Vaccination as a Tool for Cancer Prevention

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http://www.medscape.com/viewarticle/725132

From Medscape Public Health & Prevention> Perspectives in Prevention From the

American College of Preventive Medicine

Vaccination as a Tool for Cancer Prevention

H. Raabe, MD, PhD; M. Kim, MD, MPH; Miriam , MD, MPH

Authors and Disclosures

Posted: 07/15/2010

Abstract

Infectious agents, such as viruses and bacteria, are the causes of several

common cancers. Infection with the bacterium Helicobacter pylori predisposes to

gastric cancer. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are

associated with liver cancer, and Epstein-Barr virus (EBV) is associated with

lymphoma and nasopharyngeal cancer. Human papillomavirus (HPV) is a major cause

of cervical, anal, penile, and oropharyngeal cancer. Together,

infection-associated tumors make up nearly 20% of all cases of cancer worldwide,

causing more than 2 million malignancies per year. Most of these cases occur in

developing countries. Under normal circumstances, immune surveillance helps to

keep many of these virus-associated cancers in check, but in immunocompromised

persons, such as those with late-stage HIV infection, the incidence and

aggressiveness of these cancers increase. HBV and HPV vaccines are effective and

in use, and vaccines against other cancer-causing agents are in development.

Because many virus-associated cancers occur in the developing world (such as

EBV-associated Burkitt's lymphoma in Africa and HBV-associated hepatocellular

carcinoma [HCC] in Asia), the development and deployment of vaccines to prevent

infection with HPV, HBV, HCV, and EBV can serve as effective preventative tools

to reduce the burden of cancer morbidity and mortality worldwide.

Introduction: Cancer-Causing Infections

In the developing world, cancer is estimated to afflict 10 million people per

year. Worldwide efforts to prevent cancer have generally focused on behavioral

changes, such as smoking cessation. Because infectious agents cause some of the

more common human cancers, understanding the role of the immune system is

necessary to maximize cancer prevention strategies. The immune system has an

endogenous role in preventing some cancers and can be stimulated with vaccines

to prevent infection with cancer-causing viruses.

One of the paradoxes of cancer biology is that a lack of immune surveillance

(such as in HIV-infected individuals or immunosuppressed organ transplant

recipients) can lead to cancer, and chronic inflammation due to persistent

infection can also do so. Chronic inflammation as a result of HBV or HCV

infection leads to HCC, usually after the patient progresses to cirrhosis. In

gastric cancer, nearly 60% of all cases in developed countries and 75% of cases

in developing countries are attributable to chronic infection with H pylori.[1]

It is likely that chronic inflammation due to H pylori leads to intestinal

metaplasia of the gastric epithelium and eventually to gastric cancer.[2]

Long-term infection with HPV and EBV leads to transfer of oncogenes present in

the viral genome to human cells, thereby promoting cancer development.

Harnessing the immune system to prevent or clear cancer is a major goal of

cancer research. Vaccination campaigns have been enormously successful in

reducing the global burden of infectious diseases. A worldwide infrastructure

exists for the manufacture, distribution, and administration of vaccines in

urban, suburban, and rural areas. The use of vaccines to prevent cancer caused

by chronic infection with oncogenic agents has had a substantial benefit in the

developed world and could have a major effect on cancer incidence in the

developing world. This article will review the most common infection-related

cancers and the role of vaccines for cancer prevention worldwide.

