Research ArticleClinical Studies

Poor Renal Function and a High Modified Glasgow Prognostic Score Are Predictive Factors for Nedaplatin/5-Fluorouracil Combination Therapy-induced Febrile Neutropenia

JUNYA HASHIZUME, MADOKA NAMBU, HIROO NAKAGAWA, HITOMI HARASAWA and YUKINOBU KODAMA
Anticancer Research May 2023, 43 (5) 2309-2316; DOI: https://doi.org/10.21873/anticanres.16395

Abstract

Background/Aim: Nedaplatin (NDP)/5-fluorouracil (5-FU) combination therapy frequently causes severe neutropenia and febrile neutropenia (FN). However, there is no consensus on the risk factors for FN caused by NDP/5-FU combination therapy. Mouse models of cancer cachexia are known to be susceptible to infections. Conversely, the modified Glasgow prognostic score (mGPS) is believed to reflect cancer cachexia. We hypothesized that mGPS is a predictive factor for FN caused by NDP/5-FU combination therapy. Patients and Methods: We analyzed the relationship between mGPS and FN in patients who received NDP/5-FU combination therapy at Nagasaki University Hospital using multivariate logistic analysis. Results: In total, 157 patients were studied, 20 of whom developed FN (12.7%). Multivariate analysis revealed that mGPS 1-2 [odds ratio (OR)=4.13, 95% confidence interval (CI)=1.42-12.02, p=0.009] and creatinine clearance <54.4 ml/min (OR=5.81, 95% CI=1.81-18.59, p=0.003) were significantly associated with the development of FN. Conclusion: Several guidelines suggest that patients receiving chemotherapy with an FN rate 10-20% should be considered for prophylactic granulocyte colony-stimulating factor (G-CSF), depending on the individual patient’s risk of developing FN. When NDP/5-FU combination therapy is administered to patients with risk factors identified in this study, prophylactic administration of G-CSF should be considered. In addition, the neutrophil count and axillary temperature should be monitored more frequently.

Key Words:

The most problematic dose-limiting factor in cancer pharmacotherapy is myelosuppression. In particular, patients with a low neutrophil count and fever can experience a rapid deterioration of their general condition, sometimes leading to death. Among cases of neutropenia and fever during cancer chemotherapy, febrile neutropenia (FN) is treated with empiric antimicrobials. Even if FN improves with appropriate antimicrobial therapy, prolonged hospitalization and increased healthcare costs are inevitable (1, 2).

Cis-diamminedichloroplatinum (II) (cisplatin; CDDP) plays a central role in the treatment of esophageal and head and neck cancers. However, CDDP treatment is often complicated by adverse effects including digestive disorders, such as nausea and vomiting, and renal damage. Cis-diammineglycolateplatinum (nedaplatin; NDP) is a platinum complex anticancer agent that reduces the adverse effects of CDDP (3). NDP is used in patients concerned about gastrointestinal toxicity or nephrotoxicity caused by CDDP or in those in whom CDDP treatment is ineffective. The combination of NDP and 5-FU has been effective against esophageal and head and neck cancers in clinical trials (4-7). Conversely, patients administered NDP/5-FU combination therapy frequently develop severe neutropenia and FN. The known risk factors for FN include older age, poor performance status, renal dysfunction, liver dysfunction, advanced cancer, prior anticancer treatment, prior radiotherapy, recent surgery, presence of open wounds, neutropenia, bone marrow involvement of tumor, history of FN, cardiovascular disease, multiple comorbidities, and presence of infection (8-10). However, patients receiving treatment including NDP were not included in previous reports. Therefore, identifying risk factors for FN with NDP/5-FU combination therapy is important for selecting appropriate candidate patients in clinical practice or for preventing FN.

