Influence of COVID-19 Vaccination on Treatment-Related Adverse Events and Oncologic Outcomes of Non-metastatic Nasopharyngeal Carcinoma

doi:10.21203/rs.3.rs-4611767/v1

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Influence of COVID-19 Vaccination on Treatment-Related Adverse Events and Oncologic Outcomes of Non-metastatic Nasopharyngeal Carcinoma

https://doi.org/10.21203/rs.3.rs-4611767/v1

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Background: The influence of COVID-19 vaccination on treatment of non-metastatic nasopharyngeal carcinoma (NPC) who were newly diagnosed after the widespread vaccination against COVID-19 and subsequently treated withchemoradiotherapy is not known.

Methods: We performed a retrospective cohort study, patients in the vaccinated group had received at least one COVID-19 vaccination before chemoradiotherapy and those in the control group had not. Propensity score matching was used to minimize potential selection bias between groups. Primary endpoints were acute and late treatment-relatedadverse events (TRAEs). Secondary endpoints included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) at 2 years.

Results: Our study enrolled 893 patients with newly diagnosed non-metastatic NPC between May 2020 and December 2021. At last follow-up on December 31, 2023, the median follow-up was 31.6 months (interquartile range [IQR], 28 to 35.5 months). On propensity score matching analysis, vaccinated group had higher prevalence of grade-3–4 neutropenia (24.2% vs. 18.0%, P=0.048), grade-1–2 fatigue (41.9% vs. 23.9%, P＜0.001), grade-1–2 nausea/vomiting (66.7% vs. 58.4%, P=0.026) during induction chemotherapy, and grade-1–2 fatigue (58.4% vs. 43.1%, P＜0.001) during radiotherapy. No significant differences were observed in OS (97.6% vs. 98.5%, P=0.401), PFS (91.7% vs. 87.9%, P=0.097), DMFS (93.2% vs. 91.4%, P=0.385), or LRRFS (95.3% vs. 94.1%, P=0.494) at 2 years in matched groups.

Conclusions: COVID-19 vaccination is associated with higher prevalence of acute TRAEs, while no significant influence is observed on the oncologic outcomes of patients with non-metastatic NPC.

Nasopharyngeal carcinoma

COVID-19 vaccination

Treatment-related adverse events

Oncologic outcomes

Cohort Study

Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharynx mucosa[1]. The global distribution of NPC is unbalance and this tumor is endemic to southern China, southeast Asia, and north Africa[2]. Due to the high sensitivity to irradiation and special anatomy of the nasopharynx, radical radiotherapy (i.e., use of high doses of radiotherapy to cure cancer) is the fundamental treatment choice for non-metastatic NPC. Addition of chemotherapy to radiotherapy has led to an improvement in survival[3–5].

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Various vaccines against SARS-CoV-2 have been developed and shown to be safe and efficacious[6–11]. Vaccination against COVID-19 (hereafter termed “COVID-19 vaccination”) achieves protection of the body by activating T cells, B cells, and the immune response and then formation of the corresponding memory cells[11]. Owing to the high risk of developing severe COVID-19, patients with cancer were prioritized for vaccination in most countries[12]. Nevertheless, some patients suffering from cancer refused to receive COVID-19 vaccination. One of the most common concerns was a perceived negative interaction with concomitant antitumor therapy[13]. Little evidence is available regarding the influence of COVID-19 vaccination on subsequent antitumor therapy in patients with cancer.

SARS-CoV-2 first infects cells and replicates in the nasopharynx and oropharynx of the upper respiratory tract[14]. Vaccination is the most effective way to achieve the prevention of SARS-CoV-2 infection and subsequent severe COVID-19[11]. In China, many patients with NPC have received COVID-19 vaccination before their received anti-tumor therapy. Nevertheless, data concerning the influence of COVID-19 vaccination on patients with NPC are scarce. Thus, we conducted a study to assess the influence of COVID-19 vaccination on treatment-related adverse events (TRAEs) and 2-year oncologic outcomes in patients with non-metastatic NPC who were newly diagnosed after the widespread vaccination against COVID-19 and subsequently treated with radical radiotherapy alone or in conjunction with chemotherapy.

Study design and patient selection

The medical records of patients (≥ 18 years) with newly diagnosed non-metastatic NPC between May 2020 and December 2021, who were subsequently treated with radiotherapy alone or in conjunction with chemotherapy, were collected from the Department of Radiotherapy of the Affiliated Hospital of Guilin Medical College, Wuzhou Red Cross Hospital, and Nanxishan Hospital. The study was approved by the Medical Ethics Committees of the three hospitals. Informed consent was not required due to the retrospective nature of the study. All patients identified in the study were excluded from SARS-CoV-2 infection, as the restrictive COVID-19 screening wasn’t lifted until December 7, 2022 in China. That is to say, all of these patients were COVID-19 negative. Since there were no confirmed or suspected COVID-19 patients in our study, and clinicians believed that the presence or absence of antibodies in patients was not a contraindication to treatment, we did not require patients to complete antibody tests.