HPV and Cancers of the Anogenital Tract and Oropharynx

HPVs are commonly spread through sexual contact. These viruses are the cause of

genital warts, and subtypes 16, 18, 31, 33, and 35 are the major subtypes that

cause cervical, anal, and head and neck cancer.[3] HPV infection is associated

with 100% of cases of cervical cancer. The incidence of infection with HPV is

far higher than the incidence of cancer, because the immune system clears most

infections.[4] However, more than 500,000 new cases of cervical cancer are

estimated to occur worldwide in 2010.[3] Routine Papanicolaou smears can monitor

for early signs of cervical cancer, but many at-risk women in the United States

and elsewhere do not receive appropriate gynecologic care.[5] These women are

more likely to be from nonwhite, lower-income, and immigrant groups, and they

are more likely to develop and die of cervical cancer.[5]

During the past 30 years, the incidence of aggressive serotype HPV-associated

squamous-cell carcinoma of the anus has increased. This increase largely began

in men who have sex with men, but increases in women have also been observed.[3]

HPV is also associated with cancer of the vagina, vulva, and penis, although

these are much less common than cervical cancer.

Squamous-cell carcinoma of the oropharynx and head and neck is associated with

tobacco and alcohol use, but HPV serotypes 16 and 18 are commonly observed in a

subset of persons with this cancer.[3] Of interest, the percentage of

HPV-positive oral cancers is reported to be increasing in several countries.[6]

This increase is attributed to changing sexual practices, suggesting that

HPV-associated oral cancer, like HPV-associated anal and cervical cancer, can be

considered a sexually transmitted infection.[6]

Hepatitis B and C Viruses and HCC

Chronic HBV infection is highly prevalent throughout the developing world,

particularly in Asia and Africa, where some countries have a prevalence rate as

high as 12% of the total population. It is estimated to cause more than 1

million annual deaths worldwide, with one third of these deaths caused by HCC

and the remainder by cirrhosis.[1] Chronic HBV infection confers a 20 times

increased risk for HCC. HBV vaccination is now included in the standard

childhood vaccination series in the United States, but immigrant and older

populations can have high HBV carrier rates.[7] Intrapartum transmission is a

major cause of transmission of HBV to children. To prevent HBV infection,

hepatitis B immune globulin, along with hepatitis B vaccine, must be given to

neonates of HBV-positive mothers (see " Key Recommendations for Healthcare

Providers to Prevent Cancers Caused by Infectious Disease " ).

HCV infection is another a major cause of HCC. Whereas the carrier rate of HCV

in the United States was estimated at 1.6% in 2002, in Africa the prevalence

ranged from more than 8% in Northern Africa to less than 2% in Southern

Africa.[1] Vaccines for HCV are in development, but for patients who have

already contracted HCV, a regimen involving 6 months of pegylated interferon

alpha and ribavirin can lead to eradication in up 60% to 80% of patients.[8]

Active surveillance for HCV and aggressive attempts at eradication can therefore

reduce the subsequent risk for cancer in populations at risk.

EBV-Associated Cancers

EBV is the primary cause of infectious mononucleosis, a typically benign disease

of adolescence and young adulthood. However, the virus is also a causative agent

in many aggressive neoplasms, including 20% of cases of Hodgkin's lymphoma (one

of the most common lymphomas of adolescence), nasopharyngeal carcinoma, and a

subtype of Burkitt's lymphoma.[1] Nasopharyngeal cancer affects approximately

80,000 people each year, predominantly in less developed countries. Most of

these cases are attributable to EBV infection.[1] Although this cancer is

curable with intensive chemotherapy and radiation therapy, most of the people

affected by this cancer do not have access to these treatments.

More than 28,000 worldwide cases of Hodgkin's lymphoma are attributed to EBV

infection.[1] Like nasopharyngeal cancer, Hodgkin's lymphoma is highly

treatable. More than half of Hodgkin's lymphoma cases occur in less developed

countries, however, and curative treatment is often not available. The iconic

image of a sub-Saharan African child with a very large facial or neck mass is an

easily recognizable sign of endemic Burkitt's lymphoma caused by EBV infection.

