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ARTICLE TITLE: The Importance of Immunization in Cancer Prevention, Treatment, and Survivorship
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EDUCATIONAL OBJECTIVES:
After reading the article “The Importance of Immunization in Cancer Prevention, Treatment, and Survivorship,” the learner should be able to:
1. Summarize the relevance of human papillomavirus and hepatitis B virus infection and vaccination to cancer prevention.
2. Highlight the importance of individual-level and population-level adherence to vaccination against preventable infections (such as measles, influenza,
Streptococcus pneumoniae, and varicella-zoster virus) to preventable mortality and morbidity among cancer survivors and individuals undergoing
immunosuppressive cancer treatment.
3. Describe barriers and facilitators to achieving high levels of adherence to vaccination recommendations and clinical and public health strategies for
overcoming these factors.
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ACS CONTINUING PROFESSIONAL EDUCATION COMMITTEE DISCLOSURES:
Editor: Ted Gansler, MD, MBA, MPH, has no financial relationships or interests to disclose.
Lead Nurse Planner: Cathy Meade, PhD, RN, FAAN, has no financial relationships or interests to disclose.
NURSING ADVISORY BOARD DISCLOSURES:
Maureen Berg, RN, has no financial relationships or interests to disclose.
Susan Jackson, RN, MPH, has no financial relationships or interests to disclose.
Barbara Lesser, BSN, MSN, has no financial relationships or interests to disclose.
AUTHOR DISCLOSURES:
Robert A. Bednarczyk, PhD, reports grants from the National Institutes of Health, personal fees from Three Rivers Area Health Education Network, and personal fees from
University of Calgary, outside the submitted work. Christopher R. Flowers MD, MS, reports consulting fees from Gilead, Bayer, Celgene, and AbbVie; uncompensated
consulting for Genetech/Roche; contracted research for AbbVie, Acerta, the Eastern Cooperative Oncology Group, Genetech/Roche, Gilead, Infinity, the Mayo Clinic,
Millennium/Takeda, the National Institutes of Health, Pharmacyclics, and TG Therapeutics; and grants from the National Institutes of Health/National Cancer Institute,
V Foundation, and Burroughs Wellcome Fund; outside the submitted work. Elizabeth M. Ward, PhD, Ted Gansler, MD, MBA, MPH, and Saad B. Omer, MBBS, MPH, PhD
have no financial relationships or interests to disclose.
The peer reviewers disclose no conflicts of interest. Identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review.
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398 VOLUME 67 | NUMBER 5 | SEPTEMBER/OCTOBER 2017 SPONSORED BY THE AMERICAN CANCER SOCIETY, INC.
CA CANCER J CLIN 2017;67:398–410

The Importance of Immunization in Cancer Prevention,


Treatment, and Survivorship
Elizabeth M. Ward, PhD1; Christopher R. Flowers, MD, MS2; Ted Gansler, MD, MBA, MPH 3
;
Saad B. Omer, MBBS, MPH, PhD4; Robert A. Bednarczyk, PhD5

Abstract: A measles outbreak originating in California during 2014 and 2015 called
1
Senior Vice President of Intramural attention to the potential for infectious disease outbreaks related to underimmu-
Research (retired), American Cancer nized populations in the United States and the potential risk to pediatric patients
Society, Atlanta, GA; 2Director, Lymphoma with cancer attending school when such outbreaks occur. Compliance with vaccine
Program, Department of Hematology and
Oncology, Winship Cancer Institute, Emory
recommendations is important for the prevention of hepatitis B-related and human
University, Atlanta, GA; 3Strategic Director papillomavirus-related cancers and for protecting immunocompromised patients
of Pathology Research, American Cancer with cancer, and these points are often overlooked, resulting in the continued occur-
Society, Atlanta, GA; 4Professor of Global rence of vaccine-preventable neoplastic and infectious diseases and complications.
Health, Epidemiology, and Pediatrics, This article provides an overview of the importance of vaccines in the context of can-
Rollins School of Public Health and Emory cer and encourages clinician, health system, and public policy efforts to promote
University School of Medicine, Emory
adherence to immunization recommendations in the United States. CA Cancer J Clin
University, Atlanta, GA; 5Assistant
Professor of Global Health and
2017;67:398-410. V C 2017 American Cancer Society.

Epidemiology, Rollins School of Public


Health, Emory University, Atlanta, GA. Keywords: hepatitis B, herpes zoster, human papillomavirus, immunization, influ-
enza, neoplasms, Streptococcus pneumoniae
Corresponding author: Elizabeth M. Ward,
PhD, Senior Vice President of Intramural
Research (retired), American Cancer Society,
250 Williams St, Atlanta, GA 30303;
eward04@gmail.com
DISCLOSURES: This study was supported by
Practical Implications for Continuing Education
the American Cancer Society Intramural
Research Department. Christopher Flowers
> Increased adherence to human papillomavirus and hepatitis B virus vaccination
reports uncompensated consulting for
Genentech/Roche; consulting fees from recommendations could substantially diminish the morbidity and mortality from
Gilead, Bayer, Celgene, and AbbVie; and cancers causally associated with these viruses.
contracted research work for AbbVie, Acerta,
the Eastern Cooperative Oncology Group, > Adherence to vaccination recommendations for children and adults during and
Genentech/Roche, Gilead, Infinity, the Mayo
Clinic, Millennium/Takeda, the National after chemotherapy and immunotherapy is important for decreasing morbidity
Institutes of Health, Pharmacyclics, TG and mortality from preventable infections in these immunocompromised
Therapeutics, the National Institutes of populations.
Health/National Cancer Institute, V
Foundation, and the Burroughs Wellcome > Individuals undergoing immunosuppressive anticancer treatment who are
Fund. Robert A. Bednarczyk reports grants
from the National Institutes of Health during exposed to several vaccine-preventable infections face increased risks of
the conduct of the study and speaker fees becoming infected and of death or serious morbidity from these infections.
and travel expenses from the Three Rivers
Area Health Education Network and the > Because individuals undergoing immunosuppressive anticancer treatment often
University of Calgary outside the submitted
work. Elizabeth M. Ward, Ted Gansler, and
lose immunity acquired from having been vaccinated, a high level of herd
Saad B. Omer made no disclosures. immunity is essential to protecting this vulnerable population.
doi: 10.3322/caac.21407. Available online
at cacancerjournal.com Introduction
On January 5, 2015, the California Department of Public Health received reports
of 7 suspected measles cases, all of which were linked to visits to 1 of 2 adjacent
Disney theme parks in Orange County, California, between December 17 and 20,
2014. By February 11, 125 measles cases had been confirmed in US residents con-
nected with this outbreak, 110 of them among California residents. Among the
110 California patients, 49 (45%) were unvaccinated, including 12 infants who
were too young to be vaccinated.1 This outbreak raised to national attention the
potential for widespread transmission of vaccine-preventable diseases when popula-
tions are not protected by a high rate of immunization (herd immunity). Although
the measles outbreak was the most widely publicized outbreak in recent history,
resurgence of other infectious diseases preventable by childhood immunization,

