Risk factors associated with febrile neutropenia in patients with esophageal cancer receiving 5-fluorouracil plus cisplatin combination chemoradiotherapy

Risk factors associated with febrile neutropenia in patients with esophageal cancer receiving 5-fluorouracil plus cisplatin combination chemoradiotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk factors associated with febrile neutropenia in patients with esophageal cancer receiving 5-fluorouracil plus cisplatin combination chemoradiotherapy Daiki Eto, Ken Shiraiwa, Ryota Tanaka, Takahiro Sumimoto, Ryosuke Tatsuta, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8027424/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To identify risk factors for febrile neutropenia (FN) in patients with esophageal cancer receiving the first cycle of definitive chemoradiotherapy with 5-fluorouracil plus cisplatin and concurrent radiotherapy (FP + R therapy). Methods We conducted a retrospective single-center cohort study of patients who started FP + R at Oita University Hospital between April 2011 and June 2023. The primary outcome was FN onset in cycle 1. Univariate tests and multivariable logistic regression [forced entry: age, C-reactive protein (CRP), prognostic nutritional index (PNI), dysphagia) were used to evaluate association with FN development. Receiver operating characteristic (ROC) analysis was conducted to evaluate the predictive performance of baseline CRP for FN. Results Among 120 patients studied, grade ≥ 3 neutropenia occurred in 37 (30.8%) and FN in 14 (11.7%) during the first cycle. In multivariable analysis, higher baseline CRP was independently associated with increased FN risk [odds ratio (OR) 1.790; 95% confidence interval (CI) 1.120–2.850; p = 0.014), whereas dysphagia showed a non-significant association (OR 2.890; p = 0.145). Age and PNI were not independent predictors. ROC analysis for baseline CRP yielded area under the ROC curve of 0.699 (95% CI 0.520–0.877; p = 0.021) with optimal cut-off value of 0.68 mg/dL (sensitivity 61.54%; specificity 70.65%). Conclusion Baseline systemic inflammation, indicated by elevated CRP, is an independent risk factor for FN development during FP + R therapy. Despite the regimen having an intermediate FN risk, patients with elevated pre-treatment CRP may need closer monitoring and consideration of intensified supportive care including primary prophylaxis with granulocyte colony-stimulating factor. Febrile neutropenia risk factor 5-fluorouracil plus cisplatin concurrent radiotherapy esophageal cancer C-reactive protein primary granulocyte colony-stimulating factor prophylaxis Figures Figure 1 Introduction Among the diverse adverse events associated with cancer chemotherapy, febrile neutropenia (FN) represents a serious toxicity characterized by fever accompanied by neutropenia. FN is a critical complication not only causing treatment delay and dose reduction, but also potentially leading to life-threatening conditions such as septic shock [ 1 ]. For chemotherapy regimens associated with high risk of FN (incidence ≥ 20%), international guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF), defined as administration of G-CSF concurrent with the initiation of chemotherapy for preventive purposes [ 2 ]. When the overall FN risk, including patient-specific factors, reaches 20% or higher, G-CSF prophylaxis is considered desirable, with advanced age and medical history recognized as risk-enhancing factors [ 3 ]. Indeed, guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) identify "age ≥ 65 years" as a significant risk factor for chemotherapy-induced FN development [ 2 , 3 ]. Docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) combination therapy (DCF regimen), which has become the standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma in recent years, is associated with a high incidence of FN [ 4 ]. Nomura et al. [ 5 ] reported a FN incidence of 20.3% during the first cycle of DCF therapy for esophageal cancer, with grade 3 or 4 neutropenia occurring in 56.3% of the patients. Their analysis identified “older age (≥ 60 years)” and “living alone” as independent risk factors for FN development, suggesting that primary G-CSF prophylaxis should be considered in patients with these risk factors [ 5 ]. 5-FU plus CDDP concurrent with radiotherapy (FP + R therapy), which is used as definitive chemoradiotherapy (CRT) for esophageal cancer, has been widely adopted as a standard treatment for unresectable advanced esophageal cancer, based on the results of the JCOG9516 trial [ 6 ]. In the JCOG9516 phase II study, the response rate to FP + R therapy was 68.3% and the complete response rate was 15%; however, the primary toxicity was myelosuppression and treatment-related death [ 6 ]. Although FP + R therapy represents one of the definitive treatment modalities for esophageal cancer, risk factors associated with FN development have not been thoroughly investigated, and there is currently no clear consensus regarding G-CSF prophylaxis in this setting. Given this background, the aim of the present retrospective study was to elucidate the risk factors for FN development during the first cycle of FP + R therapy in patients with esophageal cancer, which may provide insights for FN prevention and management strategies. Materials and methods Study design and subjects This study was a retrospective, single-center, observational cohort study. The subjects were patients who received initial FP+R therapy for esophageal cancer at Oita University Hospital between April 2011 and June 2023. Patients were excluded if they had no serum C-reactive protein (CRP) measurement within 7 days before FP+R therapy, if they were receiving active treatments for any infectious disease at baseline (including antibacterial, antiviral, and antifungal agents), or if they were taking oral antibiotics for prophylactic purposes. This study was conducted after obtaining approval by the Ethics Committee of Oita University Faculty of Medicine (approval number: 1901). Because the study used existing clinical data and posed minimal risk, the requirement for individual informed consent was waived. In accordance with institutional policy, information about the research and the use of patient data was publicly announced on the hospital website giving opportunity for patients to opt out. Patients who expressed their refusal to participate were excluded. All data were de-identified before analysis, and the study adhered to the Declaration of Helsinki and relevant guidelines. Treatment The FP+R regimen comprised chemotherapy of CDDP plus 5-FU with concurrent radiotherapy. The standard protocol at our institution consisted of CDDP at 70-80 mg/m² administered intravenously on day 1, and 5-FU at 700-1000 mg/m²/day administered as a continuous intravenous infusion for 4 days (days 1–4). Concurrently, thoracic radiotherapy was initiated on day 1, delivering 2 Gy per fraction for a total planned dose of 60 Gy (2 Gy × 30 fractions). Supportive care included antiemetic agents and adequate hydration. No patients received routine primary prophylaxis with G-CSF during the initial FP+R therapy. However, therapeutic G-CSF (secondary prophylaxis) was administered when FN or grade 4 neutropenia developed. Outcome definition Patients were divided into non-FN and FN groups based on whether they developed FN after the initial FP+R therapy. Referring to the Japanese guidelines [7], FN patients were defined as those with “a neutrophil count below 500/μL, or a count below 1,000/μL with a predicted decline below 500/μL within 48 hours, accompanied by axillary temperature ≥ 37.5°C”. Hematologic adverse events were graded according to the Common Toxicity Criteria for Adverse Effects (CTCAE) version 5.0. Data collection Total 5-FU and CDDP doses per body surface area (mg/m 2 ), patient characteristics at baseline, clinical laboratory test values before initial FP+R therapy, and status of G-CSF use following FP+R therapy were extracted from the electronic medical records. Patient characteristics included age, sex (male or female), status of dysphagia, clinical stage, and Eastern Cooperative Oncology Group (ECOG) performance status (PS). Clinical laboratory test values included white blood cell count, neutrophil count, lymphocyte count, basophil count, eosinophil count, monocyte count, platelet count, hemoglobin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum albumin, standardized estimated glomerular filtration rate, blood urea nitrogen, and CRP. Moreover, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and prognostic nutritional index (PNI), which are known indicators for assessing the nutritional status and severity of cancer patients, were calculated. The calculation method for PNI is as follows: PNI = 10 × albumin + 0.005 × total lymphocyte count [8]. Statistical analysis Statistical analyses were performed using SPSS version 30 (IBM Japan Ltd., Tokyo, Japan) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Data of baseline patient characteristics and clinical laboratory test values are expressed as numbers for categorical variables and median (interquartile range) for continuous variables. Categorical variables were analyzed using Fisher’s exact test. Continuous variables were analyzed using Mann−Whitney U test. A p -value < 0.05 was considered statistically significant. Multiple logistic regression analysis using the forced entry method was performed to identify risk factors independently associated with the development of FN. The four factors based on previous reports; age, CRP, PNI, and presence of dysphagia, were selected as independent variables [5, 9-15]. The independent variables entered into the model were checked for multicollinearity using a variance inflation factor (VIF) threshold of 10. Furthermore, since PNI is calculated using albumin and total lymphocyte count, and NLR and PLR also utilize lymphocyte count in the calculations, including these parameters simultaneously as independent variables is undesirable from the perspective of multicollinearity. Therefore, PNI, which showed a significant difference between the non-FN and FN groups and is a reliable nutritional indicator, was selected as the covariate. Additionally, we performed receiver operating characteristic (ROC) analysis to evaluate the performance of baseline CRP in predicting FN development. We calculated the area under the ROC curve (AUC) with 95% confidence intervals (CI) and determined the optimal cut-off value using the Youden index (maximizing sensitivity + specificity). The statistical significance of the AUC was assessed, and two-sided p -values < 0.05 were considered significant. Results Incidence