Short term safety of coronavirus disease 2019 vaccines in patients with solid tumors receiving systemic therapy

Ronald E Cox, Marie Parish, Carolyn Oxencis, Edward Mckenna, Bicky Thapa, Sakti Chakrabarti

Ronald E Cox, Student, Medical College of Wisconsin, Wauwatosa, WI 53222, United States

Marie Parish, Carolyn Oxencis, Pharmacy, Froedtert & the Medical College of Wisconsin, Wauwatosa, WI 53222, United States

Edward Mckenna, Bicky Thapa, Sakti Chakrabarti, Department of Hematology and Oncology, Medical College of Wisconsin, Wauwatosa, WI 53222, United States

Abstract BACKGROUND There are currently three coronavirus disease 2019 (COVID-19) vaccines approved by the United States Food and Drug Administration to prevent coronavirus infection. However, robust data are unavailable on the adverse events of the vaccines in patients with solid tumor malignancies undergoing systemic therapies.AIM To evaluate the safety of COVID-19 vaccines in patients with solid tumors undergoing systemic therapies.METHODS The study included patients with solid tumors treated in an academic tertiary care center who received COVID-19 vaccination between January 1, 2021 and August 15, 2021, while undergoing systemic therapy. Electronic medical records were accessed to collect information on patient characteristics, systemic therapies, type of vaccine received, and adverse effects associated with the vaccine administration. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events, version 5.0.RESULTS The analysis included 210 patients; the median age was 70 years, and 51% of patients were female. The most common chemotherapy, immunotherapy, and targeted therapy administered were taxane-based regimens 14.2% (30/210), antiprogrammed death 1 (PD-1) agents 22.8% (48/210), and antiangiogenic agents 7.1% (15/210), respectively. The most common cancers were gastrointestinal 43.8% (92/210), thoracic 30.4% (64/210), and genitourinary 17.6% (37/210). Patients received the following vaccines: 2 doses of BNT162b2 by Pfizer 52% (110/210), 2 doses of mRNA-1273 by Moderna 42% (89/210), and 1 dose of JNJ-78436735 by Johnson & Johnson 5% (11/210). At least 1 AE attributable to the vaccine was observed in 37 patients 17.6% (37/210). The total number of AEs attributable to vaccines was 62: Fifty-three grade 1 and nine grade 2. Most adverse events occurred after the second dose 59.7% (37/62). The most frequent grade 1 AEs included fatigue 17% (9/53), fever 15% (8/53), injection site reaction 13.2% (7/53), and chills 9.4% (5/53). The most frequent grade 2 AEs were fatigue 33.3% (3/9) and generalized weakness 22.2% (2/9). Therapy was delayed by 2 wk because of the AEs possibly related to vaccine administration in 3 patients 1.4% (3/210).CONCLUSION The present study demonstrates that the adverse events associated with COVID-19 vaccination are infrequent, mild, and rarely delay treatment in patients with solid tumors receiving systemic therapies.

Key Words: COVID-19; Adverse events; Solid tumor; Chemotherapy; Immunotherapy; Targeted therapy

lNTRODUCTlON

The coronavirus disease 2019 (COVID-19) pandemic, caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has profoundly impacted and transformed healthcare systems across the globe. In addition to comprehensive modification in healthcare delivery, patients have encountered immeasurable emotional and socioeconomic hardships[1,2]. SARS-CoV-2 is a novel singlestranded, enveloped RNA virus that primarily spreadsviathe respiratory route and causes respiratory infection, including pneumonia with or without multiorgan failures[3]. While many patients remain asymptomatic, infection with the SARS-CoV-2 virus has been shown to cause a myriad of symptoms, including severe acute respiratory distress syndrome[1]. Analysis of comprehensive observational data has shown increased mortality, hospitalization, and intensive care admission in cancer patients who received anticancer therapy within 3 mo of infection[4,5]. A study from China reported a 3.5-fold increased risk of respiratory failure requiring mechanical ventilation in cancer patients infected with the SARS-CoV-2 virus[6]. The interplay between COVID-19 infection and cancer is complex, attributable to a wide variety of factors including immunosuppression, co-morbidities, aging, and the biology of the cancer itself[7].

