Predictive factors of febrile neutropenia after pegfilgrastim as primary prophylaxis in patients treated with neoadjuvant chemotherapy of docetaxel, cisplatin, and 5-fluorouracil for esophageal cancer: Impact of febrile neutropenia on changes in neutrophil counts and relative dose intensity

Abstract

Purpose　

We investigated factors predicting febrile neutropenia (FN) after the administration of pegfilgrastim as primary prophylaxis in patients with esophageal cancer who received neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) to support the appropriate management of FN. We evaluated changes in neutrophil counts and relative dose intensity (RDI) after the incidence of FN.

Methods　

The retrospective study included 122 patients with esophageal cancer who were treated with DCF and pegfilgrastim at the Showa University Hospital, Japan, between April 2016 and August 2021. The primary outcome was the FN incidence after cycle 1 of DCF chemotherapy. The significant independent factors associated with FN incidence were selected using the multivariate analysis. Changes in neutrophil counts and RDI were compared between the FN and non-FN groups.

Results　

A total of 100 patients were included in the analysis. The incidence of FN was 21%. In the multivariate analysis, geriatric nutritional index (GNRI) < 92 (odds ratio [OR] 13.162, P < 0.001) and combination of platelet and neutrophil to lymphocyte ratio (COP-NLR) score of 0 (OR 4.619, P = 0.012) were independent predictors of FN. The neutrophil counts on day 7–10 and RDI in the FN group were significantly lower than those in the non-FN group (all P < 0.05).

Conclusion　

GNRI < 92 and COP-NLR score of 0 are important indicators to predict patients at high risk of DCF chemotherapy-induced FN. Furthermore, we showed that FN incidence after pegfilgrastim administration had a strong impact on delayed neutrophil recovery and reduced RDI.

Introduction

Esophageal cancer, which is highly malignant and aggressive, is the sixth most common cause of cancer-related death worldwide [1]. In the treatment of esophageal cancer, neoadjuvant therapy followed by surgery has improved survival benefits [2–4]. As an option of standard neoadjuvant therapy for resectable advanced esophageal cancer, chemoradiotherapy is widely performed in Western countries, whereas neoadjuvant chemotherapy is used in several countries, including Japan.

In Japan, neoadjuvant chemotherapy with cisplatin and 5-fluorouracil (CF) is used as standard treatment for locally advanced esophageal cancer based on the results of the Japan Clinical Oncology Group (JCOG) 9907 trial [5–6]. Additionally, in the JCOG1109 trial, neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF), compared with chemoradiotherapy (CF with radiotherapy), significantly improved overall survival. This suggested that DCF represents a new standard treatment for esophageal squamous cell cancer [7]. However, DCF chemotherapy induces high rates of Grade ≥ 3 neutropenia and febrile neutropenia (FN) [7–10].

Chemotherapy-induced FN is a life-threatening complication [11]. According to the American Society of Clinical Oncology (ASCO) guidelines, granulocyte-colony stimulating factor (G-CSF) is recommended as primary prophylaxis for chemotherapy with FN incidence of ≥ 20% [12]. Additionally, a single fixed dose of long-acting pegfilgrastim significantly reduced the incidence of FN compared with daily injections of G-CSF [13]. Pegfilgrastim, as primary prophylaxis, should be administered to patients who are treated with DCF chemotherapy with an FN incidence of ≥ 20% [14]. However, some patients develop FN despite the administration of pegfilgrastim [15]. These patients experienced prolonged initiation of treatment for the next cycle, which may be related to a delay in surgery. Thus, predicting the incidence of FN after the administration of pegfilgrastim is very important.

Previous studies have reported that older age, living alone, non-usage of pegfilgrastim, and dysphagia were the significant risk factor of FN after DCF chemotherapy [16–18]. However, the predictors of FN after the administration of pegfilgrastim as primary prophylaxis in patients treated with DCF chemotherapy have not been identified. If the incidence of FN after the administration of pegfilgrastim when commencing DCF chemotherapy can be predicted, we will be able to determine appropriate early management of FN.