of hematologic toxicity in initial FP+R therapy The frequencies of hematologic adverse events during the initial course of FP+R therapy in 120 patients are shown in Table 1. Grade 3 or higher neutropenia (severe neutropenia) was observed in 30.8% (37/120) of patients overall, and grade 4 neutropenia (neutrophil count < 500/μL) in 3.3% (4/120). Furthermore, FN developed in 14 patients, with an incidence of 11.7%. Grade 3 or higher leukopenia was observed in 45.8% (55/120). Severe anemia (grade 3 or higher; hemoglobin 8 g/dL or lower) occurred in 4.2% (5/120), and severe thrombocytopenia (grade 3 or higher) in 6.7% (8/120). In summary, this cohort showed a high frequency of bone marrow suppression, particularly neutropenia. Although the incidence of FN was less than 20% (the high-risk threshold), it remained relatively high compared to the JCOG9516 trial [6]. Univariate comparison between non-FN and FN groups Patient characteristics were compared between 106 patients who did not develop FN (non-FN group) and 14 patients who developed FN (FN group) during the first treatment cycle (Table 2). The median age was comparable between two groups (68 years in the non-FN group vs. 69 years in the FN group, p = 0.505). No significant differences were observed in sex distribution (male: 90.6% vs. 92.9%, p > 0.999), clinical stage (stage III/IV: 52.8% vs. 50.0%, p > 0.999), and ECOG performance status (PS ≥ 2: 3.8% vs. 7.1%, p = 0.465). However, dysphagia was significantly more frequently found in the FN group than in the non-FN group (50.0% vs. 78.6%, p = 0.044). Thus, dysphagia showed a significant association with FN development in univariate analysis. Comparison of baseline laboratory parameters revealed a significant difference in CRP level between the two groups (median: 0.23 in non-FN group vs. 1.43 mg/dL in FN group, p = 0.020). Elevated CRP levels at baseline were more frequently observed in the FN group. No significant differences in other hematological or biochemical parameters were detected between the two groups. PNI indicated a tendency of poorer nutritional status in the FN group (45.62) compared to the non-FN group (48.74), but this difference was not statistically significant ( p = 0.194). Multivariate analysis of risk factors for FN Multiple logistic regression analysis with the development of FN as the dependent variable and CRP, dysphagia, PNI and age as independent variables identified baseline CRP level as an independent factor associated with FN development (Table 3). Elevated baseline CRP level was significantly associated with increased FN risk [odds ratio (OR): 1.790, 95% CI: 1.120–2.850, p = 0.014], indicating that higher CRP levels was associated with greater FN susceptibility. Although the presence of dysphagia showed a trend toward increased FN risk in multivariate analysis (OR: 2.890, 95% CI: 0.694–12.100), this association did not reach statistical significance ( p = 0.145). Age and PNI were not identified as independent predictors in the final model. Baseline CRP cut-off value for predicting FN risk ROC analysis was performed to examine the cut-off baseline CRP level in predicting FN (Figure 1). The AUC was 0.699 (95% CI, 0.520–0.877), indicating a statistically significant ability to discriminate patients who developed FN from those who did not ( p = 0.021). The optimal cut-off value identified by the Youden index was 0.68 mg/dL, which yielded a sensitivity of 61.54% and a specificity of 70.65%. Discussion In this retrospective study of 120 esophageal cancer patients receiving initial FP + R chemoradiotherapy, we observed a considerably high incidence of myelosuppression. Severe neutropenia (grade ≥ 3) occurred in 30.8% of patients, and 14 patients (11.7%) developed FN during the first treatment cycle. Although the FN incidence was below the 20% high-risk threshold, it still represents a clinically significant risk. This FN incidence was higher than the reported hematologic toxicity rate of 0% for a 5-FU plus CDDP regimen combined with radiation therapy in the JCOG9516 trial [ 6 ]. Notably, the median age of our cohort was higher (around 69 years) than that in the JCOG9516 trial (62 years), which may have contributed to higher susceptibility to neutropenic toxicity. Older age (particularly ≥ 65) is a well-established risk factor for FN in clinical practice guidelines [ 12 ], and the inclusion of older, real-world patients in our study likely explains the higher rates of severe neutropenia and FN compared to clinical trial populations. These results demonstrate that even with modern supportive care, concurrent FP + R therapy carries an intermediate (approximately 10–12%) risk of FN in real-world clinical practice. In univariate analysis, dysphagia was significantly more frequently found in patients who developed FN (78.6% with FN vs. 50.0% without FN, p = 0.044). This suggests that patients with swallowing difficulty, often indicative of advanced locoregional disease and poor oral intake, were more vulnerable to develop FN. This observation supports the findings of previous studies [ 9 , 10 ]. Hagi et al. [ 10 ] reported that esophageal cancer patients with high dysphagia scores (grade ≥ 3) had a dramatically higher incidence of FN during DCF chemotherapy compared to those with lower scores (79.3% vs 35.7%, p < 0.001). Their logistic regression analysis confirmed baseline dysphagia as an independent predictor of both FN and severe diarrhea in patients receiving the DCF regimen [ 10 ]. Similarly, Nakahara et al. [ 9 ] found that patients aged ≥ 65 years and those with pre-treatment dysphagia had significantly higher FN risk during DCF treatment. Based on these findings, they recommended primary prophylaxis with G-CSF for high-risk patients. Taken together, previous studies and our present findings suggest that markers of disease severity and nutritional compromise (such as significant dysphagia or cachexia) are associated with chemotherapy tolerance. Other indicators of poor nutritional status have also been linked to greater toxicity. Low pre-treatment skeletal muscle mass (sarcopenia) increased the odds of FN approximately 7-fold in esophageal cancer patients on the DCF regimen [ 16 ]. We observed that PNI tended to be higher in the FN than in the non-FN group, although the difference did not reach statistical significance ( p = 0.194). This finding, along with existing literature suggest that patients who are frail or malnourished (often presenting with weight loss, low muscle mass, or dysphagia) are more vulnerable to chemotherapy-induced neutropenia and its complications. Most notably, our multivariate analysis identified elevated baseline CRP level as the only independent risk factor for developing FN in this setting. Higher CRP level prior to treatment was associated with significantly higher risk for FN (OR: 1.790, 95% CI: 1.120–2.850, p = 0.014). In contrast, other variables comprising age, PNI, and dysphagia did not show significant independent association with FN in the adjusted model. CRP is an acute-phase reactant produced by the liver in response to pro-inflammatory cytokines such as IL-6, and is frequently elevated in patients with cancer, chronic inflammation, or infection [ 17 – 20 ]. Elevated CRP thus serves as a surrogate marker for underlying inflammatory state or ongoing infection [ 19 , 20 ]. Hashizume et al. [ 11 ] recently reported similar finding in esophageal cancer patients treated with a 5-FU plus platinum doublet (nedaplatin/5-FU). Patients with modified Glasgow prognostic scores (mGPS) 1–2, defined by elevated CRP and/or hypoalbuminemia, had more than four-fold higher odds of developing FN compared to those with mGPS 0. Their multivariate analysis identified mGPS and poor renal function as significant predictors of FN (incidence 12.7%), reinforcing the concept that systemic inflammation (reflected by CRP) and overall frailty may adversely affect bone marrow tolerance to chemotherapy [ 14 ]. It is noteworthy that baseline albumin and lymphocyte count (both components of PNI) in our cohort were not independent predictors of FN development, whereas CRP was. This suggests that the inflammatory burden indicated by CRP may be more directly relevant to FN risk than nutritional status alone. CRP has been associated with worse outcomes and chemotherapy tolerance in various cancers. For example, elevated CRP and IL-6 levels in patients receiving cytotoxic chemotherapy have been associated with increased toxicity and poorer survival [ 14 , 21 – 24 ]. Our findings add to this body of evidence by specifically linking pre-treatment CRP to neutropenia-related complications. Our ROC analysis identified a baseline CRP cut-off value of 0.68 mg/dL for predicting FN during the first cycle of FP + R therapy. Clinically, this threshold is only slightly above the upper limit of the reference range reported for healthy individuals (typically < 0.3 mg/dL) [ 17 , 25 ], suggesting that even low-grade systemic inflammation may significantly increase the susceptibility to developing FN. In oncology and immune-mediated diseases, chronic inflammatory states commonly manifest persistently elevated CRP levels usually in the range of 0.3–1.0 mg/dL, and levels above 1.0 mg/dL are sometimes used as a marker of elevated systemic inflammation and adverse outcomes [ 17 , 22 ]. In this context, a threshold of 0.68 mg/dL, although below 1.0 mg/dL, appears biologically plausible as an indicator of increased inflammatory tone that may impair bone marrow resilience and delay neutrophil recovery after cytotoxic therapy. From the clinical view point, this cut-off value provides a simple and actionable criterion to identify patients who may benefit from intensified supportive care (such as closer surveillance during the expected nadir or consideration of primary prophylaxis with G-CSF) even when receiving a regimen with overall intermediate risk of FN. Several hypotheses could explain why elevated CRP levels predispose patients to FN. One possibility is that elevated CRP levels indicate occult infection or tumor-related inflammation, which lowers the threshold for developing fever during neutropenia. Patients with esophageal cancer and dysphagia are at increased risk of aspiration pneumonia, which may cause subclinical increase in CRP level [ 26 , 27 ]. Once neutropenia develops following chemotherapy, these patients may be more prone to develop overt febrile infections. Another potential mechanism is the interplay between chronic inflammation and bone marrow function. CRP elevation reflects cytokine-driven inflammation. IL-6 and other inflammatory cytokines not only induce CRP production but can also promote the production and release of