Eighteen million American adults are currently living with a diagnosis of cancer. In addition to the challenges inherent to cancer treatment and survivorship, the disease- and treatment-related immunosuppression experienced by many patients with cancer increases their risk of morbidity and mortality when exposed to viral or bacterial pathogens. For example, patients with cancer who contract influenza are more likely to experience complications, require hospitalization, or die when hospitalized than otherwise healthy individuals.

Vaccination is a cornerstone of helping to prevent infection in patients with cancer and is recommended by national and international organizations such as the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the Spanish Society of Medical Oncology. However, vaccination rates in patients with cancer remain suboptimal, resulting in avoidable healthcare costs, treatment delays, and diminished outcomes. These coverage gaps can be attributed to a range of patient, provider, and health system factors, including:

• Vaccine hesitancy (fueled by misinformation and inadequate provider-patient communication)
• Fragmented care delivery
• Limited awareness of vaccination guidelines
• Complex and inconsistent reimbursement structures

Adequate immunization against vaccine-preventable diseases remains a significant public health issue,1-3 particularly for individuals whose immune defenses are compromised.2,3 A recent analysis of 2021 National Health Interview Survey data indicates that 6.6% of adults in the US—roughly 17 million people—may be immunocompromised.4,5 Patients with cancer represent a sizeable proportion of this high-risk group.6-8

As of January 2022, the American Cancer Society estimated that 18 million American adults were living with a history of cancer, including approximately 5 million individuals who were within 5 years of diagnosis.9 An analysis of US cancer and mortality statistics from the Surveillance, Epidemiology, and End Results registries projected that more than 690,000 Americans would be living with metastatic breast, prostate, lung, colorectal, melanoma, or bladder cancer by January 2025.10

The immune defenses of these individuals can be weakened in a variety of ways— encompassing both the disease process and its treatment—that can persist for months or even years after treatment has been completed.11,12 The impact of these deficits is evident in the increased morbidity and mortality experienced by cancer patients who contract vaccine-preventable respiratory diseases:

• Individuals living with cancer may be 3 to 10 times more likely to be hospitalized with influenza-related infections (depending on age) and up to 10 times more likely to die while hospitalized than the general population.13,14
• In patients with recently diagnosed cancer, SARS-CoV-2 infection was associated with a 7-fold increase in death.15
• Compared with the general population of healthy adults, patients with hematological cancers or solid tumors have been found to have a 38-fold and 23fold higher risk, respectively, of invasive pneumococcal disease (IPD).16 Patients with multiple myeloma have been reported to have a 62.8 times greater risk.17

The disproportionate impact of these conditions on patients with cancer illustrates the unique vulnerability of this group to infectious diseases and the importance of vaccines in protecting this vulnerable population.11,18 In this white paper, we will explore the potential of vaccinations to help reduce the morbidity, mortality, and healthcare costs associated with vaccine-preventable diseases in patients with cancer and cancer survivors, with a focus on:

• How cancer and its treatment increase the risk of both contracting vaccinepreventable diseases and experiencing adverse outcomes—during and after treatment
• Current vaccine recommendations for patients with cancer from NCCN and ASCO
• Gaps in vaccine coverage of cancer patients and survivors
• Evidence-based strategies to optimize vaccination and minimize infectious disease risk in cancer patients, including vaccination of healthcare providers and household contacts
• Actionable recommendations for key stakeholders and decision makers

It is noteworthy that despite wide recognition that patients with cancer are at high risk of vaccinepreventable diseases, these authors found that limited data are available on vaccine coverage, benefits, and barriers specific to patients with cancer in the United States. This gap underscores both the need for greater awareness of the role of vaccines in the care of patients with cancer and the need for more research on optimizing vaccine coverage in the US.

Infectious Disease in Patients with Cancer:

Understanding the Risks Immunosuppression in patients with cancer is a multifactorial process that involves the effects of the disease process and of the therapies used to treat it. In some cancers (eg, non-small-cell lung, colorectal), tumor progression itself is associated with systemic immune suppression that reduces defenses against viral and bacterial pathogens.12

Cancer treatments such as cytotoxic chemotherapy, radiation, and hematopoietic stem cell transplantation (HSCT) damage bone marrow, suppressing the production of immune cells crucial to mounting a defense against infectious agents (Table 1).12,19 In addition, treatment-related adverse effects such oral mucositis can disrupt natural defensive barriers, increasing the risk of infections.12 (See page 4 of the article for the table.)