VOLUME 67 _ NUMBER 5 _ SEPTEMBER/OCTOBER 2017 399


Immunization in Cancer Prevention, Treatment and Survivorship

including pertussis and mumps, has also occurred in the 1000 cases develop acute encephalitis, 6-7 in 1000 cases
United States.2 Such outbreaks pose a special hazard for develop seizures, and approximately 1.5 in 1000 cases develop
vulnerable populations, including children too young to be subacute sclerosing panencephalitis), and hearing loss.8,9
vaccinated, children and adults receiving chemotherapy or Pediatric patients with cancer are recognized as being par-
other immunosuppressive therapies, and other immuno- ticularly vulnerable to measles infection, although infection
compromised patients. among adult recipients of bone marrow transplants has also
The importance of immunization in the context of cancer been reported.10 Even children who were fully immunized
goes beyond the protection of immunocompromised patients before their diagnosis may lose immunity because of immu-
through herd immunity. Currently, vaccines for 2 carcino- nosuppressive chemotherapy drugs and are at high risk of
genic viruses—oncogenic human papillomavirus (HPV) severe complications and death should they develop measles.
types and hepatitis B—are recommended specifically because Although data on measles in immunosuppressed children
they are protective against cancer.3,4 Several other vaccines with cancer are very limited, a case series report in 1992
recommended for the general population are particularly found a case fatality rate of 55% among 40 pediatric patients
important for patients with cancer as well as cancer survivors, with cancer, 32 of whom had acute lymphoblastic leukemia.
because they reduce the probability of complications during Twenty-three (58%) patients developed pneumonitis, 8 (20%)
and after treatment. This article reviews information on sev- developed encephalitis, and 3 (8%) had both.11 A more recent
eral aspects of the relationship between immunizations report suggests that prior measles immunization mitigates the
and cancer. Although we describe vaccine recommendations severity of illness, that early ribavirin therapy prevents compli-
for the general population, individuals with cancer, and/or cations, and that postexposure prophylaxis with ribavirin pre-
other immunocompromised patients, the article is not vented the development of measles among pediatric patients
intended to serve as a primary reference for vaccine recom- who were close contacts of cases.12 Vaccination of pediatric
mendations or clinical guidance for vaccination in patients patients with cancer during measles outbreaks is not recom-
with cancer or others with immunocompromising conditions mended, because it is a live vaccine.13
but, rather, to call attention to the important relationships The first live (attenuated) vaccine against measles was
between vaccination and cancer across the cancer-control con- licensed for use in the United States in 1963; measles vac-
tinuum. We address this topic by reviewing outbreaks, guide- cine is now available combined with vaccines against mumps
lines, guideline adherence, and infection incidence in the and rubella (MMR) or combined with mumps, rubella, and
United States. The extent of international differences in varicella vaccines as MMRV (ProQuad; Merck & Company
health care and public health systems precludes a broader Inc, West Point, Pennsylvania). Before 1963, epidemic
scope, although we include some international information cycles occurred every 2 to 3 years. Although approximately
that raises unique points relevant to the United States. None- 500,000 measles cases and 500 related deaths were reported
theless, it is important to recognize that much of this informa- annually in the United States, the actual number of cases
tion applies to many other countries and that other nations’ was estimated at 3 to 4 million annually.5 The highest inci-
successes and challenges are relevant to the United States. dence was among children ages 5 to 9 years, who generally
comprised more than one-half of reported cases. In the years
Why Did the Recent Measles Outbreak after licensure of the vaccine, the incidence of measles fell
Generate So Much Concern? by 95%, and 2-year to 3-year epidemic cycles no longer
The 2014 to 2015 measles epidemic attracted national atten- occurred.5 Although high immunization coverage elimi-
tion in part because of its origin at a national tourist attrac- nated endemic measles (interruption of year-round endemic
tion, the size of the epidemic and the high rate of transmission) from the United States in 2000, continuing
transmission, and the potential severity of measles infection importations of measles cases from endemic regions led to
and its complications. Measles is a highly transmissible dis- secondary measles cases and outbreaks in the United States,
ease; the likelihood of a susceptible person developing mea- primarily among individuals who had not been vaccinated.14
sles after face-to-face contact with an infected person is The incidence of measles in the United States rebounded,
approximately 90%.5 Approximately 20 million cases occur with a recent record number of cases—668 cases from 27
globally each year, with highest incidence in countries with states—reported to the National Center for Immunization
developing economies. These infections result in approxi- and Respiratory Diseases of the Centers for Disease Control
mately 164,000 deaths, with the highest case fatality rates and Prevention (CDC) during 2014, including 1 large out-
among children aged younger than 5 years.6 In the United break of 383 cases, occurring primarily among unvaccinated
States, about 28% of young children with measles are hospi- Amish communities in Ohio.15 Many of the cases reported
talized, and about 3 in 1000 die from it.7 Serious complica- in the United States during 2014 were associated with cases
tions include pneumonia, neurologic involvement (eg, 1 in imported from the Philippines, which experienced a large