The inclusion criteria were patients: (i) with newly diagnosed NPC of stage II–IVa according to the eighth edition of the American Joint Committee on Cancer/International Union Against Cancer staging system; (ii) treated with radiotherapy alone or in conjunction with chemotherapy (induction chemotherapy (IC), concurrent chemotherapy (CC), or adjuvant chemotherapy (AC); (iii) Karnofsky performance status (KPS) score ≥ 90. The exclusion criteria were patients: (i) who had a first shot of COVID-19 vaccination after starting antitumor therapy; (ii) did not complete radical radiotherapy; (iii) who did not have follow-up after radiotherapy completion.

Patients had at least one shot of COVID-19 vaccination before treatment were defined as the “vaccinated group”. COVID-19 vaccines included inactivated vaccines (BBIBP-CorV[15] and CoronaVac[16]), a vaccine based on protein subunits (ZF2001[9]), and a vaccine based on adenoviral vectors (Ad5-nCoV[17]). Patients did not receive COVID-19 vaccination were defined as the “non-vaccinated” group. Data of COVID-19 vaccination were obtained from Guilin Center for Disease Control and Prevention. The study flowchart is shown in Fig. 1.

Treatment

Pretreatment evaluation comprised: clinical and laboratory examinations (hematologic and biochemistry profiles); fiberoptic endoscopy of the nasopharynx; magnetic resonance imaging (MRI) of the nasopharynx and neck for staging of the primary tumor. Staging of distant metastasis was completed with computed tomography (CT) of the chest and abdomen and skeletal scintigraphy.

All patients underwent with intensity-modulated radiotherapy. The total prescribed dose was delivered in 31–35 fractions and was: 66–70 Gray (Gy) to the planning target volume (PTV) of the primary gross tumor volume (GTVnx); 60–70 Gy to the PTV of the nodal gross tumor volume (GTVnd); 54–66 Gy to the PTV of the high-risk clinical target volume (CTV1); 50–56 Gy to the PTV of the low-risk clinical target volume (CTV2). Radiation was delivered once-daily at five fractions per week.

Chemotherapy included induction chemotherapy (IC), concurrent chemotherapy (CC) and adjuvant chemotherapy (AC), chemotherapy protocols were consistent with the National Comprehensive Cancer Network Guidelines for Head and Neck Cancers[18]. IC regimens were repeated every 3 weeks and included GP (gemcitabine: 1000 mg/m² body surface area on day 1 and day 8; cisplatin 80 mg/m² on day 1), TPF (docetaxel 60–75 mg/m² on day 1; 5-fluorouracil 600–750 mg/m² on days 1–5; cisplatin 60–75 mg/m² on day 1) or TP (docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1). The CC regimens consisted of cisplatin (40 mg/m²) administered every week or cisplatin/nedaplatin (80–100 mg/m²) administered every 3 weeks. AC regimens were GP or capecitabine (50 mg/m² twice-daily for 1 year).

Nimotuzumab was an engineered, intermediate affinity anti-EGFR antibody and was administered at 100 or 200 mg weekly throughout radiotherapy weekly.

Endpoints and follow-up

The primary endpoints were the prevalence of acute and late TRAEs, which were graded according to the Common Terminology Criteria for Adverse Events 5.0[19] and scoring criteria for radiation-related morbidity set by the Radiation Therapy Oncology Group. Secondary endpoints were oncologic outcomes at 2 years, including overall survival (OS; defined as the time from the date of diagnosis to the final follow-up or to death from any cause), progression-free survival (PFS; defined as the time from the date of diagnosis to local or regional relapse, distant metastasis, or death due to any cause), distant metastasis-free survival (DMFS; defined as the time from the date of diagnosis to distant metastasis or death due to any cause), and locoregional relapse-free survival (LRRFS; defined as the time from the date of diagnosis to locoregional relapses or death due to any cause). All patients were followed up every 3–6 months during the first 2 years, and every 6–12 months thereafter, with appropriate interval imaging studies and physical examinations.