Once treatment is complete, cancer survivors remain at risk due to the late effects of cancer and the lingering effects of treatment.11,22 Long term immune deficits are particularly common in patients who receive HSCT, chimeric antigen receptor T-cell therapy, or monoclonal antibody treatment, and in those whose bone marrow has not recovered after undergoing chemotherapy.11 As a result of this ongoing immune suppression, the immune response to vaccines may be impaired in cancer survivors.23

Impact of vaccine-preventable diseases on patients with cancer

The profound immunosuppression experienced by many patients with cancer increases their risk of poor outcomes when exposed to viral or bacterial pathogens. For example:

• Cancer patients who contract influenza are at much higher risk of complications and have longer lengths of stay when hospitalized, with reported mortality rates that range from 5% to as high as 33% (varies by cancer diagnosis).14,19,24,25
• Patients with lung cancer and some hematologic cancers (eg, chronic lymphocytic leukemia, lymphoma, multiple myeloma) have a high risk of IPD.24
• In a retrospective cohort study using administrative healthcare databases in Ontario, Canada, COVID-19-associated 14-day hospitalization and 28-day mortality rates were significantly higher in individuals with cancer than individuals without cancer. Patients with hematologic malignant neoplasms were 75% more likely to be hospitalized and twice as likely to die, and those with solid tumors were 11% more likely to be hospitalized and 31% more likely to die.26

These risks are not limited to respiratory diseases. In patients receiving chemotherapy, inactivated hepatitis B virus (HBV) can become reactivated, leading to liver damage. In addition, up to 50% of patients with pre-existing immunity to HBV who undergo stem cell transplantation lose that immunity following treatment. The rate of HBV infection-related mortality in patients with cancer has been estimated at up to 5%.24

Disease- or treatment-related decreases in T-cell immunity can also allow reactivation of herpes zoster (HZ) in patients with cancer.27 A meta-analysis of studies on risk factors for HZ found that hematological malignancies such as lymphoma or leukemia more than doubled patients’ risk of latent HZ compared to controls.27 A systemic review found that rates of postherpetic neuralgia were as high as 41% in patients with hematologic cancers or a history of HSCT.28

The increased risk of infection in cancer patients is often accompanied by increased costs. In an analysis of cost of HZ infections in immunocompromised patients in the US, costs during the first quarter after HZ diagnosis were $2,500 to $3,100 higher for patients with cancer and HZ infection than for those with cancer without HZ.29

Gaps in vaccine coverage

Studies of immunization rates for vaccine-preventable diseases in adults in general and cancer patients in particular have consistently found rates below those recommended by health authorities (Table 2).23,30,31 An analysis of data from the 2016–2017 and 2017–2018 National Health Interview Surveys (NHIS) found that 64% of respondents with self-reported cancer had received the influenza vaccine—a rate that was higher than that for respondents without cancer, but still below the target rate of 70%.31

A similar pooled analysis of data on patients with a history of cancer (aka cancer survivors) from the 2008–2018 NHIS datasets found overall patient-reported vaccination rates of 62.9% for influenza, 72.2% for pneumococcal pneumonia, 21.5% for HBV, and 30.8% for HZ, with an increase in vaccination rates over time. Of note, this analysis also found that African American race, lower education levels, lower income, and lack of private insurance were associated with lower adherence to recommended vaccinations, an indicator of the enduring socioeconomic disparities in vaccine coverage in the US.32 (See page 6 of the article for the table.)

Approach to Vaccination in Cancer Patients and Survivors

US and international guidelines are clear on the importance of vaccination as “a cornerstone of infection prevention” in patients with cancer as well as the importance of vaccinating family members and others in close contact with cancer patients (see Herd Immunity at Home: The Importance of Vaccinations in Caregivers and Close Contacts of Patients with Cancer on page 9).12,19,23,35 Inactivated (inactivated or killed pathogens), subunit/conjugate, and mRNA vaccines are recommended in patients with cancer, as these vaccines will not replicate and cause infections in immunocompromised or weakened patients (Table 3).12,35 Live-attenuated vaccines (eg, measles, mumps, rubella, varicella) are contraindicated due to the potential risk of virus replication and infection.12,35 (See page 7-8 of the article for the table.)

The Importance of Improving Vaccine Coverage in Patients with Cancer

Optimal timing and adherence to vaccination schedules are crucial to maximizing protection. Prior to initiating anticancer therapy, clinicians should determine patients’ vaccination status and ensure that they are up to date on seasonal and age- and risk-based vaccines (Figure 1).3,24,35 (See page 9 of the article for the table.)

