What is the oncologist’s role in vaccination?

“The role of the oncologist is crucial in promoting successful adherence to the main vac-cines in cancer patients”

One of the main causes of morbidity and mortality in patients with cancer is infections caused by both bacteria and viruses. Infections lead to a delay in the correct timing of cancer therapies and affect the financial system with prolonged hospital stays due to complications and over-infections. For some diseases nowadays, healthcare professionals have effective preventive tools and vaccines, but they often know little about them. If they are not the first to be convinced of the importance of vaccinations, they will hardly be able to convince their patients to receive them.

In this commentary, we will analyze all the arguments that should motivate oncologists to be more aware of the issue and promote vaccinations to their patients.

1. Infections & cancer: a never-ending story

One in five tumors are induced by an infectious agent. Human papillomavirus, hepatitis B virus, hepatitis C virus, Epstein–Barr virus, human herpesvirus type 8, human T-cell lymphotropic virus, human polyomaviruses, Merkel cell polyomavirus and human immunodeficiency virus have been identified by The International Agency for Research on Cancer as carcinogens [1]. Human oncogenic viruses are different from each other in genome type, cell tropism and tumor-induced pathology. However, all of them are transmitted between humans and are capable of inducing chronic infections, initially without obvious symptoms. During this long phase, oncogenic viruses co-opt cellular processes for replication and damage immune recognition. Dysregulation of signaling pathways controlling cell growth, proliferation and survival through mutations or viral factors produced by human oncogenic viruses is implicated in many cancers [2]. The role of bacteria and helminths in triggering tumors in humans is more debated. Helicobacter pylori (H. pylori) infection is definitely associated with gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma, while the role of two helminths Clonorchis sinensis and Opisthorchis viverrini in the cancerogenesis of cholangiocarcinoma is more debated [3].

The human microbiota is naturally composed of bacteria, eukaryotic fungi protozoa and viruses, and colonizes both exposed body tissues (e.g., gastrointestinal tract) and unexposed sites (e.g., brain) [4]. In the past, the tumor was considered to be sterile. The identification of bacteria both pathogenic and commensal, viruses and fungi in tumor tissues has shown that the microbiota is involved in carcinogenesis, both as bystander and effector. The tumor microenvironment (TME) plays a key role in carcinogenesis and includes noncellular components and noncancerous host cells, such as endothelial and immune cells, and microbiota is one of the cellular components of TME [5]. Persistent bacterial and viral infection can remodel TME to facilitate their colonization, modulate cancer pathogenesis and also to modify the immune response to anticancer treatments [6]. For example, the influenza virus can induce chronic inflammation in cancer patients, particularly in lung cancer patients. The prolonged viral infection modulates the TME, with increased secretion of inflammatory cytokines and chemokines (involved in immune cell migration) and Type I interferon production that can lead to treatment resistance [7].

In an animal model, acute influenza A virus shows a reduced tumor-specific T-cell response, leading to an immune exhaustion mechanism of memory CD8þ T cells and induced PD-L1 expression on tumor cells. Influenza A virus infection seems to be able to modulate the transcriptomic profile of the TME [8].

2. Antibiotic resistance in the patient with cancer: a growing issue

A patient with cancer has a three-times higher risk of dying from a fatal infection than a patient without cancer and there may be additional bacterial infections in ongoing or following viral infections [9]. A group of six pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter spp.) deserves special attention because they are commonly associated with antibiotic resistance referred to the acronym of ESKAPE pathogens [10]. Teillant and colleagues published an interesting meta-analysis about post chemotherapy infections. They demonstrated that 26.8% of pathogens identified in post chemotherapy infections, were resistant to the standard prophylactic antibiotics [11]. The increasing rate of resistant microbes resistance shows an impact on outcomes in this vulnerable population. Indeed, Bodro et al. reported an increased persistence of bacteremia (25 vs 9.7%), metastatic infection (8 vs 4%) and early case-fatality rates (23 vs 11%) among patients with cancer infected by antibiotic-resistant ESKAPE pathogens [12].

The recent SARS-CoV-2 pandemic has exacerbated antimicrobial resistance, and several papers have estimated that by 2050 more than 10 million people will die from infections with multi-drug-resistant pathogens with a reduction of up to 3.5% in gross domestic product [13]. Antimicrobial stewardship was developed to optimize the use of antibiotics and to decrease the undesirable consequences of antibiotic use and excessive healthcare costs [13]. Reducing infection rates means reducing the possible use of antibiotics in cancer patients with neutropenia or undergoing invasive procedures.