endogenous G-CSF and neutrophils as part of the acute phase response [ 28 – 32 ]. In patients with persistently high inflammatory tone before treatment, the bone marrow may be chronically stimulated by G-CSF to produce neutrophils. This state could paradoxically deplete the bone marrow reserve or blunt granulopoietic response when cytotoxic chemotherapy is administered. In other words, patients with high baseline CRP may already exhibit augmented neutrophil turnover and cytokine consumption, leading to slower neutrophil recovery and prolonged nadir after chemotherapy. This hypothesis is speculative but consistent with our observation that CRP emerged as a key risk factor for FN. Our results have important clinical implications for FN risk stratification and prophylaxis. FP + R therapy is currently considered a regimen with intermediate FN risk, as demonstrated by our observed incidence of approximately 12%, which is within the 10–20% range for intermediate risk. International guidelines (ASCO, EORTC, and NCCN) recommend primary prophylaxis with G-CSF for regimens with FN risk ≥ 20%, and advise a case-by-case approach for intermediate-risk regimens based on patient-specific risk factors [ 2 , 3 , 33 ]. Conventionally, factors such as age ≥ 65, comorbidities, poor performance status, and advanced disease have been used to identify patients at increased risk, who may benefit from G-CSF prophylaxis even when the regimen alone has a moderate risk [ 9 , 10 , 12 , 16 ]. Our findings suggest that elevated pre-treatment CRP levels should be considered an additional factor in risk assessment. In clinical practice, this suggests that esophageal cancer patients scheduled to receive FP + R, who have markedly high CRP levels (reflecting active systemic inflammation), may require closer monitoring and possibly primary G-CSF prophylaxis to mitigate FN risk. Currently, there is no consensus on G-CSF use in concurrent chemoradiotherapy for esophageal cancer. At our institution, prophylactic G-CSF was not routinely given during the first cycle of FP + R. However, our new findings suggest the need for a more individualized approach. Prophylactic strategies may include not only G-CSF, but also enhanced supportive care including prophylactic antibiotics and earlier follow-up during the neutropenic window for patients with high CRP. Several limitations of this study should be acknowledged. First, the sample size (especially the FN group, n = 14) was small, and the data were collected retrospectively from medical records of a single institution. This potentially limits statistical power and generalizability. Our multivariate model, while informative, should be interpreted with caution due to the relatively low event count; validation in a larger cohort is needed. Second, our study did not investigate other potential risk factors such as specific comorbidities (including diabetes and chronic infections) or other inflammatory markers (such as IL-6). We used CRP as a convenient surrogate marker, but further research could explore a panel of biomarkers to enhance risk prediction. Additionally, nearly all patients in our cohort had relatively good performance status (those with poor performance status or organ dysfunction probably did not receive this aggressive therapy), which may explain why performance status and comorbidities were not significant predictors. Despite these limitations, our study provides novel insight by identifying CRP as a measurable inflammatory biomarker for FN risk, thereby contributing to the existing evidence generated from similar chemoradiotherapy regimens. Conclusions The present study demonstrates that elevated baseline CRP level is an independent predictor of FN in esophageal cancer patients receiving FP + R therapy. This research highlights the importance of incorporating baseline inflammation status into FN risk assessment. Patients with elevated CRP levels before commencing FP + R therapy should be considered for enhanced supportive care such as primary prophylaxis with G-CSF, even though this regimen is generally classified as having intermediate risk for FN. Declarations Author contributions Study design: Ken Shiraiwa; data collection: Daiki Eto, Ken Shiraiwa; data analysis: Daiki Eto, Ken Shiraiwa, Takahiro Sumimoto, Ryota Tanaka; supervision: Ken Shiraiwa, Ryota Tanaka; writing – original draft: Daiki Eto, Ken Shiraiwa; writing – review and revision: Ryota Tanaka, Takahiro Sumimoto, Ryosuke Tatsuta, Hiroki Itoh; Approval: All authors. Funding None. Data availability The data sets generated during this study are available from the corresponding author on responsible request. Competing interests The authors declare no competing interests. Conflict of interest None. 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Wang Y, Wang K, Ni J, Zhang H, Yin L, Zhang Y, Shi H, Zhang T, Zhou N, Mao W, Peng B (2021) Combination of C-Reactive Protein and Neutrophil-to-Lymphocyte Ratio as a Novel Prognostic Index in Patients With Bladder Cancer After Radical Cystectomy. Front Oncol 11:762470. https://doi.org/10.3389/fonc.2021.762470. Han CL, Meng GX, Ding ZN, Dong ZR, Chen ZQ, Hong JG, Yan LJ, Liu H, Tian BW, Yang LS, Xue JS, Li T (2022) The Predictive Potential of the Baseline C-Reactive Protein Levels for the Efficiency of Immune Checkpoint Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis. Front Immunol 13:827788. https://doi.org/10.3389/fimmu.2022.827788. Wang Y, Hu X, Huang Y, Xu WY, Wu YM, Li PF, Che GW (2020) Prognostic value of the C-reactive protein to albumin ratio in esophageal cancer: A systematic review and meta-analysis. Kaohsiung J Med Sci 36(1):54-61. https://doi.org/10.1002/kjm2.12129. 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Bogeska R, Mikecin AM, Kaschutnig P, Fawaz M, Büchler-Schäff M, Le D, Ganuza M, Vollmer A, Paffenholz SV, Asada N, Rodriguez-Correa E, Frauhammer F, Buettner F, Ball M, Knoch J, Stäble S, Walter D, Petri A, Carreño-Gonzalez MJ, Wagner V, Brors B, Haas S, Lipka DB, Essers MAG, Weru V, Holland-Letz T, Mallm JP, Rippe K, Krämer S, Schlesner M, McKinney Freeman S, Florian MC, King KY, Frenette PS, Rieger MA, Milsom MD (2022) Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell 29(8):1273-1284.e8. https://doi.org/10.1016/j.stem.2022.06.012. Ho NP, Takizawa H (2022) Inflammation Regulates Haematopoietic Stem Cells and Their Niche. Int J Mol Sci 23(3):1125. https://doi.org/10.3390/ijms23031125. Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis M, Kearney N, Lyman GH, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C; European Organisation for Research and Treatment of Cancer (EORTC) Granulocyte Colony-Stimulating Factor (G-CSF) Guidelines Working Party (2006) EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 42(15):2433-2453. https://doi.org/10.1016/j.ejca.2006.05.002. Tables Table 1. Frequencies of hematological toxicity Grade 1 Grade 2 Grade 3 Grade 4 Leukopenia 15 (12.5%) 46 (38.3%) 52 (43.3%) 3 (2.5%) Neutropenia 20 (16.7%) 45 (37.5%) 33 (27.5%) 4 (3.3%) Anemia 49 (40.8%) 22 (18.3%) 5 (4.2%) 0 (0%) Thrombocytopenia 29 (24.2%) 14 (11.7%) 6 (5.0%) 2 (1.7%) Febrile Neutropenia - - 14 (11.7%) 0 (0%) Data are expressed as number of patients (%). Hematologic adverse events were graded according to the Common Toxicity Criteria for Adverse Effects (CTCAE) version 5.0. Table 2. Patient characteristics and baseline laboratory values for the non-FN group and FN group non-FN FN p- value Characteristics Age (years) 68 (62-73.5) 69 (64.5-76.5) 0.505 Sex (n) > 0.999 male 96 13 female 10 1 Stage (n) > 0.999 I, II 50 7 III, IV 56 7 Dysphagia (n) 0.044 present 53 11 absent 53 3 Therapeutic G-CSF use (n) < 0.010 yes 16 8 no 90 6 Performance Status (n) 0.465 0, 1 102 13 2, 3, 4 4 1 Total dose of 5-FU (mg/m 2 ) 2,740 (2,304-2,800) 2,752 (2,333-2,800) 0.992 Total dose of CDDP (mg/m 2 ) 66.1 (56.0-77.0) 68.7 (57.5-70.0) 0.464 Laboratory values White blood cell (/μL) 5,820 (4,560-7,220) 6,125 (4,417-6,935) 0.880 Neutrophil (/μL) 5,083 (4,409-5,757) 5,424 (4,830-5,930) 0.210 Lymphocyte (/μL) 2,254 (1,647-2,850) 2,038 (1,677-2,226) 0.298 Basophil (/μL) 49 (33-75) 33 (25-54) 0.098 Eosinophil (/μL) 224 (158-374) 204 (160-316) 0.714 Monocyte (/μL) 540 (449-653) 516 (460-566) 0.600 Platelet (×10 3 /μL) 227 (185-302) 222 (193-295) 0.854 Hemoglobin (g/dL) 12.6 (11.2-13.5) 12.8 (11.0-13.5) 0.860 AST (U/L) 21.3 (16.5-25.1) 18.0 (16.1-32.6) 0.860 ALT (U/L) 13.7 (10.6-21.5) 13.9 (10.8-18.1) 0.905 Total bilirubin (mg/dL) 0.6 (0.46-0.80) 0.66 (0.51-0.84) 0.797 Serum albumin (g/dL) 3.72 (3.39-4.03) 3.63 (3.29-3.81) 0.319 Serum creatinine (mg/dL) 0.83 (0.72-0.94) 0.76 (0.71-0.81) 0.066 eGFR (mL/min/1.73 m 2 ) 70.4 (59.5-79.9) 75.4 (72.6-78.2) 0.083 BUN (mg/dL) 13.3 (10.8-16.6) 11.1 (9.8-13.3) 0.063 CRP (mg/dL) 0.23 (0.07-0.96) 1.43 (0.26-4.00) 0.020 NLR 2.24 (1.56-3.55) 2.66 (2.01-3.75) 0.281 PLR 102.5 (74.3-177.8) 108.3 (76.9-188.8) 0.514 PNI 48.74 (43.81-54.10) 45.62 (43.23-50.65) 0.194 Data are expressed as numbers for categorical variables and median (interquartile range) for continuous variables. Categorical variables were analyzed using Fisher’s exact test, and continuous variables using Mann−Whitney U test. FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; 5-FU, 5-fluorouracil; CDDP, cisplatin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, standardized estimated glomerular filtration rate; BUN, blood urea nitrogen; CRP, C-reactive protein; NLR, neutrophil/lymphocyte ratio; PLR, platelet/lymphocyte ratio; PNI, prognostic nutritional index. Table 3. Multivariate analysis for factors associated with the development of febrile neutropenia Variables OR 95% CI p- value VIF CRP 1.790 1.120-2.850 0.014 1.496 Dysphagia (absent = 0, present =1) 2.890 0.694-12.100 0.145 1.037 PNI 1.020 0.918-1.130 0.713 1.501 Age 1.010 0.934-1.090 0.847 1.023 OR, odds ratio; 95% CI, 95% confidence interval; CRP, c-reactive protein; PNI, prognostic nutritional index, VIF; variance inflation factor. Additional Declarations No competing interests reported. 