Herd Immunity at Home: The Importance of Vaccinations in Caregivers and Close Contacts of Patients with Cancer

Family members and household-based caregivers in close proximity to patients with cancer can potentially transmit vaccine-preventable diseases to these vulnerable patients. To fully protect immunocompromised patients with cancer, it is important to leverage the concept of herd immunity at the level of the home environment, by ensuring close contacts are fully vaccinated in accordance with current recommendations.43,44 This approach is analogous to the wellestablished practice of “cocooning” newborns from pertussis by vaccinating parents, siblings, and other close contacts for Tdap.45

Guidelines from ASCO, the Infectious Diseases Society of America (IDSA) and the NCCN all stress that immunocompetent adults and children who live with or come in close contact with immunocompromised patients should receive all recommended vaccines.23,35,43 Vaccines containing recombinant viral antigens (eg, HPV or HBV) or inactivated or purified antigens or bacterial components (eg, influenza, Tdap) are considered safe for close contacts of cancer patients and survivors23; however, live attenuated vaccines such as the oral polio vaccine may be contraindicated due to the risk of viable virus transmission to immunocompromised patients.23

Despite broad recognition of the need for vaccine coverage in family, caregivers, and other close contacts of patients with cancer, messaging around this issue has been limited. An analysis of National Cancer Institute cancer center websites recently found that although 53 of the 70 sites included information on preventative health for caregivers and patients, only 1 had information on vaccination for caregivers or family contacts.46

Promoting routine vaccinations for close contacts is critical to ensuring individual- and community-level protection from vaccine-preventable diseases for patients with cancer. The potential impact of this approach can be inferred from the shift in the incidence of IPD among cancer patients at a major urban cancer center following the introduction of routine childhood immunization with the first pneumococcal conjugate vaccine. A retrospective analysis of IPD rates in patients treated at Memorial Sloan Kettering Cancer Center in the decade prior to the introduction of the vaccine and those treated in the ensuing 10 years (2001–2010) revealed dramatic drops in the rates of IPD in adults (≥15 years) with a wide range of cancer diagnoses.47 Overall, the incidence of IPD decreased by 64% in patients with hematologic cancers and 49% in those with solid tumors. Of note, the impact was most pronounced in high-risk patients such as those with multiple myeloma, in whom the rate of IPD declined by 74%.47

Ideally, vaccination should occur before the start of systemic therapy: at least 2 weeks before for inactivated vaccines and at least 4 weeks before for live vaccines.23,43 Patients who have completed chemotherapy can generally receive both inactivated and live virus vaccines 3 months after the end of treatment, but consultation with a specialist familiar with vaccination in survivors or patients with cancer is recommended.23 In patients receiving targeted therapy that causes immunosuppression, timing of vaccination should be adjusted accordingly. Patients treated with anti–B-cell therapy should be vaccinated at least 4 weeks before therapy or at least 6 months after cessation of treatment.20

Benefits of ensuring adequate vaccine coverage for cancer patients and survivors

Vaccination of cancer patients has been associated with reduced hospitalizations and intensive care admissions, faster recovery times, fewer treatment delays, and improved survival.26,48 One large-scale retrospective analysis found that a history of just one COVID-19 vaccination reduced patients’ risk of 14-day hospitalization by 32%, of 21-day Intensive Care Unit admission by 24%, and of 28-day mortality by 43%. Risks for each outcome in patients with ≥2 vaccinations dropped by 58%, 26%, and 50%, respectively.26

These benefits can also yield cost savings. For example, a 2008 analysis of the cost-effectiveness of influenza vaccination in adults with cancer in Taiwan found that influenza vaccination had the potential to prevent 42% of influenza infections and 45% of serious cases—saving up to $2107 (US) in medical costs and $6338 in medical and non-medical costs per case averted.49

Barriers to Vaccination in Cancer Patients
Patient level:

Vaccine hesitancy is an enduring challenge when trying to improve vaccine coverage in adults and takes on a particular urgency when dealing with immunocompromised patients.1,19,50,51 Researchers at the University of Texas Health Science Center in Houston recently surveyed 60 patients with cancer on their perceptions of vaccination.52 Although 73% agreed that it is important to get up to date with vaccines, just 58% were willing to take a vaccine if it was offered to them, and only 43% indicated they received a yearly influenza vaccine. Qualitative analysis revealed that most patients were unaware of the importance of vaccination at the time of their cancer diagnosis, a knowledge gap that typically was not addressed by oncologists. In fact, 32% of patients indicated they were never told of the importance of vaccination.52