The modified Glasgow prognostic score (mGPS) is based on the combination of elevated C-reactive protein (CRP, >1.0 mg/dl) and hypoalbuminemia (<3.5 g/l), and it is indicative of both an underlying systemic inflammatory response and nutritional decline (11). Regarding the scoring system, patients with elevated CRP (>1.0 mg/dl) are given a score of 1 or 2, depending on the absence or presence of hypoalbuminemia (<3.5 g/dl). Patients with CRP ≤1.0 are given a score of 0 regardless of the albumin (ALB) level. Previous studies illustrated that mGPS is a predictor of prognosis in multiple cancer types (12-14), and it is associated with adverse events, including FN, in CDDP-based chemotherapy (15). High mGPS is an indicator of cancer cachexia (16). Previous research reported that Klebsiella oxytoca counts were increased in the intestines of cancer cachexia mouse models (17). This bacterium also alters the intestinal barrier function of mice with cachexia and acts as an intestinal pathogen. Thus, we hypothesized that patients with high mGPS experience changes in the intestinal microbiota, resulting in the induction of FN. In this study, we analyzed the association between mGPS and the development of FN among patients treated with NDP/5-FU combination therapy at Nagasaki University Hospital. Furthermore, we also explored factors other than mGPS that are associated with the incidence of FN.

Patients and Methods

Patients. This study was performed in accordance with the Declaration of Helsinki (Ninth revision, Fortaleza, Brazil, 2013) and under the approval of the Nagasaki University Ethics Committee (No. 20042013). 177 patients with esophageal or head and neck cancer received their first course of NDP and 5-FU at Nagasaki University Hospital from January 2010 to December 2019. Fifteen patients were excluded from this study because their ALB or CRP levels were not measured. Furthermore, five patients were excluded because they were transferred to another hospital fewer than 28 days after the first dose or they did not complete the first course of chemotherapy. Patients were administered a 2 h intravenous infusion of NDP combined with a continuous intravenous infusion of 5-FU. The treatment schedules were as follows: 5-FU 700 mg/m2 on days 1-5 and NDP 130 mg/m2 on day 6 (4, 5), NDP 100 mg/m2 on day 1 and 5-FU 700 mg/m2 on days 2-6 (6), and NDP 90 mg/m2 on day 1 and 5-FU 800 mg/m2 on days 1-5 (7). Doses were reduced in some patients based on the judgments of their physicians. The interval of chemotherapy was 4 weeks. Some patients were treated with radiation therapy (5 days a week at 1.8 Gy a day), which was administered concomitantly or alternately with chemotherapy. Granulocyte-colony stimulating factor (G-CSF) was employed as a therapeutic intervention for neutropenia, but not for prevention.

Data collection and assessment. This study was performed retrospectively. We obtained data on age, sex, and weight. White blood cell, platelet, and neutrophil counts and hemoglobin, serum creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, ALB, and CRP levels before NDP and 5-FU administration were evaluated. These data were defined as the baseline values. The doses of NDP and 5-FU displayed a bimodal distribution (Figure 1). Therefore, the dose of NDP was divided into two groups: >100 mg/m2 and other. The dose of 5-FU was also divided into two groups: >700 mg/m2 and other. Furthermore, FN was investigated in the first treatment course. In this study, FN was defined as a neutrophil count of less than 500/μl and an armpit temperature exceeding 37.5°C. In addition, patients administered G-CSF and broad-spectrum antimicrobial agents such as tazobactam/piperacillin, cefepime, and meropenem indicated the development of FN.

Figure 1.
Figure 1.

The dot plot of Nedaplatin (A) and 5-fluorouracil (B) doses (n=157).

Statistical analysis. Baseline characteristics were summarized as frequencies and percentages for categorical data and as medians plus ranges for continuous data. Differences between the two groups were assessed using Fisher’s exact test for categorical data and Wilcoxon’s rank test for continuous data. The incidence of FN was analyzed using Fisher’s exact test. Univariate logistic regression analyses were performed to evaluate the odds ratio (OR), 95% confidence intervals (CIs), and p-Values for FN after NDP/5-FU combination therapy. In addition, the relationship between the incidence of FN and mGPS was evaluated using multivariable logistic regression. The multivariate logistic regression model was adjusted for mGPS and potentially confounding factors for the incidence of FN, which were detected as p<0.10 in the univariate analyses [age, weight, creatinine clearance (CCr)]. The cutoff for CCr was the value obtained from the receiver operating characteristic (ROC) analysis for the highest Youden’s index. All tests were two-sided. The level of significance was p<0.05. Analyses were performed using JMP Pro version 16 (SAS Institute Inc., Cary, NC, USA).