Pegfilgrastim should be administrated at least 24 hours after completion of chemotherapy [12]. In clinical practice, we need to consider the optimal administration schedule of pegfilgrastim at the start of DCF chemotherapy. This is because some patients have a decrease in neutrophil counts before the efficacy of pegfilgrastim is obtained. Additionally, FN is the major dose-limiting toxicity of cancer chemotherapy [19]. Therefore, the cause of dose reductions and treatment delays makes it difficult to maintain a high relative dose intensity (RDI). However, the clinical impacts of FN on changes in neutrophil counts and RDI when treated with DCF chemotherapy have not been well studied. Clarifying the impacts of FN on changes in neutrophil counts and RDI will enable the demonstration of the importance of the appropriate management of FN in high-risk patients, which may lead to a high RDI.

In this study, we investigated predictors of FN after the administration of pegfilgrastim as primary prophylaxis to support appropriate early management of FN in patients with esophageal cancer who were treated with DCF chemotherapy. We also evaluated changes in neutrophil counts and RDI after the incidence of FN.

Methods

Treatment

The DCF regimen consisted of docetaxel (70 mg/m²) given as a 1-h intravenous infusion on day 1, cisplatin (70 mg/m²) given as a 2-h intravenous infusion on day 1, and 5-fluorouracil (750 mg/m²) given as a continuous 24-h peripheral infusion on day 1–5 of a 21-day cycle. Patients underwent repetition of the regimen every 3 weeks, up to three courses until severe toxicity or progressive disease occurred [20]. Antiemetic therapy was received according to the guidelines [21]. A single dose of pegfilgrastim (3.6 mg) was administrated after the completion of DCF chemotherapy. All patients received chemotherapy cycles in the hospital.

Measurement

Definition Of Variables

Clinical staging was defined based on the site and classification of malignant tumor (TNM) of the Union for International Cancer Control 8th edition [22]. Dysphagia was described with the Mellow and Pinkas score [23] using the records of dietary patterns as follows: 0, able to eat a normal diet; 1, able to eat some solid food; 2, able to eat semi-solid food only; 3, able to swallow liquids only; and 4, complete dysphagia. We classified Grade < 2 as patients with no dysphagia and Grade ≥ 3 as patients with dysphagia. These scores were evaluated before the DCF chemotherapy. Hb levels were divided into two groups according to the World Health Organization definition of anemia (male, < 13.0 g/dL; female, < 12.0 g/dL). PNI was calculated as 10 × Alb (g/dL) + 0.005 × TLC (/mm³) [24]. GNRI was calculated as 14.89 × Alb (g/dL) + 41.7 × body weight (kg) /ideal body weight (kg) [25]. Ideal body weight was calculated as follows: (male, height (cm) − 100 - [height (cm) − 150]/4; female, height (cm) − 100 - [height (cm) − 150]/2.5). Patients were classified into four risk groups based on GNRI values as follows: severe risk, < 82.0; intermediate risk, 82.0–91.9; low risk, 92.0–97.9; no risk, ≥ 98. CONUT scores were calculated based on Alb, TLC, and T-cho levels as follows: Alb (0, ≥ 3.50; 2, 3.00– 3.49; 4, 2.50–2.99; 6, < 2.50), TLC (0, ≥ 1600; 1, 1200–1599; 2, 800–1199; 3, < 800), and T-cho (0, ≥ 180; 1, 140–179; 2, 100–139; 3, < 100) [26]. The CONUT score was defined based on the total scores for these points. NLR was calculated as neutrophil counts/TLC, PLR as Plt/TLC, and CAR as CRP/Alb. COP-NLR was calculated as follows: patients with elevated platelet counts (> 30 × 10⁴/mm³) and NLR (> 3.0) were assigned a COP-NLR score of 2. Patients with one or no abnormal values were assigned a COP-NLR score of 1 or 0, respectively [27]. The mGPS was calculated as follows: patients with elevated CRP (> 0.5 mg/dL) and hypoalbuminemia (< 3.5 g/dL) were assigned to mGPS of 2. Patients with one or no abnormal values were assigned an mGPS of 1 or 0, respectively [28].