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CA CANCER J CLIN 2017;67:398–410

measles outbreak.15 Low rates of vaccine coverage in com- author that the measles component of the MMR vaccine
munities in the United States contribute to the transmission was associated with increased incidence of autism.23 That
and spread of measles from imported cases.2 A recent study article was retracted by The Lancet in 2010 based on conclu-
estimated that 8.7 million US children and adolescents ages sions that that several elements of the paper were incor-
17 years and younger are susceptible to measles and cau- rect.24 Concerns about the paper included its claim to have
tioned that there is a potential for large measles outbreaks investigated a “consecutive series” of 12 children, whereas
even in the context of generally high vaccination coverage.16 further investigation revealed that the patients had been
Measles is not the only vaccine-preventable disease carefully selected and that attorneys acting for parents who
undergoing a resurgence in the United States. Unlike mea- were involved in lawsuits against vaccine manufacturers had
sles, pertussis remains endemic in the United States, with provided some of the funding for this research.25 Several
an estimated 20,762 reported cases in 2015.17 A recent arti- well-designed epidemiologic studies have found no evidence
cle summarized studies that examined the relationship for an association between MMR vaccination and
between vaccine delay, refusal, or exemption and the risk of autism,26,27 and a recent systematic review of the safety of
outbreak-related measles or pertussis in the United States.2 vaccines concluded that there is strong evidence that the
Several studies have estimated the relative risk of outbreak- MMR vaccine is not associated with autism.26 Public con-
related infection for vaccinated versus unvaccinated chil- cerns about childhood immunizations and neurodevelop-
dren, but only a few have examined associations between mental defects have also focused on thimerosal, an
rates of illness and rates of vaccine exemption at the popula- ethylmercury-containing preservative that has been used in
tion level. A study in Colorado found an association very low concentrations in some vaccines since the 1930s.28
between county-level frequency of vaccine exemptions and Because of theoretical concerns about the potential toxicity
measles and pertussis incidence rates among vaccinated chil- from ethylmercury, in 1999, the American Academy of
dren.18 Another study, which used national measles surveil- Pediatrics and the US Public Health Service issued a joint
lance data and state immunization reports, used statistical statement calling for the removal of thimerosal from vac-
models to estimate that, if the number of exemptions dou- cines.29 The Institute of Medicine supported this recom-
bled, then the incidence of measles infection in nonexempt mendation as “a prudent measure in support of the public
individuals would increase by 5.5%, 18.6%, and 30.8% for health goal to reduce mercury exposure of infants and chil-
intergroup population mixing ratios of 20%, 40%, and 60%, dren as much as possible.”30 Since 2001, with the exception
respectively (a higher percentage reflects greater likelihood of inactivated influenza vaccine, all vaccines manufactured for
of contact between exempt and nonexempt individuals).19 the US market and routinely recommended for children ages
Another study, which evaluated spatial clustering of non- 6 years and younger have contained no thimerosal or only
medical vaccine exemptions in children and geographic trace amounts (1 lg of mercury per dose) remaining from
overlap between exemption clusters and clusters of reported the manufacturing process.31,32 Removal of thimerosal has
pertussis cases in Michigan, found that census tracts in generally resulted in the distribution of vaccines in single-
exemptions clusters were about 3 times more likely to be in dose rather than multidose vials, which is feasible in high-
pertussis clusters.20 Although it does not appear that recent income countries but not in low-resource countries, where
outbreaks of vaccine-preventable diseases in the United thimerosal remains an important vaccine preservative.28 Stud-
States have affected patients with cancer or health care facili- ies from around the world have not found evidence of signifi-
ties, should these outbreaks become more frequent, the cant harm from thimerosal-containing vaccines.28
potential will increase for patients with cancer to be exposed Potential associations between childhood immunizations
to infectious cases in the community and health care settings. and childhood cancer do not appear to be a significant pub-
It is worth noting that the first measles death in the United lic concern; however, it is reassuring to note that 4 high-
States in 12 years was reported by Washington state health quality epidemiologic studies have investigated the potential
officials in 2015; the woman who died had several health relationship between vaccinations and childhood leukemia,
conditions, was taking immunosuppressive drugs, and lived and none found a positive association.26 In fact, one study
in a county where a measles outbreak had occurred.21 found that that several vaccines may have a protective effect
against acute lymphoblastic leukemia,33 and another study
Immunization Requirements and Parental found a protective effect of complete immunization sched-
Concerns ules for rhabdomyosarcoma.34
Parental concerns about childhood vaccinations are com- A comprehensive review of the safety of vaccines used for
mon.22 Many concerns have centered on a potential associa- routine immunization of children in the United States, pub-
tion between vaccines and autism, sparked by an article lished in 2014, found evidence for adverse reactions associ-
published in 1998 in The Lancet and speculation by its ated with specific vaccines but noted that severe adverse

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Immunization in Cancer Prevention, Treatment and Survivorship