Statistical analysis

Descriptive statistics of the demographic and clinical characteristics of patients at baseline were evaluated for the vaccinated and non-vaccinated groups. Differences between categorical variables were explored by the Fisher exact test or chi-square test. The summary of continuous variables included the median value along with its corresponding range and/or interquartile range. Two-group propensity score matching (PSM) was done sequentially using a 1:1 nearest-neighbor matching algorithm to minimize potential selection bias after adjusting for sex, age at diagnosis, histology (according to criteria set by the World Health Organization), T stage, N stage, tumor–node–metastasis (TNM) stage, IC regimen, CC (yes or no), nimotuzumab (yes or no) and AC (yes or no). Oncologic outcomes were obtained from the Kaplan–Meier method, and differences were compared using the log-rank test. Multivariate analyses were conducted with the Cox proportional hazards model and used to test the independent significance of potential prognostic factors. Subgroup analyses of toxicity data were carried out for TRAEs. SPSS 20 (IBM, Armonk, NY, USA) was used for statistical analyses. P < 0.05 (two-sided) was considered significant.

Patient characteristics

The study cohort comprised 893 patients (644 males [72.1%] and 249 females [27.9%]) diagnosed with stage- II–IVa NPC. Among them, 395 (44.2%) were defined as vaccinated group (median age, 50 years, interquartile range [IQR], 43–56, range = 18–83 years). Thirty-two (8.1%) patients received one COVID-19 vaccination, 253 (64.1%) patients received two vaccinations, 105 (26.6%) received three vaccinations, and five (1.3%) received four vaccinations. The remaining 498 (55.8%) patients did not receive COVID-19 vaccination and were defined as non-vaccinated group (median age, 50 years, IQR, 43–56 years, range = 19–80 years). Demographic and clinical characteristics of patients with NPC are shown in Table 1. Difference in the number of patients taking IC between the two groups was significant. In comparison with the non-vaccinated group, the vaccinated group contained significantly more female patients, were more likely to receive CC, and were more likely to receive nimotuzumab during radiotherapy. After PSM, 678 (339 pairs) patients were selected for further evaluation and the differences in the characteristics of patients at baseline between the two groups were not significant. The median time interval from receiving the first COVID-19 vaccination to the start of antitumor treatment was 104 (IQR, 61–153, range = 4–363) days.

Oncologic outcomes

At the last follow-up on December 31, 2023, the median follow-up was 31.6 months (IQR: range, 28 to 35.5 months). Patients in the vaccinated and non-vaccinated group were followed up for at least 2 years. Among the 893 patients, 11 died, 23 had distant metastases, and 11 had locoregional recurrence in the vaccinated group while 16 died, 55 had distant metastases, and 30 had locoregional recurrence in the non-vaccinated group. Two-year OS (97.2% vs. 97.8%; P = 0.576, Fig. 2A), 2-year DMFS (92.9% vs. 89.2%; P = 0.057, Fig. 2B) and 2-year LRRFS (94.7% vs. 93.6%; P = 0.497, Fig. 2D) were comparable between the groups. However, vaccinated patients had higher 2-year PFS rate than the non-vaccinated group (91.1% vs. 85.5%; P = 0.012, Fig. 2C). After PSM, 339 pairs of patients were included in our final analysis of oncologic outcomes. Two-year OS (97.6%, 95% confidence interval [CI]: 95.3%-98.8% vs. 98.5%, 95% CI: 96.4%-99.3%, P = 0.401, Fig. 3A), 2-year PFS (91.7% [95% CI, 88.2%-94.2%] vs. 87.9% [95% CI: 83.9%-90.9%], P = 0.097, Fig. 3C), 2-year DMFS (93.2% [95% CI, 89.9%-95.4%] vs. 91.4% [95% CI, 87.9%-93.9%], P = 0.385, Fig. 3B), and 2-year LRRFS (95.3% [95% CI, 92.4%-97%] vs. 94.1% [95% CI, 91%-96.1%], P = 0.494, Fig. 3D) were similar between the matched groups.

Multivariable COX analysis after PSM revealed that COVID-19 vaccination was not an independent prognostic factor for OS (hazard ratio [HR], 1.636; 95%CI, 0.518–5.173; P = 0.402), PFS (HR, 0.679; 95%CI, 0.419–1.1; P = 0.116), DMFS (HR,0.79; 95%CI, 0.456–1.368; P = 0.40), LRRFS (HR,0.819; 95%CI, 0.423–1.588; P = 0.555) (Table 2).

Treatment-related adverse events

No treatment-related death occurred during the entire course of treatment. During IC, a significantly higher proportion of vaccinated patients experienced fatigue of grade 1–2 (41.9% vs. 23.9%; P < 0.001), nausea/vomiting of grade 1–2 (67.6% vs. 58.7%; P = 0.026), and neutropenia of grade 3–4 (24.2% vs. 18.0%; P = 0.048) in comparison with matched non-vaccinated patients (Table 3). Significant differences were not found in the prevalence of other acute TRAEs regardless of grade (1–2 or 3–4). During radiotherapy, vaccinated group experienced a higher prevalence of grade-1-2 fatigue (58.4% vs. 43.1%; P < 0.001) than the non-vaccinated group, other TRAEs were not significant regardless of grade (1–2 or 3–4).