Results

The baseline characteristics of 157 patients are shown in Table I. Table II presents the results of univariate analysis of patients with or without FN after NDP/5-FU combination therapy. Among these analyses, there were significant differences in age (p=0.038), mGPS (p=0.004) ALB (p=0.025) and CRP levels (p=0.013), as well as CCr (p<0.001), between patients with and without FN.

View this table:
Table I.

Patient characteristics.

View this table:
Table II.

Comparison of patient characteristics in the febrile neutropenia (With FN) group and without febrile neutropenia (Without FN) group.

As presented in Table III, univariate logistic regression analysis showed that age, weight, CCr, ALB (<3.5 g/dl) and CRP levels (>1.0 mg/dl), mGPS 1-2 (vs. 0), and mGPS 2 (vs. 0-1) were significantly associated with FN (p<0.1). Multivariate logistic regression analyses were performed using age, weight, CCr, and mGPS 1-2 (vs. 0) as explanatory variables (model 1). We then conducted the same analysis by replacing mGPS 1-2 (vs. 0) with mGPS 2 (vs. 0-1; model 2). ALB and CRP were not selected as explanatory variables because of their multicollinearity with mGPS. The results illustrated that CCr and mGPS 1-2 (vs. 0) were significantly associated with the development of FN in model 1, and CCr and mGPS 2 (vs. 0-1) were associated with FN in model 2 (Table III). In addition, we analyzed the ROC curve for the baseline CCr values. The cutoff of CCr was defined as 54.4 ml/min by ROC curve analysis (area under the curve=0.771, specificity=0.766, sensibility=0.750). Multivariate logistic regression analysis using a CCr cutoff of 54.4 ml/min indicated that CCr <54.4 ml/min and mGPS 1-2 (vs. 0) were significantly associated with the development of FN in model 1, whereas CCr <54.4 ml/min and mGPS 2 (vs. 0-1) were associated with FN in model 2 (Table IV).

View this table:
Table III.

Logistic regression analysis of the incidence of febrile neutropenia.

View this table:
Table IV.

Multivariate logistic regression analysis using a creatinine clearance cutoff of 54.4 ml/min.

As presented in Figure 2, we divided patients into four groups according to the specified CCr and mGPS. The FN rates in the mGPS 0/CCr ≥54.4 ml/min, mGPS 0/CCr <54.4 ml/min/, mGPS 1-2/CCr ≥54.4 ml/min, and mGPS 1-2/CCr ≥54.4 ml/min groups were 3.3%, 21.9%, 14.3%, and 50.0%, respectively.

Figure 2.
Figure 2.

The combination effect of baseline creatinine clearance (CCr) and the modified Glasgow prognostic score (mGPS) on the incidence of febrile neutropenia.

Discussion

The main finding of this study was that mGPS 1-2 (vs. 0) and baseline CCr are predictors of the risk of FN associated with NDP/5-FU combination therapy. mGPS can be calculated using only ALB and CRP, which can be easily measured in daily practice. Hypoalbuminemia has been reported as a risk factor for the development of FN in several cancers, including non-Hodgkin’s lymphoma (18), prostate cancer (19), and germ cell cancer (20). Our univariate analysis illustrated that hypoalbuminemia (<3.5 g/dl) was significantly associated with the development of FN, as previously reported (Table III). In addition to these results, we found that high CRP levels (>1.0 mg/dl) were significantly associated with the development of FN (Table III). Mikoshiba et al. reported that for patients with head and neck cancer receiving CDDP-based chemotherapy, patients with mGPS 1-2 had a higher incidence of adverse events, including FN, than those with mGPS 0 (15). In this study, we recorded similar results in patients receiving NDP/5-FU as well as CDDP-based chemotherapy. Furthermore, patients with mGPS 2 were at significantly higher risk of developing FN than those with mGPS 0-1, suggesting that patients with high CRP and low albumin levels should be cautious about developing FN (Table IV). mGPS is closely related to the prognosis of esophageal or head and neck cancer. Previous reports found that 78% of patients with gastroesophageal cancer for whom palliative care is indicated have mGPS 1-2 (21). Conversely, when systemic chemotherapy is indicated, the percentage of patients with mGPS 1-2 has been reported to range from 16%-57.5% in esophageal cancer (22-25) and 14.8%-53% in head and neck cancer (15, 26-28). In our study, 157 patients received systemic chemotherapy, and 22.3% (35 patients) had mGPS 1-2 (Table I). These results were consistent with previous findings.