reactions are rare and must be weighed against the substan- to 2.2%, with striking geographical variability; for example,
tial protective benefits provided by these vaccines.26 Infor- in the state of Washington, the state-level nonmedical
mation about the frequency of adverse reactions associated exemption rate was 4.2%, but rates among counties varied
with specific vaccines is available on the CDC Web site from <1% to 26%.39 In California, the percentage of kin-
(cdc.gov/vaccines/vac-gen/side-effects.htm). For example, dergarten children with nonmedical exemptions doubled
the Web site states that studies have demonstrated a very from 1.56% to 3.06% between 2007 and 2013 and, during
slightly increased risk (approximately 1 in 3000 to 4000) of the 2013 to 2014 school year, greater than 25% of kinder-
febrile seizures among children younger than 7 years occur- gartens in California had immunization rates below the
ring approximately 6 to 14 days after MMR vaccination. 92% to 94% recommended to maintain herd immunity.40
The risk of immune thrombocytopenic purpura is elevated Several states with high nonmedical exemption rates,
during the 6 weeks after an MMR vaccination, with 1 study including California, Oregon, and Washington, increased
estimating 1 case per 40,000 vaccinated children. the stringency of their philosophical exemption procedures
Despite reassurance about the safety and efficacy of vac- during 2011 through 2013 by requiring parents to docu-
cines and the public health and medical importance of vacci- ment that they received information from a health care pro-
nation, a significant proportion of parents have questions vider about the benefits and risks of vaccination.35 The
and concerns about the decision to vaccinate.22 Disclosures recent measles epidemic and public and media attention to
about potential adverse reactions, even those that are the high rates of nonmedical exemptions in some areas in
uncommon, understandably provoke anxiety for parents. California stimulated further changes in state vaccine legis-
Environmental and social factors that may contribute to lation. On June 30, 2015, California Governor Jerry Brown
vaccine hesitancy include lack of parental experience with signed a bill that eliminated vaccine exemptions based on
the serious nature of the diseases being prevented and an philosophical and religious beliefs, making California the
increase in the number of vaccines recommended for chil- largest state to enact such strict vaccine requirements. The
dren, which raises parental concerns about associated dis- law went into effect on July 1, 2016.
comfort. Some parents may delay vaccination because they In addition to strengthening state mandates, there have
fear that multiple vaccinations may have adverse conse- been efforts to reduce financial barriers to vaccination and
quences for very young children.35 These factors and others reinforce the role of health care providers in promoting
have resulted in more frequent use of exemptions to avoid adherence to childhood immunization. In the United States,
or delay childhood vaccinations and have increased public financial barriers to childhood immunization have been
policy debate about vaccine mandates.35 reduced by the Vaccines for Children (VFC) program,
Vaccine mandates are promulgated through state law; which was created by the Omnibus Budget Reconciliation
approval by the US Food and Drug Administration (FDA) Act of 1993 and implemented in 1994. This goal of this
and recommendation by the Advisory Committee on program is to ensure that eligible children do not contract
Immunization Practices (ACIP) of the CDC are the foun- vaccine-preventable diseases because of an inability to pay.
dation for state mandates.35 State vaccine mandates across Approximately 50% of children aged <19 years are eligible
the country vary substantially with regard to reasons for to receive vaccines through the VFC, including those who
allowable exemptions and procedures for granting these are Medicaid-eligible, uninsured, American Indian/Alaska
exemptions.36 All US states permit medical exemptions for Native, or, for underinsured children (ie, whose health
immunocompromised individuals, persons with allergies to insurance does not fully cover immunizations), when they
the vaccine or its components, or those with other relevant are receiving services at a federally qualified health center or
medical contraindications. Participation of a licensed health rural health clinic.41 Furthermore, the Patient Protection
care provider is typically required to approve medical and Affordable Care Act of 2010 eliminated cost sharing in
exemptions under state immunization laws. In contrast, reli- the form of copays, coinsurance, or deductibles for vaccines
gious or philosophical or personal belief exemptions are typ- recommended by the ACIP.42 In addition to reducing
ically based on parental preference. In total, 47 states plus financial barriers, studies have been done to better under-
the District of Columbia allow religious exemptions, and 19 stand parental concerns about childhood immunizations and
states allow personal belief or philosophical exemptions.37 reasons for vaccine hesitancy, resulting in guidance for health
Less than 0.5% of children in the United States were care providers to enhance parental communication.43,44
granted medical exceptions to 1 or more immunizations
required for school attendance during 2004 through 2011, Childhood Immunizations and Pediatric
with state medical exemption rates ranging from 0.26% to Patients With Cancer
0.41% of enrolled children.38 During 2004 through 2011, Depending on their age at cancer diagnosis, the recom-
US rates of nonmedical exemptions increased from 1.48% mended childhood immunization schedule for pediatric

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CA CANCER J CLIN 2017;67:398–410