With respect to late TRAEs, no significant differences were found between vaccinated group and non-vaccinated group in deafness or otitis, tinnitus, skin fibrosis, trismus and xerostomia. Acute and late TRAEs are shown in Table 3.

Subgroup analyses

We carried out subgroup analyses of our data to assess differences in terms of acute TRAEs according to nimotuzumab use (yes vs. no), sex (male vs. female), age (< 50 years vs. ≥50 years), TNM stage (II–III vs. IVa), number of vaccinations (once vs. two or more times), and time interval between vaccination and treatment (≤ 104 days vs. >104 days) (Table S1-S6).

During induction chemotherapy and radiotherapy, a significantly higher prevalence of grade-3–4 neutropenia (vaccinated vs. non-vaccinated, 29.1% vs.19.1%; P = 0.029) was reported in patients aged ≥ 50 years (Table S3). Also, a significantly higher prevalence of grade-3–4 neutropenia (27.7% vs. 15.0%; P = 0.004), grade-3–4 leukopenia (11.6% vs. 5.3%; P = 0.029) was reported in patients with stage- II III disease (Table S4). No significant difference in the prevalence of grade-3–4-specific TRAEs was found in nimotuzumab use subgroup (Table S1), sex subgroup (Table S2). In the number of vaccinations subgroup, a significant difference in the prevalence of grade-3–4-specific TRAEs was not observed (Table S5). Comparison of the median time interval between the first COVID-19 vaccination and treatment initiation in this matched cohort revealed the prevalence of grade-3–4 TRAEs to be similar between the window for COVID-19 vaccination (≤ 104 days and > 104 days) for patients with NPC (Table S6).

With respect to grade-1–2-specific TRAEs, vaccinated patients were more likely to experience grade-1–2 fatigue during induction chemotherapy and radiotherapy across all subgroups with the exception of number of vaccinations and time interval between vaccination and treatment subgroups.

Our cohort study demonstrated that vaccinated patients were more likely to experience acute TRAEs during induction chemotherapy and radiotherapy compared with matched non-vaccinated patients, and we observed a possible interaction effect on grade-3–4 neutropenia in the subgroups of age ≥ 50 years and stage–II–III. As for oncologic outcomes, patients within the vaccinated group had similar 2-year oncologic outcomes compared with those of the non-vaccinated group.

Our observations of acute TRAEs are consistent with some previous studies, despite variations in treatment protocols. A multicenter observational study revealed that COVID-19 vaccination increased the prevalence of mild immune system-related adverse events (grade 1 or 2; 33.8% vs 19.8%, P < 0.001) in patients with cancer who received camrelizumab[20]. Another study indicated that COVID-19 vaccination could improve the response to treatment against programmed cell death protein-1 combined with chemotherapy in patients with recurrent metastatic NPC, but vaccinated patients were more likely to experience mild IRAEs (73.6% vs. 60.1%; P < 0.001)[21].

COVID-19 vaccines have been shown to be effective and safe, but numerous adverse events have been reported. As early study reported fatigue and nausea to be the common adverse events resulting from use of COVID-19 vaccines[22]. In the VOICE study, fatigue of grade 1–2 occurred in up to 44% in patients with cancer[23]. The protection induced by vaccination is mediated through a complex interplay between innate, humoral, and cell-mediated immunity[24, 25]. After vaccination, neutrophils are recruited, activated, and interact functionally with B cells by binding immunoglobulin (Ig)G and IgA and inducing antibody production directly by activating B cells[26–28]. Thus, neutrophils are recruited in immunization sites and are redistributed after vaccination. A recent study reported a small and transient drop in neutrophil after COVID-19 vaccination[29], which supports our results. Malignancy can cause a systemic immunosuppressive state[30]. The myelosuppression caused by chemotherapy can lead to neutropenia. The above might explain (at least in part) our finding of a higher prevalence of severe neutropenia in the vaccinated group in comparison with matched non-vaccinated group.

Multiple times (two or more times) COVID-19 vaccination had been shown to be effective in increasing vaccine-derived immunity[31–33], theoretically, the prevalence of adverse events of chemoradiotherapy could be influenced. However, our subgroup of analyses acute TRAEs according to number of vaccinations (once vs. two or more times) demonstrated that patients who vaccinated two or more times did not show significant difference in the prevalence of grade-3–4-specific TRAEs compared with those who vaccinated once. Possible reasons were vaccine effectiveness wanes over time and receiving chemotherapy from within 28 days to within 6 months of vaccination impaired vaccine-derived immunity[34, 35].