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Shiraiwa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIie3QoWsDMRTH8R8E7sxjOqFl+xcChcyM9l9542BqVZMVVzdT6L+yMZiaCJw4U5itmGhMVEVrxsm9joqJ5WjdGPlCICIfXhIgl/uDaaAAAwQof9gco5NIwWA+lRxPWfwYk87My7gJb+OhbVf7TejGsF6FHYYfSTIAXVuOFdnV9MUyV0KKkQbFJLm82haavSLnp6+aWdVPHk5u2aQJyiikJve+lQ3XMqX87CUDwAlpyK3vZRw3Qqh/ipnTgbQ0WceR5bsWpqEHzT1v0b6MpvOziVlWIXQ3M1y0j8+7/SL9Y7+kZN0u/Dnku+58ksvlcv+2L/WzToX8SMTFAAAAAElFTkSuQmCC","orcid":"","institution":"Oita University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Ken","middleName":"","lastName":"Shiraiwa","suffix":""},{"id":557581939,"identity":"dff6e5b2-0b79-4a64-8e98-f4f1f675ed8f","order_by":2,"name":"Ryota Tanaka","email":"","orcid":"","institution":"Oita University 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14:28:49","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":140166,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8027424/v1/cf2d598f426707817f267de6.html"},{"id":97990392,"identity":"b6dca98b-96f7-4cdb-a326-a03abbfd55e6","added_by":"auto","created_at":"2025-12-11 14:28:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65418,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curve of baseline C-reactive protein (CRP) level for predicting febrile neutropenia (FN). Area under the ROC curve (AUC) is 0.699 (95% confidence interval, 0.520–0.877; \u003cem\u003ep\u003c/em\u003e = 0.021). The optimal cut-off value determined by the Youden index is 0.68 mg/dL (sensitivity 61.54%, specificity 70.65%).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8027424/v1/0800d97fd008a0975341a9d3.png"},{"id":101796642,"identity":"783221f5-0237-45e0-9904-187cca1a3b2d","added_by":"auto","created_at":"2026-02-03 16:56:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":768543,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8027424/v1/542c1c70-456f-48d9-b6cb-879cc1c5062e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk factors associated with febrile neutropenia in patients with esophageal cancer receiving 5-fluorouracil plus cisplatin combination chemoradiotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAmong the diverse adverse events associated with cancer chemotherapy, febrile neutropenia (FN) represents a serious toxicity characterized by fever accompanied by neutropenia. FN is a critical complication not only causing treatment delay and dose reduction, but also potentially leading to life-threatening conditions such as septic shock [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. For chemotherapy regimens associated with high risk of FN (incidence\u0026thinsp;\u0026ge;\u0026thinsp;20%), international guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF), defined as administration of G-CSF concurrent with the initiation of chemotherapy for preventive purposes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. When the overall FN risk, including patient-specific factors, reaches 20% or higher, G-CSF prophylaxis is considered desirable, with advanced age and medical history recognized as risk-enhancing factors [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Indeed, guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) identify \"age\u0026thinsp;\u0026ge;\u0026thinsp;65 years\" as a significant risk factor for chemotherapy-induced FN development [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDocetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) combination therapy (DCF regimen), which has become the standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma in recent years, is associated with a high incidence of FN [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Nomura et al. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] reported a FN incidence of 20.3% during the first cycle of DCF therapy for esophageal cancer, with grade 3 or 4 neutropenia occurring in 56.3% of the patients. Their analysis identified \u0026ldquo;older age (\u0026ge;\u0026thinsp;60 years)\u0026rdquo; and \u0026ldquo;living alone\u0026rdquo; as independent risk factors for FN development, suggesting that primary G-CSF prophylaxis should be considered in patients with these risk factors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e5-FU plus CDDP concurrent with radiotherapy (FP\u0026thinsp;+\u0026thinsp;R therapy), which is used as definitive chemoradiotherapy (CRT) for esophageal cancer, has been widely adopted as a standard treatment for unresectable advanced esophageal cancer, based on the results of the JCOG9516 trial [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In the JCOG9516 phase II study, the response rate to FP\u0026thinsp;+\u0026thinsp;R therapy was 68.3% and the complete response rate was 15%; however, the primary toxicity was myelosuppression and treatment-related death [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although FP\u0026thinsp;+\u0026thinsp;R therapy represents one of the definitive treatment modalities for esophageal cancer, risk factors associated with FN development have not been thoroughly investigated, and there is currently no clear consensus regarding G-CSF prophylaxis in this setting.\u003c/p\u003e\u003cp\u003eGiven this background, the aim of the present retrospective study was to elucidate the risk factors for FN development during the first cycle of FP\u0026thinsp;+\u0026thinsp;R therapy in patients with esophageal cancer, which may provide insights for FN prevention and management strategies.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and subjects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was a retrospective, single-center, observational cohort study. The subjects were patients who received initial FP+R therapy for esophageal cancer at Oita University Hospital between April 2011 and June 2023. Patients were excluded if they had no serum C-reactive protein (CRP) measurement within 7 days before FP+R therapy, if they were receiving active treatments for any infectious disease at baseline (including antibacterial, antiviral, and antifungal agents), or if they were taking oral antibiotics for prophylactic purposes. This study was conducted after obtaining approval by the Ethics Committee of Oita University Faculty of Medicine (approval number: 1901). Because the study used existing clinical data and posed minimal risk, the requirement for individual informed consent was waived. In accordance with institutional policy, information about the research and the use of patient data was publicly announced on the hospital website giving opportunity for patients to opt out. Patients who expressed their refusal to participate were excluded. All data were de-identified before analysis, and the study adhered to the Declaration of Helsinki and relevant guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe FP+R regimen comprised chemotherapy of CDDP plus 5-FU with concurrent radiotherapy. The standard protocol at our institution consisted of CDDP at 70-80 mg/m\u0026sup2; administered intravenously on day 1, and 5-FU at 700-1000 mg/m\u0026sup2;/day administered as a continuous intravenous infusion for 4 days (days 1\u0026ndash;4). Concurrently, thoracic radiotherapy was initiated on day 1, delivering 2 Gy per fraction for a total planned dose of 60 Gy (2 Gy \u0026times; 30 fractions). Supportive care included antiemetic agents and adequate hydration. No patients received routine primary prophylaxis with G-CSF during the initial FP+R therapy. However, therapeutic G-CSF (secondary prophylaxis) was administered when FN or grade 4 neutropenia developed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome definition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were divided into non-FN and FN groups based on whether they developed FN after the initial FP+R therapy. Referring to the Japanese guidelines [7], FN patients were defined as those with \u0026ldquo;a neutrophil count below 500/\u0026mu;L, or a count below 1,000/\u0026mu;L with a predicted decline below 500/\u0026mu;L within 48 hours, accompanied by axillary temperature \u0026ge; 37.5\u0026deg;C\u0026rdquo;. Hematologic adverse events were graded according to the Common Toxicity Criteria for Adverse Effects (CTCAE) version 5.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal 5-FU and CDDP doses per body surface area (mg/m\u003csup\u003e2\u003c/sup\u003e), patient characteristics at baseline, clinical laboratory test values before initial FP+R therapy, and status of G-CSF use following FP+R therapy were extracted from the electronic medical records. Patient characteristics included age, sex (male or female), status of dysphagia, clinical stage, and Eastern Cooperative Oncology Group (ECOG) performance status (PS). Clinical laboratory test values included white blood cell count, neutrophil count, lymphocyte count, basophil count, eosinophil count, monocyte count, platelet count, hemoglobin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum albumin, standardized estimated glomerular filtration rate, blood urea nitrogen, and CRP. Moreover, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and prognostic nutritional index (PNI), which are known indicators for assessing the nutritional status and severity of cancer patients, were calculated. The calculation method for PNI is as follows: PNI = 10 \u0026times; albumin + 0.005 \u0026times; total lymphocyte count [8].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using SPSS version 30 (IBM Japan Ltd., Tokyo, Japan) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Data of baseline patient characteristics and clinical laboratory test values are expressed as numbers for categorical variables and median (interquartile range) for continuous variables. Categorical variables were analyzed using Fisher\u0026rsquo;s exact test. Continuous variables were analyzed using Mann\u0026minus;Whitney \u003cem\u003eU\u003c/em\u003e test. A \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003eMultiple logistic regression analysis\u0026nbsp;using the forced entry method was performed to identify risk factors independently associated with the development of FN. The four factors based on previous reports; age, CRP, PNI, and presence of dysphagia, were selected as independent variables [5, 9-15]. The independent variables entered into the model were checked for multicollinearity using a variance inflation factor (VIF) threshold of 10. Furthermore, since PNI is calculated using albumin and total lymphocyte count, and NLR and PLR also utilize lymphocyte count in the calculations, including these parameters simultaneously as independent variables is undesirable from the perspective of multicollinearity. Therefore, PNI, which showed a significant difference between the non-FN and FN groups and is a reliable nutritional indicator, was selected as the covariate.