patients with cancer is delayed or interrupted during chemo- Vaccines for Cancer Prevention
therapy treatment.45 Most chemotherapy drugs depress Hepatitis B
humoral and cellular immunity, which limits the patient’s
Chronic infection with hepatitis B, a double-stranded DNA
capacity to maintain previously acquired immunity against virus, is an important cause of hepatocellular carcinoma in
vaccine antigens or mount a primary immune response to the United States and globally. Chronic infection is most
new vaccine stimulation. Studies suggest that a substantial common in those who are infected at a young age; occurring
proportion of children who were vaccinated before their can- in as many as 90% of infants who acquire hepatitis B infec-
cer diagnosis have lower antibody titers than those considered tion at birth, in 30% to 50% of children infected at ages 1
protective after treatment. In addition, immunocompromised through 5 years, and in 5% of otherwise healthy individuals
patients are at increased risk of adverse events with live atten- who are infected as adults.49 An estimated 800,000 to 1.4
uated vaccines and thus cannot receive vaccines such as million persons in the United States live with chronic hepa-
MMR or varicella during their treatment.46 titis B infection, many of whom are not aware of it. The
Patients who were too young to have received recom- hepatitis B vaccine was first approved for use in the United
mended childhood immunizations before treatment can States in 1981 and, in 1982, the ACIP recommended hepa-
generally be vaccinated with inactivated or recombinant vac- titis B vaccination for adults at increased risk for hepatitis B
cines 3 months after completion of chemotherapy and with infection. In 1991, recognizing the challenges of vaccinating
live attenuated vaccines (MMR and varicella) 3 to 6 months adults at increased risk and the substantial burden of chronic
after completion of chemotherapy.13,45-47 Children who hepatitis B infections acquired in childhood, the ACIP rec-
completed their vaccination schedule before cancer treat- ommended that children receive a hepatitis B vaccine series
ment often have declines in immunity to vaccine antigens starting in infancy. In 1995, the ACIP recommended rou-
and may receive a booster dose of all vaccines, including tine vaccination for all previously unvaccinated adolescents
Haemophilus influenzae type B vaccine and pneumococcal ages 11 to 12 years and, in 1999, the recommendations for
vaccine, at 3 months postchemotherapy for inactivated or vaccination were expanded to all previously unvaccinated
recombinant vaccines and 6 months for live attenuated vac- children and adolescents ages birth to 18 years. Ensuring
cines. Alternatively, patients can receive serologic testing for that children and adolescents receive full hepatitis B virus
protection against vaccine-preventable diseases with a rec- immunization has become a high priority in the United
ognized serologic correlate of protection and vaccination for States, with many states modifying school immunization
those with inadequate serum antibody concentrations.46 laws to reflect hepatitis B recommendations.49 As of 2015,
The optimal approach for children who had received some 91.1% of adolescents ages 13 to 17 years had received 3 or
but not all doses of a specific vaccine at the time of diagnosis more doses of hepatitis B vaccine.50
is not clear; it may be recommended that they receive all of Recommendations for hepatitis B vaccination also apply
the doses usually needed to confer protection.45 to selected adult populations, including those who have
A 35-year longitudinal study found elevated incidence multiple sexual partners, household or sexual partners with
rates of infections and infectious complications among chronic infection, and individuals whose occupations involve
12,360 five-year survivors of childhood cancer compared contact with blood and body fluids. Hepatitis B vaccination
with their siblings.48 Childhood cancer survivors also had is recommended for people who travel to parts of the world
an increased risk of death from infectious complications where hepatitis B infection is common. In December 2011,
compared with the US population (standardized mortality the ACIP added the recommendation that all previously
ratio, 4.2; 95% confidence interval [95% CI], 3.2-5.4). unvaccinated adults ages 19 to 59 years with type 1 or 2 dia-
Among the 65 deaths attributed to infections, 25% were betes be vaccinated against hepatitis B as soon as possible
due to pneumonia, 17% were due to septicemia, 12% were after the diagnosis is made because of the higher incidence
due to human immunodeficiency virus-associated infections, and prevalence of hepatitis B associated with contact of
9% were due to bacterial endocarditis, and 37% were due to glucose-monitoring equipment with infected blood.51 As of
miscellaneous other causes (eg, gastrointestinal infections, 2014, hepatitis B vaccination coverage was 32.2% among
encephalitis, etc). Patients with exposure to total body irra- adults ages 19 to 49 years and 15.7% among adults age 50
diation had the highest mortality (standardized mortality years and older.52
ratio, 7.8; 95% CI, 1.8-33.0). Although additional research The role of chronic hepatitis B infection in hepatocellular
is needed to understand the immunologic factors that may carcinogenesis is well documented, and the efficacy of hepa-
explain elevated morbidity and mortality from infectious titis B vaccination programs for liver cancer prevention
diseases among cancer survivors, receipt of appropriate has been clearly shown in studies of populations for whom
immunizations and prompt care for suspected infections are this infection comprises a large portion of the attributable
recommended to mitigate these risks.48 risk for hepatocellular carcinoma.53,54 In addition to the

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Immunization in Cancer Prevention, Treatment and Survivorship

prevention of hepatocellular carcinoma, individuals and Eight years after HPV vaccines were first recommended
birth cohorts who receive hepatitis B vaccination early in in the United States, coverage remains well below the
life will be protected against primary infection and thus do Healthy People 2020 target of 80%. According to the
not face the risk of reactivation of hepatitis infection during National Immunization Survey-Teen, in 2015, coverage
receipt of immunosuppressive therapy. Because reactivation with 3 doses of HPV vaccine by age 13 to 17 years was
is a significant risk for those who receive high-dose chemo- 41.9% among girls and 28.1% among boys.50 Most states do
therapy for stem cell/bone marrow transplantation or treat- not require HPV vaccination for school attendance, and
ments that lower the number of B lymphocytes, such as such mandates have been controversial and met with limited
anti-CD20 therapy, the American Society of Clinical success.62,63 A recent study of state vaccination mandates
Oncology and other clinical guidelines recommend that found that, as of March 2015, only Virginia and the District
patients for whom such therapy is planned and those in of Columbia required HPV vaccination, and both included
groups at high risk for hepatitis B infection be screened for broad, vaccine-specific exemption procedures; a similar
prior hepatitis B infection.55 Those who are positive for requirement took effect in Rhode Island in August 2015.64
hepatitis B surface antigen are recommended to start antivi- HPV immunization rates are substantially lower than rates
ral prophylaxis before systemic therapy, and those who are of other childhood and adolescent immunizations. In
hepatitis B surface antigen-negative/anti-hepatitis B core addition to cost and parental concerns about vaccine safety,
antibody-positive are considered for antiviral prophylaxis or barriers to HPV vaccine uptake among adolescents and
are monitored closely and can start antiviral therapy if hep- young adults include the misperceptions among some
atitis B virus reactivation occurs.56 parents that HPV immunization is not needed for children
who are not sexually active and that the receipt of the vac-
Human Papillomavirus cine might increase promiscuity.65 Strategies to increase
HPV is a necessary agent in the pathogenesis of cervical HPV vaccination include reminder/recall systems; practice-
cancer and is associated with a significant proportion of can- focused interventions targeting staff, clinicians, and parents;
cers of the anus (88%), vulva (43%), penis (50%), vagina assessment and feedback activities; and school-based HPV
(70%), and oropharynx (13%-56%).57,58 HPV is a double- vaccination programs.66
stranded, encapsulated DNA virus of which there are more HPV vaccination is important for pediatric, adolescent,
than 100 types; at least 40 are known to infect the human and young adult cancer survivors because of the increased
genital tract, and 15 are potentially oncogenic.59 Ninety per- incidence of subsequent HPV-associated malignancies
cent of cervical cancers worldwide are caused by 9 HPV among long-term survivors.67 Survivors with a history of
types, with types 16 and 18 responsible for two-thirds to hematopoietic stem cell transplantation, treatment with pel-
three-quarters of cases.60 In 2006, the FDA approved the vic irradiation, and other cancer treatments resulting in sus-
quadrivalent HPV vaccine (Gardasil; Merck & Company tained immunosuppression are at the greatest increased risk
Inc) to prevent cervical, vulvar, vaginal, and anal lesions for HPV persistence and complications.65 Analyses of Sur-
associated with HPV types 6, 11, 16, and 18 for females and veillance, Epidemiology, and End Results data from 1973
males ages 9 to 26 years and, in 2009, the FDA approved to 2010 demonstrated that female pediatric and young adult
the bivalent HPV vaccine (Cervarix; GlaxoSmithKline Bio- cancer survivors had a 40% relative excess of HPV-
logicals, Rixensart, Belgium) for administration to females associated malignancies overall compared with females in
ages 9 to 25 years for the prevention of cervical cancer the general US population. The relative excess of HPV-
caused by oncogenic HPV genotypes 16 and 18. A third associated malignancies among male pediatric and young
vaccine, Gardasil 9, was approved by the FDA in December adult cancer survivors was even greater—150%.67
2014; this vaccine protects against the 4 HPV types in Gar- Two studies have examined HPV vaccine uptake among
dasil and 5 additional oncogenic types (HPV types 31, 33, childhood cancer survivors. A survey of parents of female
45, 52, and 58). Gardasil 9 was recommended by the ACIP cancer survivors 5 or more years after their diagnosis and 2
at its February 2015 meeting. It is recommended that or more years after therapy (age range, 11-18 years) at Texas
HPV vaccination occur at age 11 to 12 years, before sexual Children’s Hospital found that that 32% of cancer survivors
intercourse begins. HPV vaccination is recommended as a had initiated the 3-dose series.68 A study conducted among
2-dose schedule (at least 6 months apart) for children who patients and maternal caregivers attending a survivor clinic
initiate vaccination between the ages of 9 through 14 years, at St. Jude Children’s Research Hospital found that 32.6%
whereas 3 doses (at baseline, 1 to 2 months, and 6 months (75 of 230) of cancer survivors initiated and 17.9% com-
later) are recommended for immunocompromised persons pleted the 3-dose vaccine series, whereas 34.3% (24 of 70)
and for individuals who initiate the vaccination series at of healthy controls initiated and 20.0% completed the HPV
ages 15 through 26 years.61 vaccine series.69 Although these studies suggest that HPV