With regard to oncologic outcomes, two-year PFS in the vaccinated group was significantly higher than that for the unmatched non-vaccinated group. A possible reason for this result is that patients in the vaccinated group were more likely to received concurrent chemotherapy and nimotuzumab during radiotherapy, because this group of patients who had previous host immune dysregulation conditions. Accumulating evidence has demonstrated that nimotuzumab plus CCRT or intensity-modulated radiotherapy shows promising efficacy without increasing toxicity for patients[36–38]. Additionally, the addition of concurrent chemotherapy or nimotuzumab to radiotherapy can improve PFS in patients with NPC[39, 40]. After adjustment of the bias between the two groups using PSM, we noticed that the 2-year values for OS, PFS, DMFS, and LRRFS were comparable between the two groups. Multivariable analyses indicated that COVID-19 vaccination was not an independent predictor of OS, PFS, DMFS, or LRRFS. Our data excluded an unfavorable influence of COVID-19 vaccination on the oncologic outcomes of patients with NPC treated with chemoradiotherapy. Vaccines stimulate T cells and B cells, and leads to protection against a specific pathogen. However, recent chemotherapy (defined variably as receiving chemotherapy from within 28 days to within 6 months of vaccination) impairs vaccine-induced immune responses[41]. Moreover, immunosuppressive pathways are activated in the tumor microenvironment after irradiation[42, 43]. These phenomena might be why we noticed similar oncologic outcomes between the vaccinated and matched non-vaccinated group.

It is important to mention that this study has strengths and limitations. Our study is the first to investigate association between COVID-19 vaccination and oncologic outcomes in patients with cancer. Additionally, we integrated data from the national vaccination system of China, which enabled us to obtain specific information regarding COVID-19 vaccine types and vaccination timing and could effectively eliminate the recall bias. Other advantages include the large number of patients and the completeness of the follow-up of patients with NPC. One limitation of our study is that this study is a retrospective study, we tried to address potential selection biases with PSM, but our study remained vulnerable to unmeasured confounding. Another limitation is that the follow-up duration is short because large-scale vaccination of COVID-19 in China started from 2021. Evaluation of oncologic outcomes merits a longer duration of follow-up. In addition, more than one type of COVID-19 vaccine was used.

In conclusion, our study supports that COVID-19 vaccination was associated with higher prevalence of acute TRAEs in patients with non-metastasis NPC treated with radiotherapy alone or in conjunction with chemotherapy, and vaccinated patients had a higher prevalence of grade-3–4 neutropenia than non-vaccinated patients for those aged ≥ 50 years and those with stage–II–III disease. The number of vaccinations and window for vaccination had no influence on the prevalence of severe specific TRAEs. Nevertheless, oncologic outcomes at 2 years were similar between the two groups, COVID-19 vaccination was not associated with worse oncologic outcomes.

TRAEs, treatment-related adverse events; NPC, nasopharyngeal carcinoma; OS, overall survival; PFS, progression-free survival; DMFS, distant metastasis-free survival; LRRFS, locoregional relapse-free survival; IQR, interquartile range; COVID-19, coronavirus disease-2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; IC, induction chemotherapy; CC, concurrent chemotherapy; AC, adjuvant chemotherapy; KPS, Karnofsky performance status; Gy, gray; PTV, planning target volume; GTVnx, primary gross tumor volume; GTVnd, nodal gross tumor volume; CTV1, high-risk clinical target volume; CTV2, low-risk clinical target volume; GP, gemcitabine plus cisplatin; TPF, docetaxel plus fluorouracil plus cisplatin; TP, docetaxel plus cisplatin; HR, hazard ratio; CI, confidence interval; TNM, tumor–node–metastasis; PSM, propensity score matching; IRAE, immune-related adverse events.

Acknowledgments

We would like to thank the native English-speaking scientists of Elixigen Company (Huntington Beach, California) for editing our manuscript.

Author Contributions

All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Minglong Liu: Conceptualization, Data curation, Formal analysis, Investigation, Validation, Visualization, Writing-original draff, Writing-review and editing. Bin Zhang: Conceptualization, Data curation, Investigation, Project administration, Resources, Writing-original draff, Writing-review and editing. Yufei Pan: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Writing-original draff, Writing-review and editing. Xiaoping Lin: Data curation, Writing-review and editing. Guanhong Luo: Data curation, Writing-review and editing. Yuan Xie: Data curation, Writing-review and editing. Xiaolan Ruan: Data curation, Writing-review and editing. Yu Pan: Data curation, Writing-review and editing. Yi Liang: Data curation, Writing-review and editing. Defeng Wang: Data curation, Writing-review and editing. Yuejia Wei: Data curation, Writing-review and editing. Hengwei Chen: Data curation, Writing-review and editing. Guorong Tang: Project administration, Resources, Supervision, Writing-review and editing. Wei Jiang: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing-review and editing.

