date last accessed).
42.(1999) Global surveillance and control of hepatitis C. Report of a WHO
Consultation organized in collaboration with the Viral Hepatitis Prevention
Board, Antwerp, Belgium. J. Viral Hepat., 6, 35–47.
43.Flamm,S.L. (2003) Chronic hepatitis C virus infection. (Reprinted) JAMA,
289, 2413–2417.
44.CDC. (2004) National Hepatitis C Prevention Strategy. http://www.cdc.
gov/ncidod/diseases/hepatitis/c/plan/HCV_infection.htm (24 August 2004,
date last accessed).
45.El-Serag,H. et al. (1999) Rising incidence of hepatocellular carcinoma in
the United States. N. Engl. J. Med., 340, 745–750.
46.Sung,M. et al. (2003) Hepatitis Viruses. In: Holland,J. and Frei,E.I. (eds.),
Cancer Medicine. BC Decker Inc., Hamilton, London, p. 349–358.
47.Plummer,M. et al. (2004) Epidemiology of gastric cancer. IARC Sci. Publ.,
157, 311–326.
48.Everhart,J.E. et al. (2000) Seroprevalence and ethnic differences in Helicobacter
pylori infection among adults in the United States. J. Infect. Dis.,
181, 1359–1363.
49.Pisani,P. et al. (1997) Cancer and infection: estimates of the attributable
fraction in 1990. Cancer Epidemiol. Biomarkers Prev., 6, 387–400.
50.Blaser,M.J. (1999) Hypothesis: the changing relationships of Helicobacter
pylori and humans: implications for health and disease. J. Infect. Dis., 179,
1523–1530.
51.Newton,R. et al. (2004) Subgroup report: stomach cancer. IARC Sci. Publ.,
157, 29–32.
52.Murakami,R. et al. (1990) Estimation of validity of mass screening
program for gastric cancer in Osaka, Japan. Cancer, 65, 1255–1260.
53.Surveillance, Epidemiology, and End Results (SEER) Program SEERÃ
Stat
Database:Incidence–SEER 9 Regs Public Use, Nov 2002 Sub
(1973-2000) , 18 Age Groups ., National Cancer Institute, DCCPS,
Surveillance Research Program, Cancer Statistics Branch, released April
2003, based on the November 2002 submission http://www.seer.cancer.
gov. (8 July 2009, date last accessed).
54.(2003) Kaposi Sarcoma. In: Parkin,D.M., Ferlay,J., Hamdi-Cherif,M.,
Sitas,F., Thomas,J., Wabinga,H. and Whelan,S.L. (eds.), Cancer in Africa:
Epidemiology and Prevention. IARC Scientific Publications No. 153. International
Agency for Research on Cancer, Lyon, 286–294.
55.Scadden,D. (2003) Neoplasms in Acquired Immunodeficiency Syndrome.
In: Holland,J.F., Frei,E. (eds.) Cancer Medicine. BC Decker Inc, Hamilton,
London, pp. 2259–2275.
56.Eltom,M.A. et al. (2002) Trends in Kaposi’s sarcoma and non-Hodgkin’s
lymphoma incidence in the United States from 1973 through 1998. J. Natl
Cancer Inst., 94, 1204–1210.
57.CDC. (1998) Management of possible sexual, injecting-drug-use, or other
non-occupational exposure to HIV, including considerations related to antiretroviral
therapy. Public Health Service statement. Centers for Disease
Control and Prevention. MMWR Recomm. Rep., 47, 1–14.
Global Priorities for Prevention
109
atBiofyzikalniUstavCSAVonJanuary5,2011carcin.oxfordjournals.orgDownloadedfrom
58.Kaplan,J.E. et al. (2002) Guidelines for preventing opportunistic infections
among HIV-infected persons—2002. Recommendations of the U.S. Public
Health Service and the Infectious Diseases Society of America. MMWR
Recomm. Rep., 51, 1–52.
59.Babus,V. et al. (1998) Helicobacter pylori and gastric cancer in Croatia.
Cancer Lett., 125, 9–15.
60.Little,R.F. (2003) AIDS-related non-Hodgkin’s lymphoma: etiology,
epidemiology, and impact of highly active antiretroviral therapy. Leuk.
Lymphoma, 44 (suppl. 3), S63–S8.
Received September 16, 2009; revised October 20, 2009;
accepted October 20, 2009
M.J.Thun et al.
110
atBiofyzikalniUstavCSAVonJanuary5,2011carcin.oxfordjournals.orgDownloadedfrom