key: cord-1008367-3o0l1xnl authors: Spagnolo, Francesco; Boutros, Andrea; Croce, Elena; Cecchi, Federica; Arecco, Luca; Tanda, Enrica; Pronzato, Paolo; Lambertini, Matteo title: Influenza vaccination in cancer patients receiving immune checkpoint inhibitors: A systematic review date: 2021-05-31 journal: Eur J Clin Invest DOI: 10.1111/eci.13604 sha: f703a42194300e2742cd87ca5fb178aacbead120 doc_id: 1008367 cord_uid: 3o0l1xnl BACKGROUND: There is a concern that influenza vaccination may increase the incidence of immune‐related adverse events in patients receiving immune checkpoint inhibitors (ICIs). The aim of this systematic review was to summarize the available data on the safety and efficacy of influenza vaccination in cancer patients receiving ICIs. METHODS: Studies reporting safety and efficacy outcomes of influenza vaccination in cancer patients receiving ICIs were included. Only descriptive statistics were conducted to obtain a pooled rate of immune‐related adverse events in vaccinated patients. RESULTS: Ten studies assessing the safety and eight assessing the efficacy of influenza vaccination in cancer patients receiving ICIs were identified, for a total of 1124 and 986 vaccinated patients, respectively. Most patients had melanoma or lung cancer and received a single agent anti‐PD‐1, but also other tumour types and immunotherapy combinations were represented. No severe vaccination‐related toxicities were reported. The pooled incidence of any grade immune checkpoint inhibitor–related adverse events was 28.9%. In the 6 studies specifying the incidence of grade 3‐4 toxicities, the pooled incidence was 7.5%. No grade 5 toxicities were reported. No pooled descriptive analysis was conducted in studies reporting efficacy outcomes due to the heterogeneity of endpoints and data reporting. Nevertheless, among the eight studies included, seven reported positive efficacy outcomes of influenza vaccination. CONCLUSION: The results of this systematic review support the safety and efficacy of influenza vaccination in cancer patients receiving ICIs. These results are particularly relevant in the context of the SARS‐CoV‐2 pandemic. Immune checkpoint inhibitors (ICIs) have become a mainstay of cancer immunotherapy in recent years for a number of solid and haematologic malignancies, such as melanoma, lung cancer, renal cell carcinoma and Hodgkin lymphoma. 1 They increase antitumour immunity by blocking intrinsic downregulators of immunity, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1). The interaction between PD-1 and PD-L1 inhibits T cells in peripheral tissue, while CTLA-4 is generally believed to inhibit T-cell activation at a proximal step in the immune response. 2 With the introduction of ICIs in everyday clinical practice, a new category of anticancer therapy-related adverse events has emerged. Unlike traditional chemotherapy, ICIs can induce a spectrum of adverse events of autoimmune pathogenesis (irAEs), due to nonspecific activation of the immune system targeting healthy tissues and organs. 2 Although the exact pathophysiology underlying irAEs remains to be further characterized, it is believed to be closely related to the function that immune checkpoints play in maintaining immunological homeostasis and avoiding autoimmune reactions. 2 The backbone of immune-related toxicity management is corticosteroid therapy. Guidelines for the management of irAEs are provided by the most influent scientific societies such as the European Society for Medical Oncology (ESMO), 3 the American Society of Clinical Oncology (ASCO) 4 and the National Comprehensive Cancer Network (NCCN). 5 There is a concern that influenza vaccination may increase the incidence of irAEs in patients with cancer receiving ICIs. 6 In an early report on the safety of influenza vaccination, among 23 patients receiving anti-PD-1 monoclonal antibodies, 6 (26.1%) had severe irAEs following the administration of the influenza vaccine, including rare events such as encephalitis (8.7%) and neuropathy (4.3%). 6 The authors of that report speculated that PD-1 blockade together with vaccination could boost the breakage of tolerance by enhancing the mechanisms associated with irAEs. 6 However, cancer patients are at higher risk for developing complications related to influenza infection, [7] [8] [9] and vaccination is the most important protective strategy against this infection. [10] [11] [12] [13] A Cochrane review of influenza vaccines in patients with cancer receiving chemotherapy revealed lower mortality and infection-related outcomes with influenza vaccination. 14 The aim of this systematic review was to summarize and discuss the currently available data assessing the safety and efficacy of influenza vaccination in cancer patients receiving ICIs. Reporting of this study conforms to broad EQUATOR guidelines 15 ; specifically, Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) guidelines were used for the conduct and reporting of this systematic review ( Figure 1 ). [16] [17] [18] Studies reporting data on the safety and efficacy of influenza vaccination in cancer patients receiving ICIs were included in this systematic review. The following data were extracted from each report: study design, type of vaccine, number of vaccinated patients, incidence and severity of ICIrelated AEs (ie irAEs) in vaccinated patients, incidence of severe vaccination-related AEs, number of nonvaccinated patients and differences in outcomes between nonvaccinated and vaccinated patients (in studies comparing the two populations). Conference abstracts were included in our analysis, and additional studies were identified following review of references lists. Only English-language publications were considered for inclusion. Data were independently extracted by two investigators (FS and AB) to ensure homogeneity of collection and to rule out the effect of subjectivity in data gathering and entry. Disagreements were resolved by iteration, discussion and consensus. Only descriptive statistics were conducted to obtain a pooled response rate of irAEs by severity in vaccinated patients. The agreement rate between the two investigators who independently extracted data was 100% after iteration and consensus. Twelve records reporting data from 11 studies were identified: safety outcomes were assessed in 10 studies, while efficacy endpoints were reported in 8 studies ( Figure 1 ). Among the 10 studies assessing the safety of influenza vaccination in patients with cancer receiving ICIs, for a total of 1124 vaccinated subjects (Table 1) , 6,19-27 the majority of patients had melanoma or lung cancer, but also several other types of cancers were represented (data not shown). Most patients received an anti-PD-1 as single agent, but also patients receiving combined anti-PD-1 and anti-CTLA-4 treatment were included. 