Outcome

The primary outcome was the incidence of FN in cycle 1 of DCF chemotherapy. FN was defined as having an axillary temperature ≥ 37.5℃ and neutropenia with neutrophil counts < 500/mm³ or neutrophil counts < 1,000/mm³ that were expected to decrease to < 500/mm³ within 48 h. Neutropenia was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Changes In Neutrophil Counts

The period before the DCF chemotherapy was defined as pre-treatment. The start date of DCF chemotherapy was defined as day 1. Neutrophil counts in the FN and non-FN groups were collected from pre-treatment to day 21.

Changes In Neutrophil Counts

We compared changes in neutrophil counts between the FN and non-FN groups using Mann–Whitney–U test.

Results

Patient characteristics

Table 1 shows the characteristics of the 100 patients. The median age was 66 (range, 43–78) years and 82 patients (82%) were males. The median BMI was 20.4 (range, 14.6–28.5) kg/m². Of these patients, 3 (3%), 38 (38%), 28 (28%), and 31 (31%) had cStage Ⅱ, Ⅲ, Ⅳa, and Ⅳb, respectively. The initial full dose of DCF chemotherapy for cycle 1 was given to 49 patients (49%). In patients with prior neoadjuvant chemotherapy, 15 (15%) received 1 cycle of CF, 3 (3%) received 2 cycles of CF, and 2 (2%) received 1 cycle of SP.

Outcome

The incidence of FN in cycle 1 was 21%. Additionally, 47 patients (52%) had grade 3 or 4 neutropenia and of these 27 patients (30%) had grade 4 neutropenia. The median time of administered pegfilgrastim was 7 (range, 7–9) days, and the median incidence of FN was 9 (range, 8–10) days. 

Univariate analysis

　In the FN group, age ≥ 65 (76.2% vs. 49.4%, P = 0.028), neutrophil counts < 2000/mm³ (23.8% vs. 2.6%, P = 0.004), anemia (47.6% vs. 25.3%, P = 0.047), Alb < 3.5 g/dL (28.6% vs. 7.6%, P = 0.017), T-cho < 180 mg/dL (57.1% vs. 33.3%, P = 0.048), PNI < 45 (47.6% vs. 20.3%, P = 0.011), GNRI < 92 (52.4% vs. 8.9%, P < 0.001), CONUT score ≥ 4 (23.8% vs. 4.0%, P = 0.012), and COP-NLR score of 0 (52.4% vs. 24.4%, P = 0.013) were significantly higher than those of the non-FN group (Table 2).

Multivariate analysis

　In the multivariate analysis, GNRI < 92 (odds ratio [OR] 13.162, P < 0.001) and COP-NLR score of 0 (OR 4.619, P = 0.012) were independent significant predictors of FN in cycle 1 (Table 3). 

Changes in neutrophil counts

Fig. 1 shows changes in neutrophil counts between the FN and non-FN groups. In the FN group, day 7–10 neutrophil counts were significantly lower than those in the non-FN group (median neutrophil counts (mm³): day 7, 805 vs. 1,340, P = 0.002; day 8, 350 vs. 1,240, P = 0.001; day 9, 255 vs. 530, P = 0.001; day 10, 730 vs. 3,485, P = 0.004). In the FN group, neutrophil counts on day 11–21 were not significantly different from those of the non-FN group. 

RDI

　Table 4 shows the completion rate, % dose, duration of administration, and RDI of DCF chemotherapy. Notably, 77 patients (77%) received 3 cycles completely. The completion rate of DCF chemotherapy in the FN group were not significantly different from that in the non-FN group. 