Funding/Support

This work was supported by the Guangxi Medical and health key discipline construction project; the "139" Talent Cultivation Plan Program of Guangxi Medical High-level Backbone, the National Natural Science Foundation of China (No. 82160479); the CSCO Youth Innovative Oncology Research Fund (No. Y-Young2020-0520) and the Scientific Research and Self-funded Research Project of the Guangxi Zhuang Autonomous Region Health Council (grant No. Z-C20230185).

Data Availability Statement

The data that support the findings of this study are available from the corresponding author on reasonable request.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics Statement and Informed Consent

All procedures complied with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study design was approved by the Institutional Ethics Committee of Guilin Medical University, Wuzhou Red Cross Hospital and Nanxishan Hospital of Guangxi Zhuang Autonomous Region. The requirement for written informed consent was waived by the ethics committee of Guilin Medical University, Wuzhou Red Cross Hospital and Nanxishan Hospital of Guangxi Zhuang Autonomous Region because of the retrospective nature of the study.

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Table 1. Demographic and Clinical Characteristics of Patients.

	Before PSM			After PSM
Characteristic	Vaccinated group（n=395）	Non-vaccinated group（n=498）	P value	Vaccinated group（n=339）	Non-vaccinated group（n=339）	P value
Sex, NO. (%)			0.003			0.547
Male	265（67.1）	379（76.1）		242（71.4）	250（73.7）
Female	130（32.9）	119（23.9）		97（28.6）	89（26.3）
Age at diagnosis, NO. (%)			0.849			0.645
Range, y	18-83	19-80		18-83	19-76
＜50	191（48.4）	244（49.0）		160（47.2）	166（49.0）
≥50	204（51.6）	254（51.0）		179（52.8）	173（51.0）
KPS score, NO. (%)			NA			NA
90	395（100）	498（100）		339（100）	339（100）
Comorbidities, NO. (%)			0.906			0.533
Diabetes	15（3.8）	26（5.2）		9（2.7）	18（5.3）
Hypertension	30（7.6）	38（7.6）		28（8.3）	31（9.1）
Heart disease	2（0.5）	4（0.8）		2（0.6）	3（0.9）
Cerebral infarction	5（1.3）	5（1.3）		5（1.5）	3（0.9）
Hepatitis	30（7.6）	41（8.2）		27（8.0）	27（8.0）
WHO Histology, NO. (%)			0.673			0.062
Type I	7（1.8）	8（1.6）		7（2.1）	1（0.3）
Type II	2（0.5）	6（1.2）		2（0.6）	6（1.8）
Type III	384（97.2）	483（97.0）		328（96.8）	331（97.6）
Other types	2（0.5）	1（0.2）		2（0.6）	1（0.3）
T stage, NO. (%)			0.236			0.641
T1	25（6.3）	18（3.6）		16（4.7）	11（3.2）
T2	118（29.9）	150（28.9）		97（28.6）	107（31.6）
T3	137（34.7）	196（38.4）		125（36.9）	127（37.5）
T4	115（29.1）	151（29.1）		101（29.8）	94（27.7）
N stage, NO. (%)			0.262			0.165
N0	7（1.8）	17（3.4）		5（1.5）	13（3.8）
N1	87（22.0）	93（18.7）		69（20.4）	69（20.4）
N2	222（56.2）	277（55.6）		195（57.5）	177（52.2）
N3	79（20.0）	111（22.3）		70（20.6）	80（23.6）

(continued)

TNM stage, NO. (%)			0.127				0.577
Ⅱ	43（10.9）	35（7.0）		26（7.7）		33（9.7）
Ⅲ	184（46.6）	240（48.2）		163（48.1）		154（45.4）
Ⅳa	168（42.5）	223（44.8）		150（44.2）		152（44.8）
IC regimens, NO. (%)			＜0.001				0.929
GP	238（60.3）	223（44.8）		199（58.7）		291（56.3）
TP	78（19.7）	169（33.9）		75（22.1）		79（23.3）
TPF	24（6.1）	45（9.0）		24（7.1）		24（7.1）
No	55（13.9）	61（12.2）		41（12.1）		45（13.3）
CC, NO. (%)			0.002				0.654
Yes	346（87.6）	398（79.9）		291（85.8）		295（87.0）
No	49（12.4）	100（20.1）		48（14.2）		44（13.0）
Nimotuzumab, NO. (%)			＜0.001				0.937
Yes	253（64.1）	254（51.0）		215（63.4）		214（63.1）
No	142（35.9）	244（49.0）		124（36.6）		125（36.9）
AC, NO. (%)			0.504				0.546
Yes	70（17.7）	97（19.5）		63（18.6）	57（16.8）
No	325（82.3）	401（80.5）		276（81.4）	282（83.2）

Abbreviations: PSM, propensity score matching; NO, number; KPS, Karnofsky performance status; NA, not applicable; WHO, World Health Organization; TNM, tumor-node-metastasis; IC, induction chemotherapy; GP, gemcitabine plus cisplatin; TPF, docetaxel plus fluorouracil plus cisplatin; TP, docetaxel plus cisplatin; CC, concurrent chemotherapy; AC, adjuvant chemotherapy.