In addition to mGPS, CCr <54.4 ml/min was significantly associated with the occurrence of FN (Table III and Table IV). A potential reason for this finding was that the renal excretion rate of NDP is >90% and CCr is proportional to the clearance of NDP (29). In addition, Araki et al. revealed that decreased renal function is a risk factor for neutropenia caused by NDP (30). Thus, we believe that patients with low CCr might have higher blood NDP levels than those with normal renal function. On the contrary, 5-FU is mainly a hepatically metabolized anticancer drug with a urinary unchanged drug excretion rate of approximately 10%. Clinical trials in patients with serum creatinine levels of 1.5-3.0 mg/dl did not report decreased clearance of 5-FU or increased adverse effect rates (31). In addition, the general recommendation is that 5-FU does not require dose reduction even in patients with impaired renal function (32, 33). We consider it unlikely that the pharmacokinetics of 5-FU influenced the incidence of FN in this study.

FN is a fatal adverse event that requires appropriate prevention. The guidelines of the American Society of Clinical Oncology (8), European Organization for Research and Treatment of Cancer (9), National Comprehensive Cancer Network (10), and European Society for Medical Oncology (34) recommend prophylactic G-CSF administration in patients receiving cancer chemotherapy with an FN rate of 20% or higher. For patients receiving treatment with an FN rate of 10%-20%, the need for prophylactic G-CSF administration should be determined according to the individual patient’s risk of developing FN. Watanabe et al. reported an FN incidence of 12% among patients treated with NDP/5-FU combination therapy (7). In our study, the incidence of FN was 12.7% (20/157 patients), which is consistent with previous findings (Table II). Furthermore, 50.0% of patients with mGPS 1-2 and CCr <54.4 ml/min developed FN, whereas the incidence of FN in patients without any risk factors was 3.3% (Figure 2). We believe that for patients with mGPS 1-2 and/or CCr <54.4 ml/min, prophylactic G-CSF administration can reduce the risk of FN. In the future, the primary preventive effect of G-GSF in NDP/5-FU combination therapy needs to be examined in prospective studies.

This study had several limitations. Firstly, there was a possibility of selection bias because this was a single-center study and patients lacking CRP or ALB data were excluded. Secondly, as a retrospective study, unmeasured factors could influence the results. In particular, poor performance status, which is a risk factor for FN, was difficult to extract from the medical records. In the future, data including performance status should be collected to validate the results.

Conclusion

Patients with background CCr <54.4 ml/min and/or mGPS 1-2 are at increased risk of FN during NDP/5-FU combination therapy. When NDP/5-FU combination therapy is administered to patients with these risk factors, the neutrophil count and axillary temperature should be monitored more frequently than in patients without these risk factors. In addition, prophylactic administration of G-CSF should be considered.

Acknowledgements

We thank the patients and all medical staff at Nagasaki University Hospital who contributed to this study.

Footnotes

  • Authors’ Contributions

    Conception and design of the study: all Authors. Formal analysis and investigation: JH, MN, and YK. Interpretation of data: all Authors. Initial drafting of the manuscript: JH and MN. Critical revision of the manuscript: all Authors. All Authors reviewed and approved the final manuscript.

  • Conflicts of Interest

    All Authors have no conflicts of interest to declare in relation to this study.

  • Received February 7, 2023.
  • Revision received February 20, 2023.
  • Accepted February 24, 2023.

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Poor Renal Function and a High Modified Glasgow Prognostic Score Are Predictive Factors for Nedaplatin/5-Fluorouracil Combination Therapy-induced Febrile Neutropenia
JUNYA HASHIZUME, MADOKA NAMBU, HIROO NAKAGAWA, HITOMI HARASAWA, YUKINOBU KODAMA
Anticancer Research May 2023, 43 (5) 2309-2316; DOI: 10.21873/anticanres.16395
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