Abstract
Background/Aim: Multiple doses of vaccines against the coronavirus disease (COVID-19) provide patients with cancer the opportunity to continue cancer treatment. This study investigated the safety and efficacy of COVID-19 vaccination in patients with cancer and the optimal timing of vaccination during chemotherapy. Patients and Methods: A total of 131 patients with gastrointestinal (GI) cancer who received two doses of the COVID-19 vaccine were included in this study. This study combined two cohorts: an evaluation cohort of 79 patients receiving chemotherapy and a control cohort of 52 patients under follow-up after radical surgery. None of the patients had any history of COVID-19. Treatment- and vaccine-related adverse events (AEs) were recorded through outpatient interviews and self-reports. Results: In the evaluation cohort, 62 patients (78.4%) experienced vaccine-related AEs after the first dose, and 62 patients (78.4%) experienced vaccine-related AEs with an increased rate of fever and fatigue after the second dose. In the control cohort, vaccine-related AEs occurred in 28 (53.8%) patients after the first dose and in 37 (71.2%) patients after the second dose, with increased fever and fatigue after the second dose. Of the 79 patients, 49 received chemotherapy before vaccination. Twelve patients (24.5%) changed their treatment schedule: four for safety reasons, four for myelosuppression, and four for convenience. Three patients discontinued the treatment because of disease progression. Conclusion: Systemic chemotherapy in patients with GI cancer does not have a markedly negative effect on COVID-19 vaccination, resulting in manageable vaccine-related AEs, and minimizing the need for treatment schedule changes.
Early approval of the coronavirus disease (COVID-19) vaccine had significant benefits for patients with cancer undergoing cancer treatment during the COVID-19 global pandemic (1-3). Multiple doses of COVID-19 vaccine provide patients with cancer the opportunity to continue their treatment. According to international and Japanese guidelines, all committees endorse vaccination for all eligible patients with cancer receiving chemotherapy, targeted therapy, and immunotherapy (4-6). However, vaccination should be avoided at the nadir during chemotherapy.
In addition, there have been limited reports investigating the safety and efficacy of vaccination in patients with cancer and the optimal timing of vaccination during chemotherapy (7, 8). To investigate the effect of chemotherapy on vaccination and the safety of vaccination during chemotherapy, we assessed the differences in vaccine-related adverse events (AEs) between patients who received chemotherapy and those who did not. To determine the optimal timing of vaccination during chemotherapy, safety and treatment schedule modifications were evaluated in patients who received chemotherapy before and after vaccination.
Patients and Methods
Study design and patients. A total of 131 patients with gastrointestinal (GI) cancer who received two doses of the mRNA COVID-19 vaccine (Pfizer-BioNTech or Moderna) between May 2021 and April 2022 were included in this retrospective observational study at a single institute in Japan. This study combined two different cohorts: an evaluation cohort of 79 patients (median age, 70 years; male, 59.5%) receiving chemotherapy and a control cohort of 52 patients under follow-up after radical surgery (median age, 68.5 years; male, 69.2%). None of the patients had any history of COVID-19. Treatment- and vaccination-related AEs were recorded through outpatient interviews and self-reports. Patients with insufficient vaccination data were excluded. This study was approved by the Institutional Review Board of the Ethics Committee (approval number, M2021-138) and was conducted in accordance with the Declaration of Helsinki.
Statistical analysis. The primary endpoint of the current study was vaccination-related AEs and treatment schedule modification, whereas the secondary endpoints were overall survival (OS). OS was calculated from the date of the first vaccination dose until the date of death from any cause. For patients who discontinued follow-up, data were censored at the last follow-up date. The Chi-square test or Wilcoxon test was used to examine differences in baseline patient characteristics between the two cohorts. Changes in the number of vaccine-related AEs between the first dose and second dose of vaccination were evaluated among the cohorts by Fisher’s exact test, which were categorized as ‘decrease,’ ‘same’ and ‘increase’. The median follow-up time for survival was calculated using the reverse Kaplan-Meier method. The association between OS and cohorts was analyzed using the Kaplan-Meier method and the log-rank test. All analyses were performed using SPSS software (version 27.0; IBM Corporation, Armonk, NY, USA), and p<0.05 was considered statistically significant.
Results
Baseline demographics and clinical characteristics. The median follow-up time was 22.7 months. The baseline characteristics are listed in Table I. The median ages were 70 years in the evaluation and 68.5 years in the control cohorts. Most patient and tumor characteristics were similar between the cohorts except for ECOG PS; PS 1 or 2 was more common in the evaluation cohort because metastatic disease was included. Colorectal cancer (CRC) was more common in the evaluation cohort, while gastric cancer was more prevalent in the control cohort. Cardiovascular disease was the most common comorbidity in both cohorts.
Baseline patient and tumor characteristics.