Table 2. Multivariable Analyses for Oncologic Outcomes in Propensity Score-matched Cohort

Variable	HR(95% CI)；P value
Overall survival
Sex（male vs. female）	1.44(0.389-5.324); P=0.585
Age at diagnosis（＜50 vs. ≥50）	4.722(1.037-21.5); P=0.045
T category（T1-2 vs. T3-4）	2.055(0.412-10.264); P=0.380
N category（N0-1 vs. N2-3）	273839.263(0-8.487E+222); P=0.961
TNM stage（Ⅱ-Ⅲ vs. Ⅳa）	2.956(0.750-11.651); P=0.121
COVID-19 vaccination（yes vs. no）	1.636(0.518-5.173); P=0.402
Induction chemotherapy（yes vs. no）	0.167(0.04-0.703); P=0.015
Concurrent chemotherapy（yes vs. no）	1.124(0.214-5.912); P=0.890
Nimotuzumab（yes vs. no）	0.916(0.277-3.024); P=0.885
Adjuvant chemotherapy（yes vs. no）	1.117(0.298-4.189); P=0.870
Progression-free survival
Sex（male vs. female）	1.289(0.726-2.289); P=0.386
Age at diagnosis（＜50 vs.≥50）	0.717(0.444-1.159); P=0.175
T category（T1-2 vs. T3-4）	0.997(0.581-1.713); P=0.992
N category（N0-1 vs. N2-3）	4.494(1.717-11.760); P=0.002
TNM stage（Ⅱ-Ⅲ vs. Ⅳa）	1.369(0.811-2.311); P=0.240
COVID-19 vaccination（yes vs. no）	0.679(0.419-1.1); P=0.116
Induction chemotherapy（yes vs. no）	0.514(0.250-1.057); P=0.070
Concurrent chemotherapy（yes vs. no）	0.792(0.404-1.551); P=0.496
Nimotuzumab（yes vs. no）	0.92(0.553-1.532); P=0.750
Adjuvant chemotherapy（yes vs. no）	1.658(0.968-2.839); P=0.066
Distant metastasis-free survival
Sex（male vs. female）	1.094(0.576-2.079); P=0.783
Age at diagnosis（＜50 vs.≥50）	0.806(0.464-1.398); P=0.442
T category（T1-2 vs. T3-4）	0.74(0.400-1.369); P=0.337
N category（N0-1 vs. N2-3）	2.551(0.956-6.813); P=0.062
TNM stage（Ⅱ-Ⅲ vs. Ⅳa）	2.079(1.107-3.904); P=0.023
COVID-19 vaccination（yes vs. no）	0.79(0.456-1.368); P=0.400
Induction chemotherapy（yes vs. no）	0.721(0.290-1.793); P=0.481
Concurrent chemotherapy（yes vs. no）	0.848(0.388-1.853); P=0.680
Nimotuzumab（yes vs. no）	0.959(0.533-1.726); P=0.888
Adjuvant chemotherapy（yes vs. no）	1.781(0.970-3.269); P=0.063

(Continued)

Loco-regional relapse-free survival
Sex（male vs. female）	1.546(0.688-3.473); P=0.292
Age at diagnosis（＜50 vs.≥50）	0.912(0.472-1.764); P=0.784
T category（T1-2 vs. T3-4）	2.025(0.886-4.629); P=0.094
N category（N0-1 vs. N2-3）	7.456(1.686-32.964); P=0.008
TNM stage（Ⅱ-Ⅲ vs. Ⅳa）	0.887(0.434-1.77); P=0.713
COVID-19 vaccination（yes vs. no）	0.819(0.423-1.588); P=0.555
Induction chemotherapy（yes vs. no）	0.318(0.130-0.779); P=0.012
Concurrent chemotherapy（yes vs. no）	0.775(0.308-1.954); P=0.590
Nimotuzumab（yes vs. no）	0.93(0.458-1.885); P=0.840
Adjuvant chemotherapy（yes vs. no）	1.351(0.617-2.960); P=0.452

Abbreviation: HR, hazard ratio; CI, confidence interval.