\u003c/p\u003e\n\u003cp\u003eAdditionally, we performed receiver operating characteristic (ROC) analysis to evaluate the performance of baseline CRP in predicting FN development. We calculated the area under the ROC curve (AUC) with 95% confidence intervals (CI) and determined the optimal cut-off value using the Youden index (maximizing sensitivity + specificity). The statistical significance of the AUC was assessed, and two-sided \u003cem\u003ep\u003c/em\u003e-values \u0026lt; 0.05 were considered significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eIncidence of hematologic toxicity in initial FP+R therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe frequencies of hematologic adverse events during the initial course of FP+R therapy in 120 patients are shown in Table 1. Grade 3 or higher neutropenia (severe neutropenia) was observed in 30.8% (37/120) of patients overall, and grade 4 neutropenia (neutrophil count \u0026lt; 500/\u0026mu;L) in 3.3% (4/120). Furthermore, FN developed in 14 patients, with an incidence of 11.7%. Grade 3 or higher leukopenia was observed in 45.8% (55/120). Severe anemia (grade 3 or higher; hemoglobin 8 g/dL or lower) occurred in 4.2% (5/120), and severe thrombocytopenia (grade 3 or higher) in 6.7% (8/120). In summary, this cohort showed a high frequency of bone marrow suppression, particularly neutropenia. Although the incidence of FN was less than 20% (the high-risk threshold), it remained relatively high compared to the JCOG9516 trial [6].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUnivariate comparison between non-FN and FN groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics were compared between 106 patients who did not develop FN (non-FN group) and 14 patients who developed FN (FN group) during the first treatment cycle (Table 2). The median age was comparable between two groups (68 years in the non-FN group vs. 69 years in the FN group, \u003cem\u003ep\u003c/em\u003e = 0.505). No significant differences were observed in sex distribution (male: 90.6% vs. 92.9%, \u003cem\u003ep\u003c/em\u003e \u0026gt; 0.999), clinical stage (stage III/IV: 52.8% vs. 50.0%, \u003cem\u003ep\u003c/em\u003e \u0026gt; 0.999), and ECOG performance status (PS \u0026ge; 2: 3.8% vs. 7.1%, \u003cem\u003ep\u003c/em\u003e = 0.465). However, dysphagia was significantly more frequently found in the FN group than in the non-FN group (50.0% vs. 78.6%, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.044). Thus, dysphagia showed a significant association with FN development in univariate analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComparison of baseline laboratory parameters revealed a significant difference in CRP level between the two groups (median: 0.23 in non-FN group vs. 1.43 mg/dL in FN group, \u003cem\u003ep\u003c/em\u003e = 0.020). Elevated CRP levels at baseline were more frequently observed in the FN group. No significant differences in other hematological or biochemical parameters were detected between the two groups. PNI indicated a tendency of poorer nutritional status in the FN group (45.62) compared to the non-FN group (48.74), but this difference was not statistically significant (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.194).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultivariate analysis of risk factors for FN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultiple logistic regression analysis with the development of FN as the dependent variable and CRP, dysphagia, PNI and age as independent variables identified baseline CRP level as an independent factor associated with FN development (Table 3). Elevated baseline CRP level was significantly associated with increased FN risk [odds ratio (OR): 1.790, 95% CI: 1.120\u0026ndash;2.850, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.014], indicating that higher CRP levels was associated with greater FN susceptibility. Although the presence of dysphagia showed a trend toward increased FN risk in multivariate analysis (OR: 2.890, 95% CI: 0.694\u0026ndash;12.100), this association did not reach statistical significance (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.145). Age and PNI were not identified as independent predictors in the final model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline CRP cut-off value for predicting FN risk\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eROC analysis was performed to examine the cut-off baseline CRP level in predicting FN (Figure 1). The AUC was 0.699 (95% CI, 0.520\u0026ndash;0.877), indicating a statistically significant ability to discriminate patients who developed FN from those who did not (\u003cem\u003ep\u003c/em\u003e = 0.021). The optimal cut-off value identified by the Youden index was 0.68 mg/dL, which yielded a sensitivity of 61.54% and a specificity of 70.65%.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective study of 120 esophageal cancer patients receiving initial FP\u0026thinsp;+\u0026thinsp;R chemoradiotherapy, we observed a considerably high incidence of myelosuppression. Severe neutropenia (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) occurred in 30.8% of patients, and 14 patients (11.7%) developed FN during the first treatment cycle. Although the FN incidence was below the 20% high-risk threshold, it still represents a clinically significant risk. This FN incidence was higher than the reported hematologic toxicity rate of 0% for a 5-FU plus CDDP regimen combined with radiation therapy in the JCOG9516 trial [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Notably, the median age of our cohort was higher (around 69 years) than that in the JCOG9516 trial (62 years), which may have contributed to higher susceptibility to neutropenic toxicity. Older age (particularly\u0026thinsp;\u0026ge;\u0026thinsp;65) is a well-established risk factor for FN in clinical practice guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and the inclusion of older, real-world patients in our study likely explains the higher rates of severe neutropenia and FN compared to clinical trial populations. These results demonstrate that even with modern supportive care, concurrent FP\u0026thinsp;+\u0026thinsp;R therapy carries an intermediate (approximately 10\u0026ndash;12%) risk of FN in real-world clinical practice.\u003c/p\u003e\u003cp\u003eIn univariate analysis, dysphagia was significantly more frequently found in patients who developed FN (78.6% with FN vs. 50.0% without FN, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044). This suggests that patients with swallowing difficulty, often indicative of advanced locoregional disease and poor oral intake, were more vulnerable to develop FN. This observation supports the findings of previous studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Hagi et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] reported that esophageal cancer patients with high dysphagia scores (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) had a dramatically higher incidence of FN during DCF chemotherapy compared to those with lower scores (79.3% vs 35.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Their logistic regression analysis confirmed baseline dysphagia as an independent predictor of both FN and severe diarrhea in patients receiving the DCF regimen [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Similarly, Nakahara et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] found that patients aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years and those with pre-treatment dysphagia had significantly higher FN risk during DCF treatment. Based on these findings, they recommended primary prophylaxis with G-CSF for high-risk patients. Taken together, previous studies and our present findings suggest that markers of disease severity and nutritional compromise (such as significant dysphagia or cachexia) are associated with chemotherapy tolerance. Other indicators of poor nutritional status have also been linked to greater toxicity. Low pre-treatment skeletal muscle mass (sarcopenia) increased the odds of FN approximately 7-fold in esophageal cancer patients on the DCF regimen [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We observed that PNI tended to be higher in the FN than in the non-FN group, although the difference did not reach statistical significance (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.194). This finding, along with existing literature suggest that patients who are frail or malnourished (often presenting with weight loss, low muscle mass, or dysphagia) are more vulnerable to chemotherapy-induced neutropenia and its complications.\u003c/p\u003e\u003cp\u003eMost notably, our multivariate analysis identified elevated baseline CRP level as the only independent risk factor for developing FN in this setting. Higher CRP level prior to treatment was associated with significantly higher risk for FN (OR: 1.790, 95% CI: 1.120\u0026ndash;2.850, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014). In contrast, other variables comprising age, PNI, and dysphagia did not show significant independent association with FN in the adjusted model. CRP is an acute-phase reactant produced by the liver in response to pro-inflammatory cytokines such as IL-6, and is frequently elevated in patients with cancer, chronic inflammation, or infection [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Elevated CRP thus serves as a surrogate marker for underlying inflammatory state or ongoing infection [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Hashizume et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] recently reported similar finding in esophageal cancer patients treated with a 5-FU plus platinum doublet (nedaplatin/5-FU). Patients with modified Glasgow prognostic scores (mGPS) 1\u0026ndash;2, defined by elevated CRP and/or hypoalbuminemia, had more than four-fold higher odds of developing FN compared to those with mGPS 0. Their multivariate analysis identified mGPS and poor renal function as significant predictors of FN (incidence 12.7%), reinforcing the concept that systemic inflammation (reflected by CRP) and overall frailty may adversely affect bone marrow tolerance to chemotherapy [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt is noteworthy that baseline albumin and lymphocyte count (both components of PNI) in our cohort were not independent predictors of FN development, whereas CRP was. This suggests that the inflammatory burden indicated by CRP may be more directly relevant to FN risk than nutritional status alone. CRP has been associated with worse outcomes and chemotherapy tolerance in various cancers. For example, elevated CRP and IL-6 levels in patients receiving cytotoxic chemotherapy have been associated with increased toxicity and poorer survival [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our findings add to this body of evidence by specifically linking pre-treatment CRP to neutropenia-related complications.