The United States Food and Drug Administration approved three COVID-19 vaccines to prevent coronavirus infection. These include the BNT162b2 from Pfizer, mRNA-1273 from Moderna, and JNJ-78436735 vaccine from Johnson & Johnson. Patients with cancer should be considered a high-priority group for COVID-19 vaccination due to their higher risk of morbidity and death associated with COVID-19 disease[5,6,8-10]. However, the trials reporting efficacy and safety of COVID-19 vaccines were conducted in healthy volunteers, excluding the immunocompromised cancer patients on treatment[11-13]. Although several cancer societies recommend COVID-19 vaccination in patients with cancer, the data confirming the safety of vaccines are sparse[14,15]. This lack of rigorous scientific inquiry into vaccine safety has led to increased apprehension and hesitation to receive vaccination in the patient population with cancer. As the incidence of cancer continues to rise, solid tumor malignancies continue to emerge among the most prevalent diagnoses. Frequently used therapeutic regimens include chemotherapy, immunotherapy, and targeted therapy. We conducted a study to assess the safety and determine the spectrum of adverse events (AEs) associated with COVID-19 vaccination in patients with solid tumors receiving systemic therapy.

MATERlALS AND METHODS

The aim of this study was to determine the real-world incidence and spectrum of AEs in patients with solid tumor malignancies receiving systemic therapy. This was a retrospective study of cancer patients who received COVID-19 vaccination between January 1, 2021 and August 15, 2021 at Froedtert and the Medical College of Wisconsin Cancer Center (Milwaukee, WI, United States of America). Inclusion criteria required that patients be at least 18 years of age at the time of inoculation and have a histologically confirmed solid tumor diagnosis for which they were receiving systemic therapy (chemotherapy, immunotherapy, or targeted therapy). Patients were excluded from the study if they had an active hematologic malignancy, were being treated with hormonal therapy, or had a benign tumor diagnosis that did not require anti-neoplastic treatment. Patients for this study were identified from the cancer center database using a tool available in the electronic medical record software (EPIC SlicerDicer tool). The initial screen identified 1480 cancer patients who received COVID-19 vaccines. Of these, 349 were omitted due to an active hematologic malignancy, and 183 patients were excluded due to diagnoses of benign solid tumors. An additional 401 patients who were receiving hormonal therapies (i.e., leuprolide for prostate cancer or tamoxifen/anastrozole for breast cancer) were excluded. Finally, 337 patients were excluded who were not receiving active treatment for malignancies (e.g., patients on surveillance following completion of their initial treatment) or active malignancies being treated with modalities other than chemotherapy, immunotherapy, or targeted therapies (e.g., radiation therapy). After review, 210 patients were found to meet the study requirements (Figure 1). Electronic medical records for these patients were examined to collect information on patient characteristics, tumor characteristics, details of systemic therapy, type of vaccine received, and any AEs associated with the vaccine administration. Clinic and hospital notes were further analyzed to capture AEs occurring in a period between the first vaccination and day 30 after the second/final vaccination. In the case of the Johnson & Johnson vaccines, patient charts were reviewed for the 30-d period following the single dose of vaccination. AEs were graded in accordance with version 5.0 of the Common Terminology Criteria for Adverse Events[16]. The institutional review board of the Medical College of Wisconsin approved this study protocol.

RESULTS

Patient characteristic, systemic therapy, and vaccination types

Between January 1, 2021 and August 15, 2021, 210 patients were included in the study (Table 1). The median age of the cohort was 70 years (range, 23-91), 51% (108/210) of patients were female, and 87.1% (183/210) of the study population was Caucasian. Distribution of vaccine types included BNT162b2 from Pfizer 52.3% (110/210), mRNA-1273 from Moderna 42.3% (89/210), and JNJ-7843 vaccine from J&J 5% (11/210). All patients who received either the Pfizer or Moderna vaccine completed the 2-dose vaccination series. Gastrointestinal cancers were the most frequent diagnoses 43.8% (92/210), followed by thoracic cancers 30.4% (64/210) and genitourinary cancers 17.6% (37/210).

