Abstract
Background/Aim: This study aimed to determine whether a high neutrophil-lymphocyte ratio (NLR) was associated with the occurrence of febrile neutropenia (FN). Patients and Methods: Japanese patients with esophageal cancer who had been treated with first-line 5-fluorouracil and cisplatin therapy at Fujita Health University from April 2016 to March 2021 were enrolled in this retrospective cohort study. The primary outcome was the identification of independent risk factors for FN. Results: One hundred and fourteen patients were enrolled. Advanced cancer (hazard ratios (HR)=6.731) and an NLR ≥3 (HR=4.849) were identified as risk factors for FN. Furthermore, FN occurred earlier in patients with high NLR than in patients with low NLR. Conclusion: Advanced cancer and a high NLR might be predictors of the occurrence of severe neutropenia and FN in patients treated with 5-fluorouracil and cisplatin therapy.
Patients with esophageal cancer are treated with definitive chemo-radiotherapy according to the clinical stage of the tumor. In Japan, 1-year post-treatment survival time reaches 59.3% in patients with clinical stage IV tumor (1). 5-fluorouracil and cisplatin (FP) therapy is recognized as a standard treatment for esophageal cancer (2). Although FP therapy has a high response rate in patients with esophageal cancer, the frequency of neutropenia (NP) and febrile NP (FN) remains high (3, 4).
Granulocyte colony-stimulating factor (G-CSF) plays a major role in NP management. In patients receiving docetaxel, cisplatin, and 5-fluorouracil therapy, non-use of G-CSF increases the risk of FN (5). Moreover, administration of G-CSF, even for secondary prophylactic use, is useful in maintaining the dose intensity of these chemotherapy agents (3). However, there is no evidence regarding the secondary prophylactic use of G-CSF in patients receiving FP therapy. Elucidation of risk factors for FN is useful in screening patients who require prophylactic G-CSF administration. The National Comprehensive Cancer Network (NCCN), Infectious Diseases Society of America (IDSA), and American Society of Clinical Oncology (ASCO) have reported older age, poor performance status, and comorbidities as risk factors for FN (6). Because primary G-CSF support improves survival, (7) NCCN and ASCO recommend it in patients at high risk for FN (6). Meanwhile, G-CSF support increases the risk of pulmonary toxicity induced by bleomycin in patients who received bleomycin-containing regimens (8); furthermore, splenic rupture was reported in patients with solid tumors (9-11). Therefore, assessing the risks and benefits of G-CSF support is essential in patients with solid tumors.
Because systemic inflammatory response (SIR) is induced by many immune response types, the concentration of specific serum proteins needs to be monitored (12). Neutrophil–lymphocyte ratio (NLR) predicts prognosis in patients with solid cancers (13, 14) and high NLR is associated with tumor-induced SIR. Although tumor-induced SIR might promote an immune response in cancer patients, its association with the occurrence of FN is unclear. Moreover, a previous study investigating risk factors for FN did not evaluate immune parameters related to SIR. To clarify whether a high NLR is associated with the occurrence of FN, we investigated potential risk factors in patients with esophageal cancer.
Patients and Methods
Data source and study design. Japanese patients (age ≥20 years) with esophageal cancer who had been treated with first-line FP therapy at Fujita Health University Hospital from April 2016 to March 2021 were enrolled in this retrospective cohort study. All data were collected from the medical records at Fujita Health University Hospital.
FN during FP therapy was defined as grade 3 or higher based on the Common Terminology Criteria for Adverse Events version 5.0, as follows:
Grade 3: absolute neutrophil count <1,000/mm3 with a single temperature >38.3°C (101°F), or a sustained temperature of ≥38°C (100.4°F) for more than one hour.
Grade 4: life-threatening consequences; urgent intervention indicated.
Grade 5: death.
Participants were divided into non-FN and FN groups to determine the risk factors for FN.
Outcome measures. To assess potential risk factors for FN occurrence, we compared baseline characteristics of the non-FN and FN groups. The Cox proportional hazards model was used to identify the independent factors associated with the occurrence of FN. The factors that have clinical importance and a statistically significant difference in the univariate analysis were applied to this model and were as follows: cancer stage ≥III and NLR ≥3. The cut-off point of the NLR was determined according to a previous report (15). To evaluate the time from FP therapy to FN event, time-to-event curves were plotted using the Kaplan-Meier method.
Statistical analyses. Continuous data are presented as medians and ranges. The Mann-Whitney U-test compared data without normal distribution. The chi-square test and Fisher’s exact test were used to analyze nominal scales. Cox proportional hazards models identified the risk factors for occurrence of FN with hazard ratios (HRs) and 95% confidence intervals (CIs). Time-to-event curves plotted using the Kaplan-Meier method were used to compare the time of initiation of an FN event. A two-sided p value <0.05 was considered significant in all statistical analyses. SPSS version 22.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.
Ethics approval. This study was approved by the ethics board of Fujita Health University Hospital (ethics committee approval number: HM20-364) and conducted in accordance with appropriate guidelines. An opt-out approach, which was approved by the ethics board, was used for informed consent.