Indeed, antibiotic administration may cause gut microbiota dysbiosis, change the biodiversity of bacteria, increase the risk of selection of resistant gut bacteria, enhance the rate of invasive infections, and impair the efficacy of oncological treatments [14]. There is a growing literature on the deleterious effects of antibiotics on the gut microbiota. Antibiotics permanently reduce the biodiversity of the intestinal microbiota. As a consequence of this loss of biodiversity, there is a reduction of signal to the intestinal mucosa with consequent impairment of the immune system. Antibiotics by altering the interaction between the immune system and gut microbiota impair T-lymphocyte activities. There is an increase in Th2/Th1 ratio and an impaired development of Th17. The change in the biodiversity of the microbiota also affects B-cell mediated immunity. In animal models, antibiotics before viral infection have been shown to cause a decrease in immunoglobulin titers [15].

The consequences of antibiotic use on the response rate and survival of patients with cancer undergoing immunotherapy have been analyzed in many studies. Progression-free survival and overall survival regardless of tumor histology seem to be reduced by the use of antibiotics during therapy with immune checkpoint inhibitors (ICIs), but not during chemotherapy. Finally, the timing of starting antibiotics versus immunotherapy seems to be particularly important: antibiotic use within 1 month before the start of ICIs worsened the progression of disease (PD) in cancer patients, whereas antibiotic use >1 month before the start of ICIs did not affect PD [16].

It seems clear how important vaccines may be in patients with cancer.

3. How confident is the oncologist about the role of vaccines in cancer patients?

Although it is known that patients with cancer may more frequently contract vaccine-preventable diseases (VPDs), a recent survey promoted by the Italian Association of Medical Oncology described low awareness of this issue and poor knowledge about vaccines among Italian oncologists. Only 30% of respondents schedule vaccinations at the first oncological visit, particularly if the cancer treatment is chemotherapy (70%) and if patients already have other comorbidities (58%). The survey showed that oncologists have very little knowledge of the complications of major VPDs and therefore do not seem to be fully aware of the importance of vaccine counseling. Furthermore, most respondents report that it is not the oncologist’s responsibility to provide vaccine counseling, due to a lack of expertise or time during oncology visits [17]. In a French hospital, an anonymous questionnaire on factors associated with vaccination coverage was administered in 2016: comprehensive information provided by general practitioners and oncologists/hematologists to their patients was found to be a relevant and statistically significant factor in the acceptance of vaccines [18].

Oncologists sometimes undervalue the consequences of VPDs, including the increased all-cause healthcare costs. Poor knowledge on the issue of vaccination in patients with cancer has also emerged from other studies. For example, Maeda and colleagues conducted a national web survey among Japanese medical oncologists about their attitudes toward flu vaccination. They reported that over 36% of physicians did not actively encourage flu vaccine to cancer patients undergoing chemotherapy for lack of evidence of efficacy and doubts about the appropriate timing. Surprisingly, almost half of oncologists discourage flu vaccination during immunotherapy and do not recommend vaccination to caregivers (cocoon vaccination) [19].

These answers must induce a change of mentality in the oncologist.

4. Clinical practice recommendations

Several papers have shown that oncology patients tend to trust their oncologist’s recommendations, hence major national and international societies wrote recommendations about vaccination in patients with cancer. The guidelines suggest scheduling vaccination before the start of cancer therapies, although many studies seem to demonstrate the efficacy of the vaccine regardless of the timing of administration. The lack of time and specific skills can be resolved by implementing a network of multidisciplinary specialists involving hygienists, infectious disease specialists and virologists. Patients with cancer may be worried about possible drug–drug interactions, so a constant and tailored dialogue with them allows us to dispel many doubts and misconceptions. There should be no doubt about the safety of vaccines in patients with cancer even if they are administered during active cancer treatments [20].

5. Take home message

With the increase in the life expectancy of patients with cancer, thanks to the discovery of new therapeutic strategies, it is important for the oncologist to learn how to manage and preserve the best quality of life of their patients. Effective prevention of the main VPDs through vaccinations is of great importance not only from an infectious point of view but also from an oncological, social-health and economic point of view. There is an urgent need for more training on these topics.

Oncologists have a key role in educating their patients on the importance of vaccinations to prevent VPDs, ensuring the effectiveness and safety of oncological treatments.

Author contributions

The author approved the submitted version of the manuscript.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.