\u003c/p\u003e\u003cp\u003eOur ROC analysis identified a baseline CRP cut-off value of 0.68 mg/dL for predicting FN during the first cycle of FP\u0026thinsp;+\u0026thinsp;R therapy. Clinically, this threshold is only slightly above the upper limit of the reference range reported for healthy individuals (typically\u0026thinsp;\u0026lt;\u0026thinsp;0.3 mg/dL) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], suggesting that even low-grade systemic inflammation may significantly increase the susceptibility to developing FN. In oncology and immune-mediated diseases, chronic inflammatory states commonly manifest persistently elevated CRP levels usually in the range of 0.3\u0026ndash;1.0 mg/dL, and levels above 1.0 mg/dL are sometimes used as a marker of elevated systemic inflammation and adverse outcomes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this context, a threshold of 0.68 mg/dL, although below 1.0 mg/dL, appears biologically plausible as an indicator of increased inflammatory tone that may impair bone marrow resilience and delay neutrophil recovery after cytotoxic therapy. From the clinical view point, this cut-off value provides a simple and actionable criterion to identify patients who may benefit from intensified supportive care (such as closer surveillance during the expected nadir or consideration of primary prophylaxis with G-CSF) even when receiving a regimen with overall intermediate risk of FN.\u003c/p\u003e\u003cp\u003eSeveral hypotheses could explain why elevated CRP levels predispose patients to FN. One possibility is that elevated CRP levels indicate occult infection or tumor-related inflammation, which lowers the threshold for developing fever during neutropenia. Patients with esophageal cancer and dysphagia are at increased risk of aspiration pneumonia, which may cause subclinical increase in CRP level [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Once neutropenia develops following chemotherapy, these patients may be more prone to develop overt febrile infections. Another potential mechanism is the interplay between chronic inflammation and bone marrow function. CRP elevation reflects cytokine-driven inflammation. IL-6 and other inflammatory cytokines not only induce CRP production but can also promote the production and release of endogenous G-CSF and neutrophils as part of the acute phase response [\u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In patients with persistently high inflammatory tone before treatment, the bone marrow may be chronically stimulated by G-CSF to produce neutrophils. This state could paradoxically deplete the bone marrow reserve or blunt granulopoietic response when cytotoxic chemotherapy is administered. In other words, patients with high baseline CRP may already exhibit augmented neutrophil turnover and cytokine consumption, leading to slower neutrophil recovery and prolonged nadir after chemotherapy. This hypothesis is speculative but consistent with our observation that CRP emerged as a key risk factor for FN.\u003c/p\u003e\u003cp\u003eOur results have important clinical implications for FN risk stratification and prophylaxis. FP\u0026thinsp;+\u0026thinsp;R therapy is currently considered a regimen with intermediate FN risk, as demonstrated by our observed incidence of approximately 12%, which is within the 10\u0026ndash;20% range for intermediate risk. International guidelines (ASCO, EORTC, and NCCN) recommend primary prophylaxis with G-CSF for regimens with FN risk\u0026thinsp;\u0026ge;\u0026thinsp;20%, and advise a case-by-case approach for intermediate-risk regimens based on patient-specific risk factors [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Conventionally, factors such as age\u0026thinsp;\u0026ge;\u0026thinsp;65, comorbidities, poor performance status, and advanced disease have been used to identify patients at increased risk, who may benefit from G-CSF prophylaxis even when the regimen alone has a moderate risk [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Our findings suggest that elevated pre-treatment CRP levels should be considered an additional factor in risk assessment. In clinical practice, this suggests that esophageal cancer patients scheduled to receive FP\u0026thinsp;+\u0026thinsp;R, who have markedly high CRP levels (reflecting active systemic inflammation), may require closer monitoring and possibly primary G-CSF prophylaxis to mitigate FN risk. Currently, there is no consensus on G-CSF use in concurrent chemoradiotherapy for esophageal cancer. At our institution, prophylactic G-CSF was not routinely given during the first cycle of FP\u0026thinsp;+\u0026thinsp;R. However, our new findings suggest the need for a more individualized approach. Prophylactic strategies may include not only G-CSF, but also enhanced supportive care including prophylactic antibiotics and earlier follow-up during the neutropenic window for patients with high CRP.\u003c/p\u003e\u003cp\u003eSeveral limitations of this study should be acknowledged. First, the sample size (especially the FN group, n\u0026thinsp;=\u0026thinsp;14) was small, and the data were collected retrospectively from medical records of a single institution. This potentially limits statistical power and generalizability. Our multivariate model, while informative, should be interpreted with caution due to the relatively low event count; validation in a larger cohort is needed. Second, our study did not investigate other potential risk factors such as specific comorbidities (including diabetes and chronic infections) or other inflammatory markers (such as IL-6). We used CRP as a convenient surrogate marker, but further research could explore a panel of biomarkers to enhance risk prediction. Additionally, nearly all patients in our cohort had relatively good performance status (those with poor performance status or organ dysfunction probably did not receive this aggressive therapy), which may explain why performance status and comorbidities were not significant predictors. Despite these limitations, our study provides novel insight by identifying CRP as a measurable inflammatory biomarker for FN risk, thereby contributing to the existing evidence generated from similar chemoradiotherapy regimens.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe present study demonstrates that elevated baseline CRP level is an independent predictor of FN in esophageal cancer patients receiving FP\u0026thinsp;+\u0026thinsp;R therapy. This research highlights the importance of incorporating baseline inflammation status into FN risk assessment. Patients with elevated CRP levels before commencing FP\u0026thinsp;+\u0026thinsp;R therapy should be considered for enhanced supportive care such as primary prophylaxis with G-CSF, even though this regimen is generally classified as having intermediate risk for FN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy design: Ken Shiraiwa; data collection: Daiki Eto, Ken Shiraiwa; data analysis: Daiki Eto, Ken Shiraiwa, Takahiro Sumimoto, Ryota Tanaka; supervision: Ken Shiraiwa, Ryota Tanaka; writing \u0026ndash; original draft: Daiki Eto, Ken Shiraiwa; writing \u0026ndash; review and revision: Ryota Tanaka, Takahiro Sumimoto, Ryosuke Tatsuta, Hiroki Itoh; Approval: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets generated during this study are available from the corresponding author on responsible request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study involving human participants was conducted in accordance with the ethical standards of the institutional and national research committee, and adhered to the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The clinical study protocol was approved by the Ethics Committee of Oita University Faculty of Medicine (approval number: 1901). Because the study used existing clinical data and posed minimal risk, the requirement for individual informed consent was waived.\u003c/p\u003e"},{"header":"References","content":"\u003col class=\"decimal_type\"\u003e\n\u003cli\u003eJoudeh N, Sawafta E, Abu Taha A, Hamed Allah M, Amer R, Odeh RY, Salameh H, Sabateen A, Aiesh BM, Zyoud SH (2023) Epidemiology and source of infection in cancer patients with febrile neutropenia: an experience from a developing country. BMC Infect Dis 23(1):106. https://doi.org/10.1186/s12879-023-08058-6.\u003c/li\u003e\n\u003cli\u003eSmith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO; American Society of Clinical Oncology (2015) Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 33(28):3199-212. https://doi.org/10.1200/JCO.2015.62.3488.\u003c/li\u003e\n\u003cli\u003eGriffiths EA, Roy V, Alwan L, Bachiashvili K, Baird J, Cool R, Dinner S, Geyer M, Glaspy J, Gojo I, Hicks A, Kallam A, Kidwai WZ, Kloth DD, Kraut EH, Landsburg D, Lyman GH, Mahajan A, Miller R, Nachar V, Patel S, Patel S, Perez LE, Poust A, Riaz F, Rosovsky R, Rugo HS, Simon S, Vasu S, Wadleigh M, Westbrook K, Westervelt P, Berardi RA, Pluchino L (2022) NCCN Guidelines\u0026reg; Insights: Hematopoietic Growth Factors, Version 1.2022. J Natl Compr Canc Netw 20(5):436-442. https://doi.org/10.6004/jnccn.2022.0026.\u003c/li\u003e\n\u003cli\u003eOhkura Y, Ueno M, Udagawa H (2019) Risk factors for febrile neutropenia and effectiveness of primary prophylaxis with pegfilgrastim in patients with esophageal cancer treated with docetaxel, cisplatin, and 5-fluorouracil. World J Surg Oncol 17(1):125. https://doi.org/10.1186/s12957-019-1665-x.\u003c/li\u003e\n\u003cli\u003eNomura H, Hatogai K, Maki Y, Mochizuki N, Tanaka M, Saito S, Daiko H, Kojima T, Kawasaki T (2020) Risk factors for febrile neutropenia in neoadjuvant docetaxel, cisplatin, and 5-fluorouracil chemotherapy for esophageal cancer. Support Care Cancer 28(4):1849-1854. https://doi.org/10.1007/s00520-019-05001-x.\u003c/li\u003e\n\u003cli\u003eIshida K, Ando N, Yamamoto S, Ide H, Shinoda M (2004) Phase II study of cisplatin and 5-fluorouracil with concurrent radiotherapy in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG)/Japan Clinical Oncology Group trial (JCOG9516). Jpn J Clin Oncol 34(10):615-619. https://doi.org/10.1093/jjco/hyh107.\u003c/li\u003e\n\u003cli\u003eJapanese Society of Medical Oncology (JSMO) (2023) Guidelines for the management of febrile neutropenia (3rd edition). Nankodo, Tokyo.\u003c/li\u003e\n\u003cli\u003eWei J, Lu J, Jia H, Yang X, Guo X, Liu J, Li X (2023) Value of a preoperative prognostic nutritional index for the prognostic evaluation of gastric neuroendocrine carcinoma patients. Front Nutr 10:1043550. https://doi.org/10.3389/fnut.2023.1043550.\u003c/li\u003e\n\u003cli\u003eNakahara Y, Yamasaki M, Makino T, Miyazaki Y, Takahashi T, Kurokawa Y, Nakajima K, Takiguchi S, Mori M, Doki Y (2015) Factors Associated with Febrile Neutropenia Caused by Combined Chemotherapy with Docetaxel, Cisplatin and 5-FU for Esophageal Cancer. Journal of Japan Surgical Association 76(8):1819-1824. https://doi.org/10.3919/jjsa.76.1819.