Results
Patient characteristics. One hundred and fourteen patients were included in this study (Figure 1). Patients with or without FN were divided into non-FN (n=102) and FN groups (n=12), respectively. The baseline characteristics of both groups are presented in Table I. The number of lymphocytes in the FN group was significantly lower than that in the non-FN group (p=0.005); also, the NLR in the FN group was significantly higher than that in the non-FN group (p=0.025). The percentage of patients with an NLR ≥3 in the FN group was higher than that in the non-FN group (p=0.008). The proportion of patients with stage III cancer was higher in the FN group than in the non-FN group.
Study design. FP: 5-Fluorouracil and cisplatin; FN: febrile neutropenia.
Baseline characteristics of the non-febrile neutropenia and febrile neutropenia groups.
Risk factors of FN in patients receiving FP therapy. To determine the risk factors of FN, the factors that have clinical importance and showed a statistically significant difference in the univariate analysis were applied to the cox proportional analysis. Cox proportional hazards analysis revealed that advanced cancer (cancer stage ≥III) (HR=6.731, 95%CI=1.469-30.83, p=0.014) and NLR ≥3 (HR=4.849, 95%CI=1.307-17.98, p=0.018) were risk factors for FN (Table II).
Factors associated with febrile neutropenia.
Time from initiation of chemotherapy to the occurrence of FN. To assess the impact of these risk factors on FN, we measured the time from initiation of chemotherapy to the occurrence of FN. FN occurred earlier in patients with advanced cancer compared to patients with non-advanced cancer (p=0.002) (advanced cancer: 25.17 days, 95%CI=23.46-26.88, non-advanced cancer: 27.40 days, 95%CI=26.59-28.22). Compared to patients with NL <3, FN occurred earlier among patients with NLR ≥3 (p=0.004) (NLR ≥3: 25.00 days, 95%CI=23.12-26.88, NLR <3: 27.35 days, 95%CI=26.57-28.13) (Figure 2).
Time from initiation of chemotherapy to occurrence of febrile neutropenia. The average time for patients with advanced and non-advanced cancer was 25.17 days (95%CI=23.46-26.88) and 27.40 days (95%CI=26.59-28.22), respectively. The average time for patients with NLR ≥3 and below 3 was 25.00 days (95%CI=23.12-26.88) and 27.35 days (95%CI=26.57-28.13), respectively (log-rank test).
Discussion
Our results indicate that advanced cancer and a high NLR were associated with the occurrence of FN.
Among patients on prophylactic pegfilgrastim, cancer stage was not associated with the occurrence of FN (16). Whereas another study indicated that advanced cancer was a risk factor for chemotherapy-induced NP among patients that were not on prophylactic pegfilgrastim (17). The above studies suggest that prophylactic administration of G-CSF deceases the risk of NP and FN in patients with advanced cancer. Therefore, our results showing advanced cancer is a risk factor for FN are consistent with previous reports.
Tumor-induced SIR is associated with poor outcomes in many cancers; moreover, neutrophil and lymphocyte levels are affected by SIR (13, 18). Neutrophils and lymphocytes secrete cytokines and chemokines, which are involved in cancer progression (19); hence, the NLR is reported to be a risk factor for poor prognosis among cancer patients (13, 14, 20, 21). These previous reports support the theory of the levels of cytokines and chemokines in tumor-induced SIR promote cancer progression. Thus, the NLR is recognized as a marker of SIR severity in cancer patients. Interestingly, the NLR, which is a pre-treatment inflammatory index, was associated with the occurrence of FN in our study. Because our study was a retrospective cohort study, the underlying mechanism of NLRs on FN could not be elucidated. However, our results suggest that tumor-induced SIR increases the sensitivity of immune cells to FP therapy. Since no reports have shown an association between NLR and adverse drug events during chemotherapy, this novel finding might contribute to the screening of patients at high risk of developing FN. Ten to 14 days following the initiation of FP therapy in patients with a high NLR, FN occurred. Because lymphocyte nadir developed approximately 17-21 days after initiation of chemotherapy (22), our results suggest the need to monitor for FN before lymphocyte nadir develops in patients with a high NLR.
A limitation of this study is that the number of FN events was insufficient to validate results using Cox proportional hazards analysis because it was a single-institution retrospective study. Since the ideal number of FN events needed to validate the results is approximately 20, a multi-institution study and other external cohorts are needed in the future.
In conclusion, we found that advanced cancer and a high NLR might be predictors of the occurrence of FN in patients treated with 5-fluorouracil and cisplatin therapy.
Acknowledgements
The Authors would like to thank Editage (https://www.editage.com/) for English language editing and review of the manuscript.
Footnotes
Authors’ Contributions
SK and TM designed this study. SK and NM carried out the survey of electronic records. TM and MH performed the statistical analyses. SK, TM, TK, HM, KS, IU, and SY drafted the article. All authors approved the final article.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received June 3, 2022.
- Revision received June 24, 2022.
- Accepted June 24, 2022.
- Copyright © 2022, 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).
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