As many as 6800 cases of Burkitt's lymphoma caused by EBV occur every year, with

more than 90% of these infections occurring in less developed countries.[1]

EBV-associated non-Hodgkin's lymphoma is particularly common in patients with

advanced HIV infection. An estimated 68,000 cases of EBV-associated

non-Hodgkin's lymphoma occur annually, and two thirds occur in developing

countries.[1]

H Pylori-Associated Gastric Cancer and Mucosa-Associated Lymphoid Tissue

Lymphoma

The causative infectious agent for peptic ulcer disease, H pylori, is also a

known cancer-causing agent. Chronic infection with this pathogen predisposes to

stomach cancer and to gut mucosa-associated lymphoid tissue (MALT) lymphoma.[4]

Gastric cancer accounts for nearly 10% of all cases of cancer worldwide, and the

causative agent in more than 60% of these cases is estimated to be H pylori

(other risk factors include diet and excessive alcohol intake). In 2002, it was

estimated that H pylori caused as many as 600,000 cases of gastric cancer per

year worldwide.[1] Eradication of H pylori can be accomplished with antibiotic

therapy; however, the very high burden of infection in many countries (for

example, in sub-Saharan Africa, more than 75% of adults are infected with H

pylori) and the relative ease of reinfection make treatment of asymptomatic

carriers unfeasible.[2] Because the infection first occurs in young children, H

pylori seems to be an amenable target for vaccine development to prevent

colonization and subsequent stomach cancer and gut-associated MALT lymphoma.

Until a vaccine becomes available, healthcare providers should screen for

dyspepsia and peptic ulcer disease and offer H pylori testing to affected

patients. Healthcare providers should administer drug therapy for eradication of

H pylori in those who are symptomatic and H pylori-positive.

Human Herpesvirus 8: Kaposi's Sarcoma

Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi's sarcoma, a

once-rare sarcoma of blood vessels. Before the AIDS epidemic, Kaposi's sarcoma

was primarily known to affect Mediterranean or eastern European men or

immunosuppressed patients, such as organ transplant recipients.[9] With the

increasing worldwide prevalence of HIV infection, most cases of Kaposi's sarcoma

are now associated with HIV or AIDS. In 2002, it was estimated that more than

60,000 cases of Kaposi's sarcoma occur yearly,[1] and it is the most common type

of cancer reported in some African countries highly affected by HIV, such as

Zimbabwe. The best treatment for Kaposi's sarcoma in HIV-infected patients is

initiation of antiretroviral agents to reduce HIV viral load and allow

restoration of immune system function. Sometimes this is sufficient to cause

regression of the cancer. In other cases, the cancer continues to spread and

combination chemotherapy is required.[9]

Role of Vaccines for Cancer Prevention in the United States

HBV vaccine. In 1991, the Centers for Disease Control and Prevention (CDC)

recommended adoption of a comprehensive strategy for prevention of HBV

infection, which included:

•Routine maternal prenatal testing for HBV;

•Immediate postpartum intervention to prevent maternal to child transmission;

•Universal vaccination of children for HBV;

•Vaccination of all adolescents who had not received HBV vaccine previously; and

•Vaccination of adults at risk for becoming infected with HBV.[10]

The childhood immunization schedule, a 3-vaccine series administered in the

first year of life, confers long-term immunity to HBV. Infants born to

HBV-positive mothers must receive both vaccination and hepatitis B immune

globulin within the first 12 hours of life. This regimen is 85-95% effective in

preventing transmission of HBV. Because children are at increased risk for

becoming chronic carriers when infected with HBV, starting the vaccine at birth

and completing the series during routine well-child visits during the first year

of life decreases the risk for infection from HBV-positive household contacts.

Analysis of immunization rates in newborns in the United States from 2003-2005

showed only a 50% vaccination rate, leaving many infants unprotected from HBV

infection. Clearly, the United States needs to increase newborn vaccination

rates for HBV.[11]

HPV vaccine.