  The % dose of DCF chemotherapy in the FN group was significantly lower in cycles 2 and 3 than that in the non-FN group. The duration of administration of DCF chemotherapy in the FN group was significantly delayed in cycle 1 than in the non-FN group. The adverse events that caused dose reduction in the next cycle of DCF chemotherapy in the FN group was the development of FN (100%), whereas in the non-FN group was the development of anorexia (8.9%), diarrhea (5.1%), enteritis (2.5%), and drug-induced liver injury (1.3%). The median of the total RDI in all patients was 90.0% (range, 30–100). The RDI of all cycles in the FN group was significantly lower than those in the non-FN group.

The proportion of patients with total RDI ≥ 85%

　Fig. 2 shows the proportion of patients with total RDI ≥ 85% of DCF chemotherapy in all cycles. The proportion of patients with total RDI ≥ 85% in the FN group was significantly lower than those in the non-FN group (cycle 1, 33.3% vs. 74.7%, P < 0.001; cycle 2, 17.6% vs. 77.0%, P < 0.001; cycle 3, 20.0% vs. 79.0%, P < 0.001). Additionally, the proportion of patients with total RDI ≥ 85% in all cycles in the FN group was significantly lower than those in the non-FN group.

Discussion

In this study, we found that GNRI < 92 and COP-NLR score of 0 were independent predictors of FN incidence after the administration of pegfilgrastim as primary prophylaxis in patients with esophageal cancer treated with DCF neoadjuvant chemotherapy. In clinical practice, some patients develop FN despite the administration of pegfilgrastim as primary prophylaxis. Hence, it is important to predict patients at high risk of FN. To our knowledge, this is the first study to reveal the predictors of FN after the administration of pegfilgrastim as primary prophylaxis in patients treated with DCF chemotherapy. Therefore, GNRI and COP-NLR are useful indicators for determining appropriate early management of patients at high risk of FN when commencing DCF chemotherapy.

The FN group had a significantly lower neutrophil count at the time of pegfilgrastim administration (median day 7) and delayed neutrophil recovery compared to the non-FN group. Additionally, the FN group had a longer duration of cycle 1, resulting in a reduced dose of chemotherapy in cycles 2 and 3, which led to an increase in patients with total RDI < 85%. There have been few reports on the clinical impact of FN on changes in neutrophil counts and RDI of DCF chemotherapy. Therefore, our findings demonstrated that early administration of pegfilgrastim for FN might lead to the maintenance of a high RDI.

GNRI is the nutrition-related parameter consisting of Alb and ideal body weight ratio. Many patients with esophageal cancer have poor nutritional status because of the accompanying esophageal obstruction [29]. According to the ASCO guidelines, poor nutritional status has been reported as the predictor of FN [12]. Nevertheless, the association between FN and poor nutritional status for esophageal cancer is unclear. We identified indicators of nutritional status reflecting the pathophysiology of esophageal cancer by using various nutrition-related parameters. In addition, we also investigated the association of FN with poor nutritional status. The findings showed that GNRI is a nutritional indicator that more strongly reflects the poor nutritional status of patients with esophageal cancer compared to other nutritional indicators. In patients with esophageal cancer, GNRI, which contains ideal body weight ratio as a constituent factor, was considered to be a nutritional indicator reflecting poor nutritional status that could not be assessed by Alb alone.

Poor nutrition status has an influence on the reduction in neutrophil function [30]. It is generally known that poor nutrition status leads to weakening of the immune system, resulting in an increase in the risk of infections and tendency to become severely ill. The levels of inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α, are increased in patients with poor nutrition status related to a low Alb and BMI [30, 31]. Additionally, the increase in IL-6 levels has been reported as a predictor of FN in patients with breast cancer [32]. Therefore, we considered that patients with moderate or severe nutritional status with GNRI < 92 had reduced immunity due to decreased neutrophil function and increased inflammatory cytokines. These then resulted in an increased risk of infection and affected the incidence of FN.