An earlier survey, conducted as part of a doctoral thesis at a cancer center in Arizona, evaluated influenza vaccination status, knowledge about the flu vaccine, and general attitudes toward vaccination in 84 patients enrolled in phase 1 clinical oncology trials at the center.49 Influenza vaccination rates were lower than recommended—58% of respondents indicated they had received an influenza vaccination since their cancer diagnosis and only 48% had been vaccinated while on cancer treatment.53 Of note, although 52% of all respondents indicated that a doctor had recommended flu vaccination, only 37% of unvaccinated patients had been advised by a physician to be vaccinated against influenza. In this group, the most common reasons for not being vaccinated were a belief that they were not at risk for the flu, a belief that the flu vaccine is not effective, and concern that the vaccine can cause the flu.53

Provider level:

A common theme in both patient surveys summarized above is a lack of communication from providers on the importance of vaccination. This gap is particularly unfortunate given that a strong vaccine recommendation from a physician increases the likelihood a patient will get vaccinated.1,54

Although data on provider barriers specific to vaccination of patients with cancer are limited, ASCO guidelines and a recent multidisciplinary position paper both cite lack of awareness of guideline recommendations as a key gap among physicians caring for these patients.19,35 Of note, both groups call out the importance of increasing medical education and awareness among “frontline” and general practitioners, who play a significant role in promoting and providing vaccinations.19,35 The IDSA guidelines on vaccinating immunocompromised patients state that specialists should “share responsibility with the primary care provider” for ensuring that immunocompromised patients are appropriately immunized.43 However, inadequate communication between oncologists and primary care providers—coupled with a lack of clarity on which discipline is responsible for monitoring and administering vaccines—is a prime contributor to gaps in vaccine coverage.19 Although US-specific data are limited, a study conducted in the Netherlands found that 46% of general practitioners caring for patients with cancer (breast or colorectal) were unaware that yearly influenza vaccination is recommended in these patients and 48% stated that the responsibility for such vaccinations rested with the oncologist.55

Despite the dearth of oncology-specific research on barriers to vaccine coverage, valuable insights can be drawn from data that have been gathered on barriers to adult vaccination and vaccination of other immunocompromised groups. A 3-year (2016–2018) series of surveys of US-based clinicians (physicians, nurse practitioners, and physician assistants [N=4911]) and pharmacists (N=793) assessed implementation of the National Vaccine Advisory Committee’s (NVAC) Standards for Adult Immunization Practices (Table 4), as well as barriers to implementation of the standards.56,57

The Importance of Improving Vaccine Coverage in Patients with Cancer

The NVAC standards include components focused on assessment of vaccine status; recommending needed vaccines to patients; administration of (or referral for) recommended vaccines; documentation of vaccinations in an Immunization Information System (IIS); and a composite measure of complete implementation of the standards. Although more than 80% of clinicians and pharmacists reported implementing the assessment, recommendation, and administration components of the standards, full implementation was uniformly low, particularly among specialty care clinicians.53 The component with the lowest reported adherence was documentation of adult vaccinations in an IIS among immunizing clinicians, ranging from 28.4% among non-ob/gyn specialists to 46.5% among family medicine clinicians. In addition, only 46% of clinicians and 42% of pharmacists had a patient reminder-recall system in place.57 (See page 12 of the article for the table.)

Based on results from the 2017 survey, researchers grouped barriers to full implementation of the NVAC standards into three broad categories:56

• Assessment barriers: Many providers believe that vaccinating adults is not within their scope of practice and/or feel that the time and resources required for vaccine assessment would not be adequately reimbursed by payers. Forty percent of clinicians reported that their practices “cannot afford” to assess vaccination status of adults because the time required to counsel patients would not be sufficiently reimbursed.
• Administration barriers: Insufficient staff to administer vaccines and/or follow-up on vaccine status and insufficient space for vaccine storage were commonly cited by clinicians and pharmacists, including nearly 21% of pharmacists who said that they would lose money by stocking and administering adult vaccines.
• Documentation barriers: Most clinicians and pharmacists who did not document vaccinations in IIS reported they were unaware their region had an IIS that included adults and/or were unsure their electronic records system could link to IIS.