Two HPV vaccines are approved for use in the United States: Gardasil® (Merck &

Co., Inc., Whitehouse Station, New Jersey) and Cervarix® (GlaxoKline,

Philadelphia, Pennsylvania). Gardasil® targets the serotypes of the virus most

associated with cervical cancer (16, 18) and genital warts (8, 11). Cervarix®

also targets serotypes 16 and 18 and uses a different adjuvant than Gardasil® to

boost immune response. Both vaccines are equally effective at preventing HPV

infection caused by the serotypes contained in the vaccines, and both will

prevent development of high-grade cervical lesions caused by the corresponding

serotypes. These vaccines are most effective when given to women and girls who

have not been exposed to HPV.[12] However, in a mixed population of HPV-exposed

and HPV-unexposed young women, compared with placebo, vaccination with Gardasil®

led to a 60% reduction in genital warts and a nearly 20% reduction in the

incidence of precancerous cervical lesions. A corresponding reduction in the

number of women who required invasive surgical resection of their precancerous

lesions suggests that even in older, HPV-exposed women, vaccination may be

helpful in reducing cervical cancer rates.[13] The follow-up timeframe for these

vaccines is still short, so it is not clear how long the protective effect will

last.[12] Additional postapproval studies are ongoing to determine the duration

of protection and to determine whether post exposure vaccination is warranted.

The availability of HPV vaccines against serotypes 16 and 18 gives healthcare

providers the tools to prevent HPV infection and subsequent cervical cancer. The

US Food and Drug Administration (FDA) approved Gardasil® for girls and young

women from age 9 to 26 years and for boys and men in that same age group, on the

basis of trials showing efficacy preventing cervical neoplasia and cancer in

women and anogenital warts in both women and men.[14] The FDA approved Cervarix®

for girls and women ages 10 to 25 years for prevention of cervical neoplasia and

cancer.[12] These vaccines may also be effective in preventing cancer of the

oropharynx and anus caused by HPV 16 and 18 in both men and women.[6,15]

Whereas HPV vaccines have been approved and are being administered in the United

States, the uptake of the vaccines has been uneven. A backlash against HPV

vaccination has occurred in some communities. Further interventions are required

to improve vaccination among those most at risk for invasive cervical

neoplasia.[5] Clinicians should offer HPV vaccination to all adolescent girls

and young women who have not yet had their sexual debut, and they should

consider giving the vaccine to young women after sexual debut, on the basis of

the findings described above. These vaccines do not cover all of the subtypes of

HPV that cause cervical cancer, and widespread vaccination does not replace the

need for intermittent cervical cancer screening, although it is projected to

reduce the number of invasive procedures.[12]

Cancer Prevention Outside of the United States

Role of vaccines. The use of vaccines and eradication treatments to prevent

infection-caused cancer in the United States and other developed countries will

continue to reduce mortality and morbidity from these diseases. However, the

major burden of disease and corresponding mortality lie in the developing

world.[4] Taken together, the number of infection-related cancers is estimated

at nearly 2 million cases per year, accounting for almost 20% of all cancer

cases.[1] Widespread application of vaccines for HBV and HPV could decrease the

global burden of cancer by 900,000 cases per year, on the basis of 2002

estimates.[1]

The HPV vaccine is approved for use in more than 60 countries. Widespread

vaccination for HPV coupled with limited cervical cancer screening can be

considered cost-effective in developing countries if a vaccine can be delivered

for approximately $1 per dose (in a 3-dose regimen).[16] The current course in

the United States costs more than $300 USD. Improvements in HPV vaccines to make

them more thermostable and efficacious, and less costly, will increase the

feasibility of vaccinating adolescents in developing countries.[4]

Drug treatment of HCV and H pylori infections to prevent cancer. Development of

new vaccines or widespread identification and eradication efforts could further

reduce the global cancer burden by reducing the carriage rate of H pylori,

leading to fewer cases of gastric cancer (now estimated to be more than 500,000

cases per year).[1,2] Eradication of HCV by use of ribavirin plus pegylated

interferon, although expensive, could eliminate the nearly 200,000 cases per

year of HCC that are attributed to HCV.[1] To eliminate HCV in less developed

countries successfully and cost-effectively, either a vaccine against HCV or a

less burdensome eradication regimen is needed.