In the study cohort, 117 patients were receiving systemic chemotherapy at the time of vaccination. The median age of this cohort was 69 years, with a slight female predominance at 53% (62/117). Distribution of vaccine types were BNT162b2 from Pfizer 55.6% (65/117), mRNA-1273 from Moderna 40.1% (47/117), and JNJ-7843 vaccine from J&J 4.2% (5/117). The most common chemotherapeutic regimens included were taxane-based 25.6% (30/117) regimens followed by oxaliplatin-based regimens 22.2% (26/117).

Fifty-one patients were receiving immunotherapy at the time of vaccination. The median age of this cohort was 72 years, with a slight male predominance at 56.9% (29/51). Distribution of vaccine types were BNT162b2 from Pfizer 47% (24/51), mRNA-1273 from Moderna 45.1% (23/51), and JNJ-7843 vaccine from J&J 7.8% (4/51). The most common immunotherapeutic regimens consisted of programmed death 1 (PD-1) blocking agents 94% (48/51).

Forty-two patients were receiving targeted therapy at the time of vaccination. The median age of this cohort was 68 years, with a slight female predominance at 57% (24/42). Distribution of vaccine types were BNT162b2 from Pfizer 50% (21/42), mRNA-1273 from Moderna 45.2% (19/42), and JNJ-7843 vaccine from J&J 4.8% (2/42). The most common targeted therapy treatment administered was Osimertinib 14.2% (6/42).

Table 1 Characteristics of solid tumor patients receiving coronavirus disease 2019 vaccination

Adverse events

The total number of AEs attributable to vaccination in the current cohort was 62 (Table 2). At least 1 unique AE was noted in 17.6% of patients (37/210). The number of patients who experienced any grade AEs was 20 in the chemotherapy group, 12 in the immunotherapy group, and 5 in the targeted therapy group. There were 33 AEs related to the Pfizer vaccine, 26 to the Moderna vaccine, and 3 to the J&J vaccine. In total, there were fifty-three grade 1 AEs 85.5% (53/62) and nine grade 2 AEs 14.5% (9/62). Following the first vaccination, there were twenty-one grade 1 and four grade 2 AEs. The most frequent grade 1 AEs were injection site reaction 23.8% (5/21), fatigue 23.8% (5/21), and fever 9.5% (2/21). The four grade 2 AEs noted included fatigue, nausea, chills, and maculopapular rash. Following the second vaccination, there were thirty-two grade 1 and five grade 2 AEs. The most frequent grade 1 AEs were fever 18.8% (6/32), fatigue 12.5% (4/32), chills 12.5% (4/32), and myalgia 12.5% (4/32). The five grade 2 AEs included 2 cases of fatigue, 2 cases of generalized muscle weakness, and 1 case of fever.

Cumulatively, the most frequent grade 1 AEs included fatigue 17% (9/53), fever 15% (8/53), injection site reaction 13.2% (7/53), and chills 9.4% (5/53). The most frequent grade 2 AEs were fatigue 33.3% (3/9) and generalized muscle weakness 22.2% (2/9). Of the grade 2 AEs, 6 were associated with the Pfizer vaccine and 3 with the Moderna vaccine. No grade 2 AEs were noted in the J&J vaccine population. In those who received the Pfizer or Moderna vaccine, the majority of AEs occurred after the second dose of vaccination 59.7% (37/62).

Treatment was delayed in 3 patients 1.4% (3/210) after the second dose of the Moderna vaccine by 2 wk because of AEs possibly related to vaccine administration. None of the patients had displayed any AEs after the first vaccination dose. Two of these 3 patients receiving immunotherapy developed generalized weakness that resolved within 2 wk without any specific treatment. The third patient developed malaise and fatigue, which also resolved spontaneously. No grade 3-5 AEs or anaphylaxis were noted in this patient cohort.

DlSCUSSlON

Data on the safety of COVID-19 vaccines in cancer patients undergoing systemic therapies are sparse. The current study aimed to address this unmet need by collecting data on COVID-19 vaccine-associated AEs in real-world cancer patients with solid tumors receiving various systemic therapies. The study revealed that COVID-19 vaccines cause infrequent and minor side effects in this patient population.