\u003c/li\u003e\n\u003cli\u003eHagi T, Makino T, Yamasaki M, Tanaka K, Nishida N, Sakai D, Motoori M, Kimura Y, Satoh T, Mori M, Doki Y (2019) Dysphagia Score as a Predictor of Adverse Events Due to Triplet Chemotherapy and Oncological Outcomes in 434 Consecutive Patients with Esophageal Cancer. Ann Surg Oncol 26(13):4754-4764. https://doi.org/10.1245/s10434-019-07744-7.\u003c/li\u003e\n\u003cli\u003eHashizume J, Nambu M, Nakagawa H, Harasawa H, Kodama Y (2023) Poor Renal Function and a High Modified Glasgow Prognostic Score Are Predictive Factors for Nedaplatin/5-Fluorouracil Combination Therapy-induced Febrile Neutropenia. Anticancer Res 43(5):2309-2316. https://doi.org/10.21873/anticanres.16395.\u003c/li\u003e\n\u003cli\u003eLyman GH, Abella E, Pettengell R (2013) Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 90(3):190-199. https://doi.org/10.1016/j.critrevonc.2013.12.006.\u003c/li\u003e\n\u003cli\u003eBa Y, Shi Y, Jiang W, Feng J, Cheng Y, Xiao L, Zhang Q, Qiu W, Xu B, Xu R, Shen B, Luo Z, Xie X, Chang J, Wang M, Li Y, Shuang Y, Niu Z, Liu B, Zhang J, Zhang L, Yao H, Xie C, Huang H, Liao W, Chen G, Zhang X, An H, Deng Y, Gong P, Xiong J, Yao Q, An X, Chen C, Shi Y, Wang J, Wang X, Wang Z, Xing P, Yang S, Zhou C (2020) Current management of chemotherapy-induced neutropenia in adults: key points and new challenges: Committee of Neoplastic Supportive-Care (CONS), China Anti-Cancer Association Committee of Clinical Chemotherapy, China Anti-Cancer Association. Cancer Biol Med 17(4):896-909. https://doi.org/10.20892/j.issn.2095-3941.2020.0069.\u003c/li\u003e\n\u003cli\u003eKauffmann-Guerrero D, Kahnert K, Syunyaeva Z, Tufman A, Huber RM (2018) Pretherapeutic Inflammation Predicts Febrile Neutropenia and Reduced Progression-Free Survival after First-Line Chemotherapy in SCLC. Oncol Res Treat 41(9):506-512. https://doi.org//10.1159/000488688.\u003c/li\u003e\n\u003cli\u003eXiao AT, Tong YX, Xu XS, Zhou Y, Zhang S (2020) Preoperative Nutritional Status Contributes to the Development of Neutropenia Event in Patients With Gastric Cancer Receiving CAPEOX Adjuvant Chemotherapy. Front Oncol 10:692. https://doi.org/10.3389/fonc.2020.00692.\u003c/li\u003e\n\u003cli\u003eNara K, Yamamoto T, Sato Y, Yagi K, Kawasaki K, Toriumi T, Takada T, Seto Y, Suzuki H (2023) Low pretherapy skeletal muscle mass index is associated with an increased risk of febrile neutropenia in patients with esophageal cancer receiving docetaxel + cisplatin + 5-fluorouracil (DCF) therapy. Support Care Cancer 31(2):150. https://doi.org/10.1007/s00520-023-07609-6.\u003c/li\u003e\n\u003cli\u003ePotempa LA, Rajab IM, Olson ME, Hart PC (2021) C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms. Front Immunol 12:744129. https://doi.org/10.3389/fimmu.2021.744129.\u003c/li\u003e\n\u003cli\u003eAli SB, Cecchin A, Lucchesi C, Putty T, Edwards S, Petrou T, Coates P, Ferrante A, Pucar PA, King J, Banovic T (2023) Can C-reactive protein be used as a surrogate marker of IL-6 in a broad array of clinical entities? Biomark Med 17(24):1001-1010. https://doi.org/10.2217/bmm-2023-0708.\u003c/li\u003e\n\u003cli\u003eZhou HH, Tang YL, Xu TH, Cheng B (2024) C-reactive protein: structure, function, regulation, and role in clinical diseases. Front Immunol 15:1425168. https://doi.org/10.3389/fimmu.2024.1425168.\u003c/li\u003e\n\u003cli\u003eWu CW, Wu JY, Chen CK, Huang SL, Hsu SC, Lee MT, Chang SS, Lee CC (2015) Does procalcitonin, C-reactive protein, or interleukin-6 test have a role in the diagnosis of severe infection in patients with febrile neutropenia? A systematic review and meta-analysis. Support Care Cancer 23(10):2863-2872. https://doi.org/10.1007/s00520-015-2650-8.\u003c/li\u003e\n\u003cli\u003eWang Y, Wang K, Ni J, Zhang H, Yin L, Zhang Y, Shi H, Zhang T, Zhou N, Mao W, Peng B (2021) Combination of C-Reactive Protein and Neutrophil-to-Lymphocyte Ratio as a Novel Prognostic Index in Patients With Bladder Cancer After Radical Cystectomy. Front Oncol 11:762470. https://doi.org/10.3389/fonc.2021.762470.\u003c/li\u003e\n\u003cli\u003eHan CL, Meng GX, Ding ZN, Dong ZR, Chen ZQ, Hong JG, Yan LJ, Liu H, Tian BW, Yang LS, Xue JS, Li T (2022) The Predictive Potential of the Baseline C-Reactive Protein Levels for the Efficiency of Immune Checkpoint Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis. Front Immunol 13:827788. https://doi.org/10.3389/fimmu.2022.827788.\u003c/li\u003e\n\u003cli\u003eWang Y, Hu X, Huang Y, Xu WY, Wu YM, Li PF, Che GW (2020) Prognostic value of the C-reactive protein to albumin ratio in esophageal cancer: A systematic review and meta-analysis. Kaohsiung J Med Sci 36(1):54-61. https://doi.org/10.1002/kjm2.12129.\u003c/li\u003e\n\u003cli\u003eAllin KH, Nordestgaard BG (2011) Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci 48(4):155-170. https://doi.org/10.3109/10408363.2011.599831.\u003c/li\u003e\n\u003cli\u003ePepys MB, Hirschfield GM (2003) C-reactive protein: a critical update. J Clin Invest 111(12):1805-1812. https://doi.org/10.1172/JCI18921.\u003c/li\u003e\n\u003cli\u003eSimpson AJ, Allen JL, Chatwin M, Crawford H, Elverson J, Ewan V, Forton J, McMullan R, Plevris J, Renton K, Tedd H, Thomas R, Legg J (2023) BTS clinical statement on aspiration pneumonia. Thorax 78(Suppl 1):s3-s21. https://doi.org/10.1136/thorax-2022-219699.\u003c/li\u003e\n\u003cli\u003eLiu MY, Wang CH, Lee SH, Chang WC, Wu CE, Liu HE (2024) Effectiveness of a Protocol Intervention for Aspiration Pneumonia Prevention in Patients With Esophageal Cancer During Concurrent Chemoradiotherapy: A Randomized Control Trial. Cancer Nurs 47(4):327-335. https://doi.org/10.1097/NCC.0000000000001205.\u003c/li\u003e\n\u003cli\u003eFlorentin J, Zhao J, Tai YY, Vasamsetti SB, O\u0026apos;Neil SP, Kumar R, Arunkumar A, Watson A, Sembrat J, Bullock GC, Sanders L, Kassa B, Rojas M, Graham BB, Chan SY, Dutta P (2021) Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension. Cell Mol Immunol 18(2):374-384. https://doi.org/10.1038/s41423-020-00608-1.\u003c/li\u003e\n\u003cli\u003eCain DW, Snowden PB, Sempowski GD, Kelsoe G (2011) Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism. PLoS One 6(5):e19957. https://doi.org/10.1371/journal.pone.0019957.\u003c/li\u003e\n\u003cli\u003eCaiado F, Pietras EM, Manz MG (2021) Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. J Exp Med 218(7):e20201541. https://doi.org/10.1084/jem.20201541.\u003c/li\u003e\n\u003cli\u003eBogeska R, Mikecin AM, Kaschutnig P, Fawaz M, B\u0026uuml;chler-Sch\u0026auml;ff M, Le D, Ganuza M, Vollmer A, Paffenholz SV, Asada N, Rodriguez-Correa E, Frauhammer F, Buettner F, Ball M, Knoch J, St\u0026auml;ble S, Walter D, Petri A, Carre\u0026ntilde;o-Gonzalez MJ, Wagner V, Brors B, Haas S, Lipka DB, Essers MAG, Weru V, Holland-Letz T, Mallm JP, Rippe K, Kr\u0026auml;mer S, Schlesner M, McKinney Freeman S, Florian MC, King KY, Frenette PS, Rieger MA, Milsom MD (2022) Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell 29(8):1273-1284.e8. https://doi.org/10.1016/j.stem.2022.06.012.\u003c/li\u003e\n\u003cli\u003eHo NP, Takizawa H (2022) Inflammation Regulates Haematopoietic Stem Cells and Their Niche. Int J Mol Sci 23(3):1125. https://doi.org/10.3390/ijms23031125.\u003c/li\u003e\n\u003cli\u003eAapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis M, Kearney N, Lyman GH, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C; European Organisation for Research and Treatment of Cancer (EORTC) Granulocyte Colony-Stimulating Factor (G-CSF) Guidelines Working Party (2006) EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer 42(15):2433-2453. https://doi.org/10.1016/j.ejca.2006.05.002.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eFrequencies of hematological toxicity\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"707\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eGrade 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eLeukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e15 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e46 (38.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e52 (43.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e3 (2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e20 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e45 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e33 (27.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e4 (3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e49 (40.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e22 (18.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e5 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e29 (24.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e14 (11.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e6 (5.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e2 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003eFebrile Neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e14 (11.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed as number of patients (%). Hematologic adverse events were graded according to the Common Toxicity Criteria for Adverse Effects (CTCAE) version 5.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Patient characteristics and baseline laboratory values for the non-FN group and FN group\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"650\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003enon-FN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003eFN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e68 (62-73.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e69 (64.5-76.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.505\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eSex (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e\u0026gt; 0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eStage\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e\u0026gt; 0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003eI, II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003eIII, IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eDysphagia (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.044\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003epresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003eabsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eTherapeutic G-CSF use (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003ePerformance Status\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.465\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e0, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e2, 3, 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003cu\u003eTotal dose of 5-FU (mg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e2,740 (2,304-2,800)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e2,752 (2,333-2,800)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.992 \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003e \u003cu\u003eTotal dose of CDDP (mg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e66.1 (56.0-77.