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CA CANCER J CLIN 2017;67:398–410

vaccination rates among survivor populations are similar to may have a suboptimal response to the vaccine, it is safe to
those in the general population, the prevalence of HPV vac- administer to immunocompromised patients and has the
cination in this vulnerable population should be higher.65 potential to decrease their risk of severe infection and com-
Most children who are undergoing cancer treatment at plications and to reduce the risk of transmission among
the age when HPV vaccination is recommended can be vac- high-risk patients. Immunocompromised patients should
cinated, because current guidelines recommend administra- not receive the live attenuated influenza vaccine. (The live
tion of nonliving vaccine administration on schedule, even attenuated influenza vaccine is not recommended for any
during chemotherapy, if the patient is not severely neutro- population during the 2016-2017 flu season because of lack
penic.65 Additional research is needed to assess the need for of effectiveness in recent flu seasons.71) The effectiveness of
boosters in patients who receive vaccinations during periods influenza vaccination is likely to be lower in patients at the
of immunological compromise. It is important that health highest risk for severe disease; thus, influenza vaccination
care providers encourage childhood and adolescent cancer for family members and health care providers is strongly
survivors who have not completed their HPV vaccination encouraged. Caregivers for persons who require a protective
series to do so. environment because of severe immunosuppression should
not receive live attenuated influenza vaccine. Because of the
Selected Vaccines Important for Patients With theoretical risk for transmission of the live attenuated vac-
Cancer and Survivors cine virus to close contacts, these caregivers should also
Influenza avoid contact with persons who received the live attenuated
Routine annual influenza vaccination is recommended for influenza vaccine within the past 7 days.70
all persons aged 6 months or older for whom vaccination is Patients receiving systemic chemotherapy as treatment
not medically contraindicated.70 Ideally, vaccination should for any form of cancer are considered at high risk of
occur before the onset of influenza activity in the commu- influenza-related complications. Information about influ-
nity. Clinicians are encouraged to vaccinate patients by enza frequency and severity among adults receiving chemo-
October, if possible, and to continue to offer the flu vaccine therapy is limited, although a 2009 review article cited
for as long as influenza viruses are circulating. Children ages several studies reporting case fatality rates greater than
6 months through 8 years who require 2 doses should 10%.72 A recent multicenter study of 115 patients with
receive their first dose as soon as possible after the vaccine solid tumors who were infected with influenza A (H1N1)
for that year becomes available and should receive the sec- in 2009 found high rates of hospitalization (50%), pneu-
ond dose >4 weeks later. To avoid missed opportunities monia (23%), and death (9.5%).73 Up to two-thirds of chil-
for vaccination, vaccination should be offered to unvacci- dren receiving cancer therapy who contract influenza are
nated persons aged >6 months during routine health care hospitalized, for 2 to 7 days on average, with respiratory
encounters and hospitalizations when vaccine is available.70 complications such as pneumonia, respiratory failure, and a
Some patients and health care providers may be concerned need for ventilator support in 10% to 20% of patients.74 In
about an increased risk of Guillain-Barre syndrome after addition to influenza-related morbidity, influenza infection
influenza vaccination. An increased incidence of Guillain- in children can result in treatment delays averaging 3
Barre syndrome was observed in 1976 after receipt of weeks, potentially affecting long-term prognosis.74 Vacci-
the swine flu vaccine, with an estimated frequency of 1 nation of pediatric patients with cancer and family mem-
additional case per 100,000 vaccinated persons.71 However, bers is an important prevention strategy.74 In addition,
in studies of patients receiving influenza vaccines in subse- vaccination of health care workers is critical to prevent nos-
quent years, those that found any increased risk of Guillain- ocomial transmission of influenza to patients with cancer.
Barre syndrome estimated an additional risk of 1 or 2 addi- A recent multiyear intervention to increase influenza vacci-
tional cases per million people vaccinated. Studies have also nation rates among health care workers in a large compre-
shown an increased risk of Guillain-Barre syndrome after hensive cancer center found that an increased health care
influenza infection of higher magnitude than the risk worker vaccination rates was associated with a decreased
observed after vaccination.71 proportion of nosocomial influenza infections in patients
The receipt of inactivated influenza vaccine is generally with cancer.75 Recommendations and strategies to increase
encouraged for patients with hematologic or solid tumor influenza vaccination rates among health care providers
malignancies aged 6 months and older, with the exception have been published.76
of those receiving intensive chemotherapy, such as consoli-
dation or induction therapy for acute leukemia, and those Streptococcus pneumoniae
treated with B-cell antibodies whose B-cell depletion ren- Streptococcus pneumoniae bacteria (also called pneumococcus)
ders a response unlikely.47 Although patients with cancer cause acute bacterial infections, including pneumonia,