Vaccination-related AEs in the evaluation and control cohorts. In the evaluation cohorts, 62 patients (78.4%) experienced vaccine-related AEs: injection site pain (74.7%), fever (10.1%), fatigue (6.3%), headache (3.8%), gastrointestinal symptoms (2.5%), redness (1.3%), and sleepiness (1.3%) after the first dose. After the second dose, 62 patients (78.4%) reported vaccine-related AEs with an increased rate of fever (35.4%) and fatigue (20.3%). In the control cohort, vaccine-related AEs occurred in 28 (53.8%) patients after the first dose and in 37 (71.2%) patients after the second dose, and fever and fatigue increased after the second dose (Table II).
Vaccination-related adverse events between evaluation and control cohorts.
Vaccination-related AEs between the first and second doses. The numbers of vaccine-related AEs and their changes between the first and second doses in the evaluation and control cohorts are shown in Table III. There were no significant differences in the number of AEs or their changes between the cohorts. In both cohorts, the number of AEs increased in more than 30% of patients after the second dose (34.2% vs. 36.5%, p=0.597).
Differences in vaccination-related adverse events (AEs) between first and second dose in evaluation and control cohorts.
Comparison between the adjuvant and palliative groups in the evaluation cohort. Based on the above data, we compared the patients who received adjuvant chemotherapy (N=25) with those who underwent palliative chemotherapy (N=54) in the evaluation cohort. Consequently, no new vaccination-related AEs were associated with either receiving adjuvant or palliative chemotherapy.
Analysis of patients treated with chemotherapy before vaccination. Of the 79 patients in the evaluation cohort, 49 received chemotherapy before vaccination (Table I). Details of the vaccinations are shown in Table IV, which includes the following information: days from the last dose of chemotherapy to the first vaccination dose, median 12 days (range=0-70 days); days from the first to the second vaccination dose, median 21 days (range=21-41 days); and days from the first vaccination dose to the next dose, median 9 days (range=2-34 days). The effects of vaccination on the chemotherapy schedule are summarized in Table V. Twelve patients (24.5%) needed to change their treatment schedule for one of the following reasons: four for safety reasons, four for myelosuppression, and four for convenience. Regarding the schedule change for safety reasons, all four patients received chemotherapy with cytotoxic agents, such as 5-FU, oxaliplatin, or irinotecan, and the dates of treatment vaccination were staggered by several days. Three patients discontinued the treatment because of disease progression. No patient changed their treatment schedule or stopped treatment owing to COVID-19 vaccination-related side effects. In addition, following the first vaccination, 40 patients (81.6%) experienced vaccine-related AEs, and 39 (79.6%) experienced vaccine-related AEs. There were no differences in vaccination-related AEs between this population and those observed in the evaluation cohort. No treatment- or vaccine-related deaths occurred in this study.
Vaccination details in patients receiving chemotherapy prior to vaccination.
Impact of vaccination on treatment schedule change.
Outcomes of vaccination in the entire population. In the evaluation cohort, three patients (3.8%) with metastatic CRC developed mild-to-moderate COVID-19 after the second vaccination. One patient died of cancer progression 20.0 months after the first vaccination, and the other two remained alive while continuing chemotherapy for 24.4 and 27.8 months, respectively. The 2-year survival rates were 62.6% and 100% in the evaluation and control cohorts, respectively.
Discussion
In this study, we aimed to evaluate the differences in the frequency or characteristics of vaccine-related AEs between patients receiving chemotherapy and those who did not, as well as investigate the optimal timing of vaccination during chemotherapy. To the best of our knowledge, few studies have reported the effects of vaccination on chemotherapy schedules.
Although COVID-19 vaccines were approved early based on the results of clinical trials conducted worldwide during the COVID-19 pandemic, cancer patients and those receiving chemotherapy were not included in the study populations (1-3). However, academic societies and organizations recommended COVID-19 vaccination for all eligible patients with cancer. According to the guidelines provided by the National Comprehensive Cancer Network advisory committee for COVID-19 vaccination, patients with cancer should receive a third dose and boosters in addition to the full (two doses) vaccination (4).
A previous study evaluated the clinical characteristics and outcomes of patients with cancer who experienced COVID-19 following COVID-19 vaccination using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19) (9). According to the results from inverse probability of treatment weighting methods adjusting for differences in baseline clinical variables between fully vaccinated and unvaccinated patients, higher age, progressing cancer, ECOG ≥2, modified Charlson comorbidity index ≥2, and lymphopenia were associated with 30-day mortality. However, there were no significant differences in the 30-day mortality between fully vaccinated and unvaccinated patients. A systematic review and meta-analysis by Khoury et al. assessed the differences in clinical outcomes between patients with cancer having COVID-19 infection and non-cancer patients with COVID-19 infection, including 81 studies (N=61,532), and demonstrated a higher risk of death in patients with cancer, especially lung and hematologic cancers, compared to other cancers, including gastrointestinal cancers (10). Regarding cancer treatment, among patients receiving treatment for malignant diseases, higher mortality was associated with chemotherapy (30%) in comparison to endocrine therapy (11%) or immunotherapy (19%). Immunosuppression after chemotherapy is considered one of the contributing factors to this finding.