Table 3. Comparison of Acute and Late Treatment-Related Adverse Events in Propensity Score-matched Cohort

Events	Vaccinated group (n=339)			Non-vaccinated group (n=339)			P value for Grade 1-2	P value for Grade ≥3
Events	Grade 1-2 NO. (%)	Grade 3 NO. (%)	Grade 4 NO. (%)	Grade 1-2 NO. (%)	Grade 3 NO. (%)	Grade 4 NO. (%)
Adverse events during induction chemotherapy
Leukopenia	159（46.9）	33（9.7）	0	159（46.9）	27（8.0）	0	＞0.99	0.417
Neutropenia	126（37.2）	57（16.8）	25（7.4）	140（41.3）	44（13.0）	17（5.0）	0.271	0.048
Thrombocytopenia	14（4.1）	2（0.6）	2（0.6）	17（5.0）	3（0.9）	2（0.6）	0.581	＞0.999
Anemia	189（55.8）	9（2.7）	0	180（53.1）	11（3.2）	0	0.488	0.650
Hepatotoxic event	103（30.4）	2（0.6）	0	102（30.1）	4（1.2）	0	0.933	0.686
Nephrotoxic event	28（8.3）	0	0	40（11.8）	0	0	0.125	NA
Febrile neutropenia	0	1（0.3）	0	0	2（0.6）	0	NA	＞0.999
Fatigue	142（41.9）	0	0	81（23.9）	0	0	＜0.001	NA
Fever	5（1.5）	0	0	3（0.9）	1（0.3）	0	0.725	＞0.999
Nausea/Vomiting	226（66.7）	3（0.9）	0	198（58.4）	1（0.3）	0	0.026	0.624
Diarrhea	3（0.9）	0	0	9（2.7）	1（0.3）	0	0.081	＞0.999
Adverse events during radiotherapy
Leukopenia	225（66.4）	68（20.1）	3（0.9）	226（66.7）	75（22.1）	0	0.935	0.709
Neutropenia	158（46.6）	39（11.5）	12（3.5）	164（48.4）	51（15.0）	6（1.8）	0.644	0.529
Thrombocytopenia	62（18.3）	16（4.7）	3（0.9）	58（17.1）	14（4.1）	0	0.687	0.372
Anemia	247（72.9）	32（9.4）	2（0.6）	253（74.6）	26（7.7）	0	0.600	0.279
Hepatotoxic event	42（12.4）	0	0	36（10.6）	2（0.6）	0	0.470	0.499
Nephrotoxic event	64（18.9）	0	0	59（17.4）	0	0	0.618	NA
Febrile neutropenia	0	3（0.9）	0	0	1（0.3）	0	NA	0.624
Fatigue	198（58.4）	0	0	146（43.1）	0	0	＜0.001	NA
Fever	11（3.2）	1（0.3）	0	7（2.1）	1（0.3）	0	0.339	＞0.999
Nausea/Vomiting	269（79.4）	12（3.5）	0	252（74.3）	13（3.8）	0	0.122	0.839
Diarrhea	5（1.5）	0	0	9（2.7）	0	0	0.280	NA
Dysphagia	38（11.2）	0	0	47（13.9）	1（0.3）	0	0.297	＞0.999
Mucositis	270（79.6）	43（12.7）	1（0.3）	283（83.5）	41（12.1）	0	0.198	0.728
Xerostomia	279（82.3）	10（2.9）	0	281（82.9）	6（1.8）	0	0.839	0.312
Dermatitis	272（80.2）	15（4.4）	2（0.6）	276（81.7）	19（5.6）	0	0.638	0.732
Allergic reaction	11（3.2）	0	0	10（2.9）	0	0	0.825	NA
Late adverse events
Deafness or otitis	150（44.2）	15（4.4）	1（0.3）	168（49.6）	13（3.8）	0	0.166	0.569
Tinnitus	157（46.3）	0	0	135（39.8）	0	0	0.088	NA
Skin fibrosis	54（15.9）	0	0	69（20.4）	1（0.3）	0	0.135	＞0.999
Trismus	69（20.4）	0	0	60（17.7）	0	0	0.379	NA
Xerostomia	262（77.3）	0	0	280（82.6）	1（0.3）	0	0.084	＞0.999

Abbreviation: NA, not applicable (no adverse events in both groups).

Late adverse events defined as toxic effects that occurred 6 months after completion of radiotherapy

P values were calculated using the χ² test. No grade 5 late adverse events were found during follow-up.

No competing interests reported.

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Influence of COVID-19 Vaccination on Treatment-Related Adverse Events and Oncologic Outcomes of Non-metastatic Nasopharyngeal Carcinoma

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