COP-NLR is the immune-related parameter consisting of neutrophils, TLC, and Plt. Previous studies have reported that low levels of neutrophils, TLC, NLR, and Plt before treatment were predictors of neutropenia and FN [33–35]. Therefore, we investigated predictive factors of FN using various immune-related parameters. The findings showed that COP-NLR score of 0 had a greater impact on FN than COP-NLR scores of 1 and 2. However, TLC and Plt, which are components of COP-NLR, were not significantly associated with the incidence of FN. COP-NLR score of 0, which consists of three components, may reflect the decrease in the bone marrow function before chemotherapy rather than a single component. In other words, COP-NLR score of 0 indicates an increase in susceptibility to chemotherapy-induced myelosuppression. Hence, it was considered to cause serious infections and affect the incidence of FN.

We evaluated the impact of FN on changes in neutrophil counts and RDI. The onset of FN was within 3 days after the administration of pegfilgrastim. The peak serum concentrations of pegfilgrastim occur within 48–72 h after administration [36]; thus, the administration of pegfilgrastim may be too late for patients with FN. Kawahira et al. reported that primary prophylactic G-CSF administration on day 7 of DCF chemotherapy was not able to reduce the incidence of FN [37]. In contrast, it has been reported that early administration of G-CSF during DCF chemotherapy for head and neck cancer significantly reduced the incidence of FN and was safe [38]. Additionally, in a single-arm phase Ⅱ study of 23 patients with esophageal cancer, the administration of pegfilgrastim on day 3 reduced the incidence of grade 3 or 4 neutropenia and FN [39]. Therefore, pegfilgrastim should be administered to patients at high risk of FN within 7 days of the first cycle of DCF chemotherapy to prevent FN.

In this study, the patients with total RDI < 85% in the FN group were as high as 81%. The prospective observational study also reported that RDI < 85% was associated with shorter progression-free survival than RDI ≥ 85% [40]. Therefore, patients at high risk of FN with DCF chemotherapy may not be able to maintain RDI ≥ 85% despite the administration of pegfilgrastim. Additionally, it may lead to a lack of antitumor effect and poor prognosis after surgery; hence, it is very important to maintain a high RDI.

Limitation

This study has two limitations. First, a lack of information about the incidence of FN in outpatients. This may have led to the underestimation of the incidence rate of FN. Second, the completion rate of DCF chemotherapy was 77%. Hence, it was not possible to calculate an accurate total RDI for the entire study population.

Conclusion

We showed that GNRI < 92 and COP-NLR score of 0 are independent predictors for FN after the administration of pegfilgrastim as primary prophylaxis in patients with esophageal cancer treated with DCF neoadjuvant chemotherapy. These factors may be important indicators to predict patients at high risk of DCF chemotherapy-induced FN. Furthermore, we showed that FN incidence after pegfilgrastim administration had a strong impact on neutrophil recovery delay and reduced RDI. Therefore, it may be possible to maintain a high RDI of DCF chemotherapy by performing appropriate early management for patients at high risk of FN.

Statements & Declarations

Funding: No funding was received for conducting this study.

Competing Interests: The authors have no relevant financial and non-financial interests to disclose. 

Author contributions: All authors contributed to the study conception and design. Data collection was performed by T.I., M.K., and K.O. Statistical analysis was performed by T.I. and M.S. The first draft of the manuscript was written by T.I., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethical approval: This study was performed in line with the principles of the 1964 Declaration of Helsinki.

Approval was granted by the Ethics Committee of the Showa University School of Pharmacy, Japan (December 23, 2021/No. 393). 

Consent to participate: For this type of study, formal consent is not required.

Consent for publication: Not applicable.

Data availability: The datasets generated and analyzed during this study are not publicly available due to ethical reasons. However, they are available on reasonable request to the corresponding author.

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Tables

Tables 1 to 4 are available in the Supplementary Files section