The pandemic caused by the novel coronavirus SARS-CoV-2 has significantly impacted cancer care delivery and cancer treatment globally. The COVID-19 pandemic has affected many aspects of cancer care, including delay in cancer diagnosis and treatment, the long-term ramifications of which are yet to be determined[15]. The rapid development of coronavirus vaccines has brought the hope of preventing infection and restoring normalcy. While the initial clinical trials with COVID-19 vaccines demonstrated a high safety profile of the vaccines in the healthy population[11-13], limited safety data have been reported in cancer patients. Consequently, significant hesitancy in adopting widespread vaccination has been observed among patients with active cancer[17-20]. In a cross-sectional, internet-based survey, hesitancy to receive COVID-19 vaccination was reported in 13.4% of patients with cancer[19]. In a study with breast cancer patients, 26% of patients were hesitant to receive vaccination due to their concerns regarding vaccine-related AEs[20]. As patients with cancer are at increased risk of COVID-19 infectionassociated complications and mortality[8-10,21,22], data confirming the safety of COVID-19 vaccines in cancer patients are urgently needed. Our study provides important safety information on COVID-19 vaccines in cancer patients undergoing active cancer treatment.

Table 2 Adverse events (AEs) observed with coronavirus disease 2019 vaccination in patients with solid tumors receiving systemic therapies

Figure 1 Consort diagram illustrating patient enrollment.

Several studies have investigated the safety of COVID-19 vaccines (summarized in Table 3). Oosting and colleagues have reported a prospective, multicenter study from the Netherlands in which patients with solid tumors received the Moderna vaccine while undergoing treatment with chemotherapy, immunotherapy, or chemoimmunotherapy[23]. In this study, the incidence of grade 3 or worse AEs were reported in 2% of patients treated with immunotherapy, 2% of patients treated with chemotherapy, and 1% of patients treated with chemoimmunotherapy. No vaccine-related death was reported. A similar study from Italy reported that patients with solid tumors undergoing active treatment also demonstrated a low incidence of significant AEs associated with COVID-19 vaccination[24]. In this study, none of the 257 evaluable patients experienced grade 3 or higher AEs. The most frequently reported AE was injection site pain and/or redness occurring in 31.5% and 33.4 % of patients after the first and second vaccinations. The most frequently reported AEs after the first dose were weakness (7%), headache (8%), and muscle pain (2.7%), and after the second dose were weakness (8.9%) and fever (5.8%). A study from Israel also reported a low incidence of AEs in patients with solid tumors receiving immunotherapy with checkpoint inhibitors, with injection site pain being the most frequently reported AE at 21% (28/134)[25]. Several other studies have demonstrated similar results[26-29]. The results of our study, in conjunction with the studies discussed above, indicate that COVID-19 vaccination is safe in solid tumor patients undergoing active treatment. The high mortality rate associated with COVID-19 disease (as high as 40% in certain patient populations)[30] and the safety data available far justify routine COVID-19 vaccination in patients with solid tumors undergoing active treatment. This recommendation is further supported by several oncology societies[14,15] and echoed by the American Society of Clinical Oncology endorsement (https://www.asco.org/covidresources/vaccines-patients-cancer) which states: At this time, patients undergoing treatment may be offered vaccination against COVID-19 as long as any components of the vaccine are not contraindicated.

Table 3 Adverse events associated with coronavirus disease 2019 vaccination in published studies

It is important to reiterate that COVID-19 vaccines in cancer patients treated with immunotherapy did not cause a higher incidence of immune-related AEs, a finding supported by several other studies[23,25]. While 2 patients in our study receiving immune checkpoint inhibitors experienced treatment delay secondary to vaccination-associated AEs, their symptoms resolved quickly with supportive care only. The remaining patients in our immunotherapy cohort demonstrated mild grade 1 AEs with rapid resolution of symptoms.

Although the current study provides valuable information on COVID-19 vaccine safety in a realworld setting, it has several limitations that include the inherent biases associated with a retrospective study design, modest sample size, and reliance on physician documentation for the data related to the AEs.