Burden of HIV as a cancer predisposition syndrome. The growing HIV epidemic is

adding to the already substantial burden of cancer in lower-income countries

(and in affected populations in the United States). Chronic HIV infection should

be considered a cancer predisposition syndrome. Loss of immune surveillance as a

result of HIV infection can lead, in HPV infection, to a rapid progression of

precancerous lesions to cancer, and to increases in de novo cancer, particularly

in HHV-8 and EBV-infected individuals.[1,17] Restoration of immune function as

evidenced by normalizing CD4 helper T-cell numbers after initiation of highly

active antiretroviral therapy (HAART) can lead to stabilization or regression of

cancer. However, in lower-income countries, initiation of HAART continues to

encounter multiple barriers (lack of healthcare providers, lack of drug

distribution infrastructure, and cultural barriers to testing and starting

treatment).[18] Although initial trials of an HIV-prevention vaccine have not

succeeded, additional trials of new strategies for an HIV vaccine are ongoing

and under development.

Role of vaccines in immunocompromised hosts. For patients who are already

HIV-infected, the ability to respond to an antiviral vaccine, such as the HBV

vaccine, may be severely attenuated, depending on their CD4 count.[19]

Vaccination before HIV infection (such as in an HIV-negative child) may prevent

subsequent infection with the target of the vaccine, even if the patient has

become HIV-positive. Much depends on the degree of destruction of the immune

system and the extent to which the immune system is reconstituted after starting

antiretroviral therapy.

Future Directions

The current availability of vaccines against HPV and HBV cancer-causing viruses

could prevent nearly 1,000,000 annual cases of cancer throughout the world.[1]

Barriers to widespread vaccination include expense, lack of sufficient

healthcare personnel, problems with drug delivery and storage, and opposition of

the local population. HPV and EBV vaccines are being deployed and improved, and

an effort to develop vaccines against HCV and EBV continues. These new vaccines,

along with those currently in use, have the promise of substantially reducing

global morbidity and mortality from cancer.[4] Finally, advances in

immunobiology will further our understanding of the pathogenesis of cancer and

may enable the development of vaccines to prevent other cancers not caused by

infectious agents.[20]

Key Recommendations for Healthcare Providers to Prevent Cancers Caused by

Infectious Disease

1. Hepatitis B: Test for HBV in members of at-risk groups and offer vaccination

to all adolescent and adult patients who are HBV negative. Begin HBV

vaccinations in all neonates starting before discharge from the hospital and

continuing through well-baby checks during the first year of life, according to

Advisory Committee on Immunization Practices (ACIP) guidelines.[10] Consider

treatment of HBV-positive patients to reduce the risk for progression to

cirrhosis and HCC, according to National Institutes of Health Consensus

Conference guidelines.[21]

2. H pylori: Screen for dyspepsia and peptic ulcer disease and offer H pylori

testing to affected patients. Administer drug therapy for eradication of H

pylori in those who are symptomatic and positive for H pylori, according to

American College of Gastroenterology guidelines.[22]

3. HIV: Offer HIV testing to at-risk patients. In some areas with increasing

prevalence of HIV, this would be considered all patients aged 13-64 years,

according to CDC guidelines.[23] In HIV-positive individuals, screen for HBV,

HCV, and HPV, because HIV-positive patients are at increased risk for cancer

caused by infectious agents .

4. HPV: Offer screening Papanicolaou smears for all women according to American

Congress of Obstetricians and Gynecologists guidelines.[24] Offer vaccination

against HPV to adolescent girls and women up to age 26 years, according to ACIP

guidelines.[14]

5. Hepatitis C: Offer testing for HCV in all at-risk patients and offer

eradication of HCV in patients who test positive, according to the National

Institutes of Health Consensus Conference Statement on Hepatitis C.[8]

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