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Immunization in Cancer Prevention, Treatment and Survivorship

bacteremia, and meningitis. Approximately 400,000 persons those with other medical conditions than for immunocom-
in the United States are hospitalized each year because of petent persons to minimize the risk window for invasive
pneumococcal pneumonia.77 This bacterium is responsible pneumococcal disease caused by serotypes unique to
for approximately one-third of cases of community-acquired PPSV23 in these highly vulnerable groups.80
pneumonia. The case-fatality rate for pneumococcal pneu- Introduction of the PCV7 vaccine for children younger
monia is 5% to 7% and may be even higher for elderly than 5 years in 2000 (before the introduction of PCV13)
patients. Although the most common presentation of pneu- resulted in a rapid decline in the incidence of invasive pneu-
mococcal infection among adults is pneumonia, typical pre- mococcal disease (IPD), not only among children targeted
sentations in young children include acute otitis media and for vaccination but also among unvaccinated children and
bacteremia without a known site of infection.77 adults, demonstrating strong direct and indirect protective
There are 2 types of pneumococcus vaccines in current use effects. A study of overall, age group-specific, and serotype-
in the United States: pneumococcal polysaccharide vaccine specific IPD incidence from 1998 through 2007 found that
(PPSV23) (Pneumovax [Merck & Company Inc] or Pnu- dramatic reductions in overall and serotype-specific incidence
Immune [Wyeth Pharmaceuticals Inc/Pfizer Inc, New York, had persisted in all age groups, including older adults. Even
New York]) and pneumococcal conjugate vaccine (PCV13) greater declines occurred for PCV7 subtypes accompanied by
(Prevnar 13; Wyeth Pharmaceuticals Inc/Pfizer Inc). The increases in non-PCV7 subtypes of much smaller magni-
former consists of capsular material from 23 pneumococcal tude.83 A subsequent study examined trends in IPD inci-
serotypes. PPSV23 has been recommended for adults older dence rates after the introduction of PCV13 in 2010 and
than 65 years since 198378 but is not used in infants or tod- reported that incidence rates of IPD with serotypes included
dlers younger than age 2 years, for whom unconjugated poly- in PCV13, but not in PCV7, declined by 58% to 72%, which
saccharide antigens are poorly immunogenic. PCV13 consists is comparable to declines reported after the introduction of
of capsular polysaccharides from the 13 most common patho- PCV7, leading to overall reductions in IPD of 12% to 32%.84
genic pneumococcal serotypes covalently linked to a nontoxic Immunocompromised individuals, including those with
recombinant protein that is nearly identical to diphtheria hematologic cancers and those receiving immunosuppressive
toxin. PCV13 is recommended for infants and toddlers therapies, are at increased risk forIPD. A national study of
because of its excellent immunogenicity in this age group.77 IPD rates in adults with specific chronic conditions was
PCV13 also has been shown to stimulate good antibody conducted using 1999 and 2000 data from the Active Bacte-
responses in adults and, since 2011, has been approved by the rial Core Surveillance and the National Health Interview
FDA for use in adults ages 50 years and older.77 In 2014, the Survey. The rates of IPD in individuals at least 18 years old
ACIP began recommending sequential administration of with chronic conditions were compared with rates in healthy
both PCV13 and PPSV23 for all adults at least 65 years of adults, controlling for age, race, and the other chronic ill-
age who have not previously received a pneumococcal vac- nesses. Overall incidence rates, expressed as IPD cases per
cine.79 The recommended intervals between administration 100,000 persons, were 8.8 in healthy adults, 300.4 in adults
of the 2 vaccines vary, depending on factors such as patient with solid cancer (adjusted relative risk, 22.9; 95% CI, 11.9-
age, risk group, and which vaccine is given first.80 In 2012, 44 3), and 501.3 in adults with hematologic cancer (adjusted
the ACIP began recommending sequential administration of relative risk, 38.3; 95% CI, 15.9-92.2).85 In both the
PCV13 and PPSV23 for individuals at least 19 years of age numerator and the denominator of these rates, the defini-
who have immunocompromising conditions and, in 2013, tion of patients with cancer would likely include patients
recommended sequential administration of PCV13 and under treatment as well as posttreatment survivors.85 An
PPSV23 for children ages 6 to 18 years with immunocom- analysis of trends in IPD incidence rates from 1998 to 2009
promising conditions.81,82 In 2013, the Infectious Disease in adults of all ages showed declines for healthy individuals
Society of America issued guidelines for vaccination of the and those with high-risk conditions, although incidence
immunocompromised host stating that PCV13 should be rates in 2009 remained substantially higher for those with
administered to adults and children newly diagnosed with high-risk conditions (34.9 vs 8.8 IPD cases per 100,000).86
hematologic or solid malignancies and that PPSV23 should The most recent available data from the National Health
be administered to children 2 years and older and to adults Interview Survey (2014) found that reported pneumococcal
at least 8 weeks after the indicated doses of PCV13.46 The vaccine coverage (PPSV23 and PCV13) among adults ages
sequence of administration of PCV13 and PPSV23 is rec- 19 to 64 years with high-risk conditions was 21.3% overall,
ommended based on studies documenting a better response similar to the estimate from 2013. Coverage among whites
to serotypes common to both vaccines when PCV was was higher (21.1%) than coverage among Hispanics (16.4%)
given first.80 The interval between administration of and Asians (14.6%), but coverage was not significantly dif-
PCV13 and PCV23 is shorter for patients with cancer and ferent for blacks (20.2%) or persons of other races (25.3%).

