The Effect of Vaccination against COVID-19 in Cancer Patients: Final Results of the COICA Trial

Since December 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19), has infected more than half a billion individuals and has been responsible for over 6 million deaths [1]. Patients with a history of cancer, especially those with metastatic solid tumors, those suffering from hematologic malignancies and those who have recently received antineoplastic medications, are at higher risk of SARS-CoV-2-related outcomes, such as death and hospitalization [2]. Adenovirus-vectored and mRNA-based vaccines are effective in preventing both asymptomatic and symptomatic infection as well as COVID-19 related hospitalization and death [3]. A recently published, population-based, case-control study reported a reduced vaccine efficacy at 3–6 months in cancer patients compared to individuals without cancer [4].

The COICA study is an ambispective, observational trial that was conceived to assess the clinical course of SARS-CoV-2 infection in cancer patients. Preliminary results obtained in a cohort of 76 mainly unvaccinated patients enrolled at the coordinating institution showed that periodic screening for asymptomatic SARS-CoV-2 infection was associated with significantly lower odds of requiring O₂ therapy, hospitalization, admission to the intensive care unit, and death [5]. In this brief report, we presented the final results of the COICA trial, along with an analysis of differences in SARS-CoV-2 outcomes between vaccinated and unvaccinated patients.

Methods of the COICA study have already been published [5]. Briefly, patients with a histologically confirmed cancer diagnosis who had received any anti-neoplastic systemic treatment within 3 months since the day they tested positive for SARS-CoV-2 on RT-PCR were enrolled. The observation period started at the time infection with SARS-CoV-2 was diagnosed and ended at the time of death or confirmed recovery. The COICA study was approved by the competent Ethics Committee and conducted according to the principles of the Helsinki Declaration. Time to negativization was measured in days and was defined as time from diagnosis to confirmed negative RT-PCR test result. Patients were considered as “vaccinated” if they had received the first vaccine dose at least 7 days before diagnosis of SARS-CoV-2 infection. Descriptive statistics and frequency counts were used to summarize characteristics of the study population. Median numbers were presented with interquartile ranges, unless specified otherwise. χ² test was used to compare categorical efficacy outcomes according to baseline binary variables of interest, while the log-rank test was used to compare time to event outcomes according to baseline binary variables of interest.

All tests were 2-sided, and a value of p ≤ 0.05 was considered statistically significant. All statistical analyses were conducted using Medcalc® (Version 20.109).

A total of 141 cancer patients (80 males, 61 females) were recruited at two participating institutions from March 2020 until April 2022 and observed from the time of positive SARS-CoV-2 test to the time of negativization or death. All patients had received a systemic anticancer medication within the previous 90 days, while approximately 60% had received an anticancer medication within the previous 30 days. Approximately, 75% had metastatic cancer, 78% were screening-diagnosed, and 66% were symptomatic. Primary tumor site and the last systemic anticancer agent administered within 30 days are detailed in Table 1. Approximately, 35% of patients had been vaccinated at the time of infection (median time since last vaccine dose to infection, 123 days, interquartile range, 70–170 days). Only 4 patients had received AZD1222 vaccine against SARS-CoV-2, while the remaining had been vaccinated with an mRNA-based vaccine (BNT162b2 or mRNA-1273). Approximately, 25% of assessable patients were diagnosed with interstitial pneumonia, about 10% required hospitalization, 9% required 02 therapy and 7 patients (approximately 5%) died of COVID-19 after a median (interquartile range) of 19 (7–35) days. Median (interquartile range) time to negativization was 17 (14–19) days.

Importantly, vaccinated patients consistently and significantly (p < 0.05) showed improved COVID-19 outcomes compared to unvaccinated patients, with CT-diagnosed pneumonia, hospitalization required, O₂ therapy required, and death in 0% versus 48.6%, 2.0% versus 15.2%, 0% versus 14.1%, and 0% versus 7.6%, respectively, of assessable patients (Table 2). Finally, vaccinated versus unvaccinated patients showed a significantly shorter time to negativization, with a median (95% Confidence Interval) time of 12 (10–14) versus 20 (17–23) days, respectively (p < 0.001, log-rank test) (Fig. 1).