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e68.7 (57.5-70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.464 \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eLaboratory values\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eWhite blood cell (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e5,820 (4,560-7,220)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e6,125 (4,417-6,935)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eNeutrophil (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e5,083 (4,409-5,757)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e5,424 (4,830-5,930)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.210\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eLymphocyte (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e2,254 (1,647-2,850)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e2,038 (1,677-2,226)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.298\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eBasophil (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e49 (33-75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e33 (25-54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.098\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eEosinophil (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e224 (158-374)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e204 (160-316)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.714\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eMonocyte (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e540 (449-653)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e516 (460-566)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.600\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003ePlatelet (\u0026times;10\u003csup\u003e3\u003c/sup\u003e/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e227 (185-302)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e222 (193-295)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.854\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e12.6 (11.2-13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e12.8 (11.0-13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.860\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eAST (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e21.3 (16.5-25.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e18.0 (16.1-32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.860\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eALT (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e13.7 (10.6-21.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e13.9 (10.8-18.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.905\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eTotal bilirubin (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e0.6 (0.46-0.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e0.66 (0.51-0.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.797\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e3.72 (3.39-4.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e3.63 (3.29-3.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.319\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eSerum creatinine (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e0.83 (0.72-0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e0.76 (0.71-0.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e70.4 (59.5-79.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e75.4 (72.6-78.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eBUN (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e13.3 (10.8-16.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e11.1 (9.8-13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eCRP (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e0.23 (0.07-0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e1.43 (0.26-4.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.020\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003eNLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e2.24 (1.56-3.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e2.66 (2.01-3.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.281\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003ePLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e102.5 (74.3-177.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e108.3 (76.9-188.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.514\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 36.3077%;\"\u003e\n \u003cp\u003ePNI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.76923%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.3846%;\"\u003e\n \u003cp\u003e48.74 (43.81-54.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.7692%;\"\u003e\n \u003cp\u003e45.62 (43.23-50.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.7692%;\"\u003e\n \u003cp\u003e0.194\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed as numbers for categorical variables and median (interquartile range) for continuous variables. Categorical variables were analyzed using Fisher\u0026rsquo;s exact test, and continuous variables using Mann\u0026minus;Whitney \u003cem\u003eU\u003c/em\u003e test. FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; 5-FU, 5-fluorouracil; CDDP, cisplatin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, standardized estimated glomerular filtration rate; BUN, blood urea nitrogen; CRP, C-reactive protein; NLR, neutrophil/lymphocyte ratio; PLR, platelet/lymphocyte ratio; PNI, prognostic nutritional index.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Multivariate analysis for factors associated with the development of febrile neutropenia\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"650\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 26.0401%;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003eVIF\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 26.0401%;\"\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.790\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.120-2.850\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.496\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 26.0401%;\"\u003e\n \u003cp\u003eDysphagia\u003cbr\u003e\u0026nbsp;(absent = 0, present =1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e2.890\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e0.694-12.100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.037\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 26.0401%;\"\u003e\n \u003cp\u003ePNI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e0.918-1.130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e0.713\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.501\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 26.0401%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e0.934-1.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e0.847\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.49%;\"\u003e\n \u003cp\u003e1.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOR, odds ratio; 95% CI, 95% confidence interval; CRP, c-reactive protein; PNI, prognostic nutritional index, VIF; variance inflation factor.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Febrile neutropenia, risk factor, 5-fluorouracil plus cisplatin concurrent radiotherapy, esophageal cancer, C-reactive protein, primary granulocyte colony-stimulating factor prophylaxis","lastPublishedDoi":"10.21203/rs.3.rs-8027424/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8027424/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo identify risk factors for febrile neutropenia (FN) in patients with esophageal cancer receiving the first cycle of definitive chemoradiotherapy with 5-fluorouracil plus cisplatin and concurrent radiotherapy (FP\u0026thinsp;+\u0026thinsp;R therapy).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective single-center cohort study of patients who started FP\u0026thinsp;+\u0026thinsp;R at Oita University Hospital between April 2011 and June 2023. The primary outcome was FN onset in cycle 1. Univariate tests and multivariable logistic regression [forced entry: age, C-reactive protein (CRP), prognostic nutritional index (PNI), dysphagia) were used to evaluate association with FN development. Receiver operating characteristic (ROC) analysis was conducted to evaluate the predictive performance of baseline CRP for FN.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 120 patients studied, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia occurred in 37 (30.8%) and FN in 14 (11.7%) during the first cycle. In multivariable analysis, higher baseline CRP was independently associated with increased FN risk [odds ratio (OR) 1.790; 95% confidence interval (CI) 1.120\u0026ndash;2.850; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014), whereas dysphagia showed a non-significant association (OR 2.890; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.145). Age and PNI were not independent predictors. ROC analysis for baseline CRP yielded area under the ROC curve of 0.699 (95% CI 0.520\u0026ndash;0.877; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) with optimal cut-off value of 0.68 mg/dL (sensitivity 61.54%; specificity 70.65%).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eBaseline systemic inflammation, indicated by elevated CRP, is an independent risk factor for FN development during FP\u0026thinsp;+\u0026thinsp;R therapy. Despite the regimen having an intermediate FN risk, patients with elevated pre-treatment CRP may need closer monitoring and consideration of intensified supportive care including primary prophylaxis with granulocyte colony-stimulating factor.\u003c/p\u003e","manuscriptTitle":"Risk factors associated with febrile neutropenia in patients with esophageal cancer receiving 5-fluorouracil plus cisplatin combination chemoradiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-11 14:28:44","doi":"10.21203/rs.3.rs-8027424/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2ff4409d-6469-4a86-9a02-8c5c2bdb7ce1","owner":[],"postedDate":"December 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-28T22:38:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-11 14:28:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8027424","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8027424","identity":"rs-8027424","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}