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CA CANCER J CLIN 2017;67:398–410

TABLE 1. Vaccine Resources


Recommended Immunization Schedule for Children cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf
and Adolescents Aged 18 Years or Younger, United States, 2017
Recommended Immunization Schedule for Adults cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf
Aged 19 Years or Older, United States, 2017
ACIP disease-specific recommendations cdc.gov/vaccines/hcp/acip-recs/index.html
2013 IDSA Clinical Practice Guideline for idsociety.org/Templates/Content.aspx?id532212256011
Vaccination of the Immunocompromised Host
Abbreviations: ACIP, Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention; IDSA, Infectious Diseases Society of America.

Among adults aged at least 65 years, coverage was 61.3% Hispanics, 20.7% for Asians, and 19.6% among those iden-
overall, similar to the estimate for 2013. Coverage among tifying their race as “other.”52
whites (64.7%) was higher than among blacks (49.8%), His- Patients with cancer, especially those with leukemia and
panics (45.2%), and Asians (47.7%).52 lymphoma, have an increased risk for herpes zoster, as do
individuals with other immunosuppressive medical condi-
Herpes Zoster tions or treatments. A study of elderly patients with cancer
Varicella-zoster virus (VZV) is a neurotropic member of the diagnosed during 1991 through 2007 using Surveillance,
herpes virus family. Primary infection with VZV causes var- Epidemiology, and End Results-Medicare–linked records
icella (chickenpox). After clinical resolution of the primary found that the incidence rate of herpes zoster was 31 per
infection, VZV can remain latent in the dorsal root ganglia. 1000 person-years for patients who had hematologic cancers
Latent VZV can reactive years later, resulting in productive and 14.9 per 1000 person-years for patients who had solid
viral infection that causes a painful, maculopapular rash cancers, with adjusted risk ratios compared with patients
known as herpes zoster or shingles.87,88 Varicella vaccina- who did not have cancer of 2.36 (95% CI, 2.30-2.42) and
tion in children to prevent chickenpox, which began in the 1.19 (95% CI, 1.17-1.21), respectively.89 Another study
United States in 1995, does not prevent herpes zoster, using records from Kaiser Permanente Northern California
because it contains live attenuated VZV, which causes latent found similar incidence rates of 31 per 1000 person-years
infection that can reactivate. Children vaccinated against for patients with hematologic cancers and 12 per 1000
varicella appear to have a lower risk of herpes zoster than person-years for patients with solid malignancies diagnosed
people infected with the virus, but it is unclear whether the during 2001 through 2005.87 A more recent study con-
decreased risk will persist at older ages. The CDC estimates ducted among Kaiser Permanente Southern California
that the lifetime cumulative incidence for developing herpes members aged 60 years and older who received chemother-
zoster is almost 1 in 3 people in the United States. The inci- apy for cancer found that those who previously were vacci-
dence of herpes zoster increases with age, particularly after nated against herpes zoster had a lower cumulative
age 50 years, as does the severity of associated symptoms, incidence rate than unvaccinated patients (3.28% in vacci-
such as postherpetic neuralgia, the incidence of nonpain nated patients and 5.34% in the unvaccinated group;
complications, the need for hospitalizations, and inter- adjusted hazard rate, 0.58 [95% CI, 0.46-0.73]).90
ference with activities of daily living.
A live attenuated herpes zoster vaccine (Zostavax; Merck Conclusions
& Company Inc) was recommended by the ACIP in 2008 The development of vaccines and resulting declines in
for prevention of herpes zoster among adults aged at least infection-related morbidity and mortality during the 20th
60 years. Although the FDA approved the use of Zostavax century was a remarkable medical and public health achieve-
in 2011 for adults ages 50 through 59 years, the ACIP ment that saved countless lives. In the United States, paren-
reviewed evidence relevant to vaccination in this age group tal resistance to childhood immunizations, the reemergence
but has not broadened its recommendation for routine vac- of measles and other infectious diseases preventable by
cination beyond the initial one for adults aged at least childhood immunizations, low rates of HPV vaccination for
60 years.88 In 2014, 27.9% of adults aged at least 60 years adolescents, and suboptimal uptake of vaccines recom-
reported receiving a herpes zoster vaccination. There are mended for high-risk and older adults cause unnecessary
substantial racial disparities in vaccine coverage. Among suffering, deaths, and increased costs for the health care sys-
persons aged 60 years or older, vaccination coverage was tem. High rates of immunization and herd immunity are
32.0% among whites, 11.6% among blacks, 14.6% for critically important to protect immunosuppressed patients

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Immunization in Cancer Prevention, Treatment and Survivorship

with cancer from exposure to vaccine-preventable diseases accessed immunization records; and insufficient knowledge
when their own immunity is weakened. The trend for and awareness, as well as problems related to patient cost
decreasing receipt of oncology care as inpatients in special- and vaccine storage.91 The National Vaccine Advisory
ized cancer centers and increasing care in outpatient and Committee recently evaluated the barriers to adult immuni-
community hospital settings could increase patient expo- zation and made recommendations related to general infra-
sure to infected individuals and heightens the importance structure, expanded access, and provider-based and health
of herd immunity. Clinicians play an important role in system-based interventions.92,93 It has been estimated that
encouraging parents to vaccinate children and adoles- only 31% of family physicians and 20% of internists stock all
cents and in identifying and providing vaccines to high- vaccines routinely recommended for adults.94 Offering vac-
risk and age-eligible adults.36 Table 1 provides links to cines at retail pharmacies and clinics can expand opportuni-
up-to-date resources for more comprehensive vaccine ties for adult immunization.91 Systematic and concerted
recommendations. Clinicians caring for patients with efforts to improve vaccination adherence in the United
cancer and survivors should be aware of their heightened States is important for the prevention of cervical and hepa-
susceptibility to vaccine-preventable diseases and ensure tocellular cancer as well as the protection of vulnerable
that patients receive revaccination after treatment if patients with cancer and survivors from vaccine-preventable
necessary. infectious diseases (including, but not limited to, those
Barriers to the receipt of vaccines in adults include lack of described in this review) and should be a priority for cancer
an adult vaccine delivery system; lack of current, easily control and advocacy. 䊏

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