The 2-year study accrual of the COICA trial that started during the first months of the pandemic until recently provided data allowing us to capture major variations in outcomes that occurred during this timeframe. Vaccination has represented a major step forward against SARS-CoV-2 [6-8] in the general population. Of note, vaccination efficacy in individuals with cancer may be lower, with potential interactions with concomitant anticancer therapies [9-11]. In a large, retrospective nationwide study that matched 1 to 1 a cohort of 29,152 vaccinated adults with hematologic or solid malignancies to unvaccinated or not yet vaccinated controls, a 58% overall vaccine effectiveness was reported, with a lower efficacy in patients who had been treated with chemotherapy compared to those who had received endocrine therapy and to those who had not received any anti-neoplastic therapy (57 vs. 76% and 85%, respectively) [10]. As the COICA study was designed to include a small cohort of cancer patients who had been diagnosed with SARS, we could not estimate vaccine efficacy. Nevertheless, it clearly emerged how vaccination dramatically improved all assessable COVID-19 outcomes, with a significant drop in mortality and morbidity rates. Vaccination also improved time to negativization, which may have important therapeutic implications, as SARS-CoV-2 positive patients are generally unable to continue anticancer therapy until they test negative for the virus. Importantly, we also found that the median time from last vaccination to SARS-CoV-2 infection was approximately 4 months. This finding is consistent with the recently reported data by Lee et al. [12], who assessed a cancer cohort of 377,194 individuals and a control population cohort of over 28 million individuals. The study’s main finding was that although overall vaccine effectiveness was similar in the control and in the cancer populations, a drop in vaccine effectiveness at 3–6 months was noted in the cancer versus the control cohort (47.0% vs. 61.4%) [12]. Of note, in our study cohort, the majority of vaccinated patients had received three doses at the time of infection. As recently published by Magen et al. [13], a fourth dose has also been shown to reduce COVID-19 mortality among patients who had received a third dose at least 4 months earlier. Administration of a forth dose is currently recommended by the European Medicinal Agency for adults 80 years of age and older on the higher risk of COVID-19 and the protection guaranteed by a fourth dose [14]; although, further evidence is needed to establish optimal patient selection and timing in individuals with a history of cancer.

Our study has a number of limitations. First, we did not collect data regarding SARS-CoV-2 variants. Second, our main objective was to describe clinical outcomes in SARS-CoV-2 infected cancer patients, and the analysis presented here was unplanned. Third, sample size was limited. Fourth, being conducted at Oncology Units, only patients with solid malignancies were included. Despite these limitations, our study had the merit to add further evidence regarding vaccination efficacy in cancer patients who have recently received anti-neoplastic treatment, with potential implications from the public health perspective. In this regard, we previously showed that periodic screening for SARS-CoV-2 infection was able to reduce mortality and morbidity in a population of mainly unvaccinated cancer patients [5]. Given the results reported here, we believe that routine screening for asymptomatic SARS-CoV-2 infection may not be cost-effective in vaccinated subjects.

In conclusion, the final results of the COICA trial provided evidence regarding the clinical course of COVID-19 in cancer patients who have recently received anticancer therapy. Vaccination consistently improved all COVID-19 outcomes, with a reduction of mortality. Additional research is especially warranted to establish optimal timing and patient selection for administration of the fourth vaccination dose.

Written informed consent was obtained from participants (or their parent/legal guardian/next of kin) to participate in the study. This study protocol was reviewed and approved by the Local Ethics Committee Campania Sud, approval number 2020-3JF. The study was conducted according to the criteria set by the Declaration of Helsinki.

Dr. Di Lorenzo serves as an editorial board member of Oncology. All the other authors have no conflicts of interest to declare.

No funding was obtained for this work.

Study concept and design: Giuseppe Di Lorenzo, Bruno D’Ambrosio, Concetta Ingenito, and Carlo Buonerba. Acquisition of data, interpretation of data, and critical revision of the manuscript for important intellectual content: all authors. Analysis of data: Giuseppe Di Lorenzo and Carlo Buonerba. Drafting of the manuscript: Giuseppe Di Lorenzo, Chiara Ranieri, and Carlo Buonerba.

Anonymized data are available upon request to the corresponding author without any restriction.