An interim analysis of a prospective cohort study assessing the safety and immunogenicity of the COVID-19 vaccine BNT162b2 in patients with cancer (95 solid cancers and 56 hematological cancers) and 54 healthy controls from the United Kingdom has been previously reported (7). According to the results, 54% of the 140 patients with cancer and 38% of the 40 healthy controls reported no vaccine-related toxicity after the first dose. However, 71% of the 31 patients with cancer and 31% of the 16 healthy controls experienced no toxicity after the second dose, despite the decreased number of cases compared with the first dose. In addition, only 7% of patients with cancer experienced local and systemic effects after a booster shot, compared to 50% of 16 healthy controls. Injection site pain was the most common symptom among the cohorts after the first and second doses. Regarding immunogenicity, based on the seroconversion rate measured in the study, single-dose BNT162b2 vaccination yielded poor efficacy, and immunogenicity increased significantly after a day 21 booster shot in patients with cancer. In another prospective cohort study conducted in Israel (8), 29% of patients with cancer receiving intravenous anti-cancer therapy, including chemotherapy, biological agents, and immunotherapy, were seropositive after the first dose of the vaccine (BNT162b2) compared with 84% of healthy controls. However, the seroconversion rate increased to 86% in patients with cancer after the second dose. In terms of safety, injection site pain (69%) was the most commonly reported local reaction, whereas fatigue (24%) was the most common systemic reaction. Lee et al. also reported results from a prospective cohort study in the United Kingdom where cytotoxic chemotherapy or other anticancer treatments did not increase the risk of mortality from COVID-19 in patients with cancer compared to those without active treatment (11). Furthermore, similar results have been previously reported regarding the safety of the BNT162b2 vaccine in Japanese patients with solid tumor receiving systemic chemotherapy (12). Thus, together with previous reports, vaccination is widely considered safe for patients with cancer; however, the indications and schedule for booster shots need to be further explored through long-term observational studies focusing on immunogenicity (13-16).
Few studies have examined the optimal timing of vaccination during chemotherapy, as in the present study. According to our results, the vaccine-related AEs were similar to those previously reported and had little impact on the chemotherapy schedule or safety. However, the present study has some limitations: the retrospective study design, the non-randomized nature of the study, and the lack of detailed information on comorbidities. In addition, the evaluation cohort had a higher percentage of metastatic disease and PS1 or 2, which may have influenced the development and assessment of AEs. However, the fact that there were no significant differences in the number of AEs between the evaluation and control cohorts, or between the adjuvant and palliative groups, is considered an important finding in our study in terms of COVID-19 vaccination of patients with cancer.
In conclusion, our results show that there is a risk of fever and fatigue after the second dose of COVID-19 vaccination in both patients receiving chemotherapy and those not receiving chemotherapy. Systemic chemotherapy in patients with GI cancer had no marked negative effect on COVID-19 vaccination in either the adjuvant or metastatic setting, and there were no significant differences in vaccination-related AEs. COVID-19 vaccination-related toxicity in patients with GI cancer receiving chemotherapy is tolerable, and treatment schedule changes can be minimized. COVID-19 vaccination is recommended for cancer patients who are undergoing chemotherapy, although careful monitoring is required.
Acknowledgements
The Authors are grateful to Wakana Aikawa and Noriko Takei for their support in the data collection. The Authors would also like to thank all the patients who contributed to the data.
Footnotes
Authors’ Contributions
Guarantor of integrity of the entire study: Mitsukuni Suenaga. Study concepts and design: Mitsukuni Suenaga, Shinichi Yamauchi, Ryo Morikawa, Rika Noji, Yoshihito Kano, Masanori Tokunaga, and Yusuke Kinugasa. Literature research: Mitsukuni Suenaga. Clinical studies: Mitsukuni Suenaga, Shinichi Yamauchi, and Masanori Tokunaga. Experimental studies/data analysis: Mitsukuni Suenaga. Statistical analysis: Mitsukuni Suenaga. Manuscript preparation: Mitsukuni Suenaga and Shinichi Yamauchi. Manuscript editing: Mitsukuni Suenaga, Shinichi Yamauchi, Ryo Morikawa, Rika Noji, Yoshihito Kano, Masanori Tokunaga, and Yusuke Kinugasa.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this work.
- Received January 4, 2024.
- Revision received January 25, 2024.
- Accepted January 26, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