CONCLUSlON

Our study demonstrates that the COVID-19 vaccines cause infrequent and mild AEs in patients with solid tumors receiving systemic therapies. The study results support routine COVID-19 vaccination in cancer patients receiving active treatment.

ARTlCLE HlGHLlGHTS

Research background

In the wake of the coronavirus disease 2019 (COVID-19) pandemic, the United States Food and Drug Administration approved 3 vaccines to prevent coronavirus infection. The rapidity of vaccine approval and the limited scientific inquiry into vaccine-related adverse events notably expanded apprehension towards vaccination in patients with malignancies. Our study reports real-world data on the severity and spectrum of adverse events in solid tumor cancer patients receiving systemic therapy.

Research motivation

The motivation behind this project was to promote awareness regarding the short-term safety of COVID-19 vaccines in cancer patients with solid tumor malignancies. Our results help lessen the societal apprehension and hesitation surrounding the safety of COVID-19 vaccination.

Research objectives

The main objective of this study was to evaluate the short-term safety of COVID-19 vaccines in patients with solid tumors undergoing treatment with systemic therapies. Through rigorous analysis, we were able to document the incidence and spectrum of vaccine-related adverse events in our patient cohort.Our research forms the groundwork for future studies on long-term adverse events secondary to vaccination.

Research methods

Our study was a retrospective analysis of cancer patients who received COVID-19 vaccination between January 1, 2021 and August 15, 2021. Eligible patients were identified using the EPIC SlicerDicer tool in the Froedtert and the Medical College of Wisconsin Cancer Center database. Once identified, patients were further screened based on study inclusion/exclusion criteria. Electronic medical records for the final patients were examined to collect information on patient characteristics, tumor characteristics,details of systemic therapy, type of vaccine received, and any adverse events associated with the vaccine administration.

Research results

Analysis of our 210 patients revealed at least 1 adverse event attributable to vaccination in 17.6% of our study cohort. Of these adverse events, fifty-three were grade 1 and nine were grade 2. Our data further bolsters the sparse scientific literature regarding COVID-19 vaccination in patients with cancer.

Research conclusions

The present study demonstrates that the adverse events associated with COVID-19 vaccination are infrequent, mild, and rarely delay treatment in patients with solid tumors receiving systemic therapies.This knowledge further begs the question of whether or not patients receiving systemic therapies are mounting an appropriate response to immunogenic antigens. Further scientific inquiry exploring vaccine efficacy and adverse events in our patient cohort vs a healthy control group could elucidate the role of systemic therapy in vaccine-related adverse events.

Research perspectives

Future research will be focused on increasing study enrollment and exploring the long-term adverse events secondary to COVID-19 vaccination.

FOOTNOTES

Author contributions:Cox RE, Parish M, Oxencis C, McKenna E, Thapa B, and Chakrabarti S contributed equally to this work; All authors have read and approved the final manuscript.

lnstitutional review board statement:The study was reviewed and approved by the Medical College of Wisconsin Institutional Review Board (Approval No. PRO00040038).

lnformed consent statement:Per institutional review board approval, consent forms were not necessary since the project did not include direct contact with subjects.

Conflict-of-interest statement:Sakti Chakrabarti has received fees for serving as a speaker for Natera. Sakti Chakrabarti has received Honoraria from Haliodx and QED Therapeutics. Ronald Cox has no conflicts of interest. Marie Parish has no conflicts of interest. Carolyn Oxencis has no conflicts of interest. Bicky Thapa has no conflicts of interest. Edward McKenna has no conflicts of interest.

Data sharing statement:No additional data are available.

STROBE statement:The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.

Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin:United States

ORClD number:Ronald E Cox 0000-0003-1950-6493; Marie Parish 0000-0003-2561-3965; Carolyn Oxencis 0000-0003-3431-3016; Edward Mckenna 0000-0003-0222-7885; Bicky Thapa 0000-0002-7636-8907; Sakti Chakrabarti 0000-0002-1582-098X.

S-Editor:Liu JH

L-Editor:A

P-Editor:Liu JH