23, 24 Common Terminology Criteria for Adverse Events (CTCAE) versions 4.0 or 5.0 were used in all but one study, 27 where safety was assessed using the FDA toxicity grading scale for clinical trials; notably, this information was missing in 3 studies. 19, 24, 25 No severe vaccinationrelated adverse events were reported. The pooled incidence of any grade ICI-related irAEs was 28.9%. In the 6 studies reporting the incidence of grade 3-4 toxicities, the pooled incidence was 7.5%. 6, [20] [21] [22] [23] 27 No grade 5 toxicities were reported. Among 5 studies assessing the incidence of irAEs in vaccinated and nonvaccinated patients, two studies reported a statistically significant lower incidence in the vaccinated group 20,24 and one study a statistically significant higher frequency of irAEs in vaccinated patients, albeit with a very sample size of only 23 vaccinated patients. 6 One study comparing the safety of ICIs in 385 vaccinated and 149 nonvaccinated patients showed a trend towards lower incidence of irAEs in vaccinated patients 25 ; finally, one small study reported a trend towards lower incidence of irAEs in nonvaccinated patients. 26 The results of the eight studies assessing the efficacy of influenza vaccination in 986 patients with cancer receiving ICIs are summarized in Table 2 . 6, 19, [21] [22] [23] 25, [27] [28] [29] No pooled descriptive analysis was conducted due to the heterogeneity of efficacy endpoints and reporting of data. Nevertheless, among the eight studies included in this systematic review, seven reported positive efficacy outcomes of influenza vaccination in cancer patients receiving ICIs. 6, 19, [21] [22] [23] 25, 27, 28 Influenza vaccination is the best strategy to protect cancer patients against this infection and showed to reduce mortality and flu-related complications in those receiving chemotherapy. 14 However, in one of the first reports on the safety of influenza vaccination in cancer patients receiving ICIs, major concerns about an increased risk of severe immunological complications were raised. Despite these data being based on only 23 subjects, many clinicians started advising their patients under ICIs against vaccination. 6, 23 As highlighted in our systematic review, most subsequent and larger studies showed that the overall safety and efficacy of influenza vaccination in cancer patients receiving ICIs is not substantially different from that observed in the general population. The SARS-CoV-2 pandemic had a major impact on health system reorganization and on the management of patients with cancer, who are at increased risk of infection-related complications. [30] [31] [32] Protection of cancer patients from influenza infection is extremely important: influenza vaccination has clearly shown to lower mortality and infection-related outcomes in this setting. 14 In the context of the current SARS-CoV-2 pandemic, protecting patients from influenza infection has additional relevance also considering that influenza symptoms overlap with those of COVID-19 and may interfere with the proper prosecution of cancer treatments, ultimately decreasing their chances of survival. Our systematic review has some limitations, mostly related to the heterogeneity of study designs and endpoints among the studies included in our analysis. One of the main limitations of our safety analysis is the variability of recording toxicities outside clinical trials, especially for low-grade AEs. In fact, we found an incidence of low-grade events which suggests a probable underreporting of such events. However, clinically significant AEs, such as those requiring intervention or hospitalizations, are usually reported properly also in observational and/or retrospective studies, and the rate of severe irAEs that we observed in our analysis was in line with that reported in clinical trials, with no deaths due to treatment-related toxicity. Other potential biases include T A B L E 1 Summary of safety endpoints' results in patients who received anti-PD-1/PD-L1 immunotherapy and influenza vaccine the lack of data about reasons for receiving or not influenza vaccination (possibility of self-selection bias) and, for retrospective studies, the selection bias intrinsic to such study design. For the efficacy analysis, we could not conduct a pooled descriptive analysis due to the vast heterogeneity of efficacy endpoints and reporting of data. Despite these limitations, and in line with previous reports, 33,34 the results of our systematic review support influenza vaccination in patients with cancer receiving immune checkpoint inhibitor therapy. These results are particularly relevant in the context of the SARS-CoV-2 pandemic. The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Matteo Lambertini acted as consultant for Roche, AstraZeneca, Lilly and Novartis, and received speaker honoraria from Sandoz, Roche, Takeda, Pfizer, Lilly and Novartis outside the submitted work. Including 82 patients treated with anti-CTLA-4 + anti-PD-1, 42 patients with anti-PD-1 + experimental drugs and 15 with anti-CTLA-4 followed by anti-PD-1. 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Data from five Italian referral cancer centers Italian survey on managing immune checkpoint inhibitors in oncology during COVID-19 outbreak State of the art about influenza vaccination for advanced cancer patients receiving immune checkpoint inhibitors: when common sense is not enough Influenza vaccination in cancer patients receiving immune checkpoint inhibitors: A systematic review Sanofi and Pierre Fabre outside the submitted work. All the other authors declare no conflicts of interest. https://orcid. org/0000-0003-3287-1225 Matteo Lambertini https://orcid. org/0000-0003-1797-5296