The potential scope and impact of these issues can be seen in a study of immunization costs and barriers in another high-risk immunocompromised group: patients with HIV. A 2015 study estimated the costs of providing immunizations against HPV, pneumococcal pneumonia, and HZ to 2887 patients at an urban HIV clinic in Alabama.58 Although reimbursement for each vaccine and its administration varied depending on insurer type, overall, administration of all 3 vaccines to all eligible patients would result in a net loss to the clinic of more than $97,000 per year.58

System Level:

For vaccine providers, vaccination costs include labor and vaccine storage, as well as costs associated with vaccine wastage and inventory shrinkage.59 Due to wide variations in coverage, securing reimbursement for vaccine services can be complex and difficult to navigate, as not all healthcare providers who vaccinate adults are considered “providers” by third party payers. For example, of the 16 vaccines currently recommended for adults in the US,36 for Medicare recipients, only influenza, pneumococcal, HBV; and COVID-19 are covered as medical benefits under Medicare part B; all others are considered Part D pharmacy benefits.60 As most medical providers are not enrolled as pharmacy providers, receiving reimbursement for administration of these vaccines can be challenging.59 As a result, patient access to needed vaccines can be blocked by the limited number of clinicians available to provide them.1

These barriers are in addition to the well-documented disparities in vaccine access that have always stood in the way of optimal immunization, notably;1,35

• Racial/ethnic (lower uptake in marginalized communities/groups)
• Socioeconomic (lack of insurance, lower uptake in poor communities)
• Geographic (infrastructure/logistical barriers to distribution of vaccines)

Solutions and Best Practices

As noted in ASCO’s guidelines for vaccination of adults with cancer, improving the availability, accessibility, and use of vaccines among patients with cancer requires a multifaceted approach, particularly for patients in areas with limited resources or infrastructure.37 Incorporation of vaccination programs into oncology care settings—including integration of vaccination within the oncology care pathway (Figure 2)—is crucial to ensuring adequate coverage of this uniquely vulnerable group.19

Collaboration between oncologists, infectious disease specialists, and primary care providers is key to preventing patients from falling between the cracks during cancer treatment and survivorship.19 Digital tools such as standing orders, enhanced reminders, and recall messages can help ensure that vaccines are delivered on a timely basis,1,19,35 whereas participation in an IIS can provide consolidated immunization histories for use by vaccination providers and patients to track vaccination history and gaps.1 To expand access and facilitate “vaccinating in the moment,” healthcare systems should consider providing vaccination at locations other than medical offices and hospitals (eg, infusion centers, pharmacies, health fairs, workplaces, schools) and incorporating nonphysician healthcare providers to counsel patients and assess/administer vaccines (see Case Studies: Leveraging Electronic Health Records and Nonphysician Care Extenders on the next page).1,61

Inclusion of assessment and support for recommended adult vaccinations into payerprovided oncology care management programs may also enhance vaccine awareness and uptake. (See page 14 of the article for the flowchart.)

The National Foundation for Infectious Diseases has stated that awareness and understanding of adult vaccine recommendations by “all healthcare professionals” is key to improving rates of adult immunization in the US.1 This is particularly true for cancer patients and survivors, who come in contact with a wide range of providers, each of whom can be a touchpoint for identifying vaccine needs and encouraging appropriate immunization (see Figure 2 on previous page). Information campaigns, educational initiatives, and educational materials that address vaccine hesitancy and knowledge gaps in specific communities and high-risk groups—including providers, patients, and caregivers—can expand the safety net for patients with cancer and increase vaccine coverage.1,46

At the policy level, despite changes in Medicare/Medicaid policies that have reduced or eliminated copays and out-ofpocket expenses for recommended adult vaccines, there are still coverage gaps for uninsured adults.1 Efforts are needed to address these gaps and ensure that uninsured and underinsured individuals have access to all recommended vaccines.1 Stakeholders can be further incentivized by incorporating vaccination assessment and coverage into performance measures.1 (See page 15 of the article for the case study.)

Conclusion/Call to Action

The human and economic burdens of vaccinepreventable diseases in patients with cancer underscore the urgency of implementing robust vaccination programs for these patients. Payers and other healthcare stakeholders can play a central role in facilitating change by working to improve coverage and distribution of recommended vaccines; supporting educational initiatives targeting patients, providers, and families/close contacts; and collaborating with healthcare systems to integrate vaccination services into the oncology care pathway.

References (See page 16 of the article for the references.)

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