Research ArticleClinical Studies

Predictive Factors of Febrile Neutropenia After Primary Prophylactic Pegfilgrastim With DCF Chemotherapy for Esophageal Cancer

TAKAHITO INAGAKI, MIKI SATO, MASAOKI KIN, KOJI OTSUKA, MASAHIKO MURAKAMI and MARI KOGO
Anticancer Research December 2022, 42 (12) 6071-6081; DOI: https://doi.org/10.21873/anticanres.16119

Abstract

Background/Aim: We investigated the predictive factors of 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. Patients and Methods: This retrospective study involved 122 patients with esophageal cancer who were treated with DCF and pegfilgrastim at Showa University Hospital, Japan, between April 2016 and August 2021. The primary outcome was 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: One-hundred patients were included in the analysis. The incidence of FN in cycle 1 was 21%. In the multivariate analysis, geriatric nutritional risk 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 count on day 7-10 and RDI in the FN group were 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, FN incidence after pegfilgrastim administration had a strong effect on delayed neutrophil recovery and reduced RDI.

Key Words:

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

In Japan, neoadjuvant chemotherapy with cisplatin and 5-fluorouracil (CF) is used as a 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. On the basis of this finding, DCF was 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 a FN incidence of ≥20% (12). Additionally, a single fixed dose of long-acting pegfilgrastim significantly reduces 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, 15). However, some patients develop FN despite the administration of pegfilgrastim (16). These patients experience prolonged initiation of treatment for the next cycle, which may lead to a delay in surgery.

Some studies have reported that older age, living alone, non-usage of pegfilgrastim, and dysphagia are major risk factors of FN after DCF chemotherapy (17-19). 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 can be predicted when commencing DCF chemotherapy, appropriate early management strategies of FN can be determined.

Pegfilgrastim should be administrated at least 24 h after the completion of chemotherapy (12). In clinical practice, the optimal administration schedule of pegfilgrastim should be considered because some patients present a decrease in neutrophil counts before obtaining the efficacy of pegfilgrastim. Additionally, FN is the major dose-limiting toxicity of cancer chemotherapy (20). Therefore, the causes of dose reductions and treatment delay makes it difficult to maintain a high relative dose intensity (RDI). However, the clinical effects of FN on changes in neutrophil count and RDI when DCF chemotherapy is administered have not been well studied.

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 the neutrophil count and RDI after the incidence of FN.

Patients and Methods

Study population. We performed a retrospective cohort study involving 122 patients with esophageal cancer who were treated with DCF neoadjuvant chemotherapy and pegfilgrastim as primary prophylaxis at Showa University Hospital, Japan, between April 2016 and August 2021. All patients were diagnosed with esophageal cancer based on histological biopsy. We assessed tumor location, tumor invasion depth, lymph node metastasis, and distant metastasis using air-contrast barium esophagography; neck, chest, abdominal, and pelvic computed tomography (CT); bronchoscopy; endoscopy; and 18F-deoxyglucose positron emission tomography-CT. We excluded 22 patients for the following reasons: use of prophylactic antibiotics (n=14); performance status (PS) of 2 (n=1); having a fever before the administration of pegfilgrastim (n=3); active multiple cancers (n=2); and a history of radiotherapy (n=2). Finally, we evaluated 100 patients with esophageal cancer. This study was performed in line with the principles of the 1964 Declaration of Helsinki. The study was approved by the Ethics Committee of the Showa University School of Pharmacy, Japan (approval No. 393).

Treatment. The DCF regimen consisted of docetaxel (70 mg/m2) administered as a 1-h intravenous infusion on day 1, cisplatin (70 mg/m2) as a 2-h intravenous infusion on day 1, and 5-fluorouracil (750 mg/m2) as a continuous 24-h peripheral infusion on days 1-5 of a 21-day cycle. The patients were administered the regimen every 3 weeks for a maximum of three cycles until severe toxicity or occurrence of progressive disease (21). Antiemetic therapy was administered according to the guidelines (22). 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.

Data collection of predictive factors related to FN. Data were collected from the medical records at baseline, before the initial DCF chemotherapy. The patient background data included age, sex, body mass index (BMI), body surface area, Brinkman index, alcohol use, the Eastern Cooperative Oncology Group PS, clinical stage (cStage), metastasis sites, tumor location, and dysphagia. Blood test data included white blood cell count; total lymphocyte count (TLC); and hemoglobin (Hb), platelet (Plt), serum albumin (Alb), serum creatinine, aspartate transferase, total cholesterol (T-cho), serum sodium, C-reactive protein (CRP), and squamous cell carcinoma antigen levels. The drug-related data included prior neoadjuvant chemotherapy [CF, tegafur/gimeracil/oteracil potassium, and cisplatin (SP)] and the initial dose of docetaxel, cisplatin, and 5-fluorouracil. The nutrition-related parameters included prognostic nutritional index (PNI), geriatric nutrition risk index (GNRI), and controlling nutrition score (CONUT). The immune-related parameters included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), CRP-to-albumin ratio (CAR), combination of platelet count and NLR (COP-NLR), and modified Glasgow prognostic score (mGPS).

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 (23). Dysphagia was described with the Mellow and Pinkas score (24) 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 DCF chemotherapy. Based on the Hb level, the patients 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) (25). GNRI was calculated as 14.89 × Alb (g/dl) + 41.7 × body weight (kg)/ideal body weight (kg) (26). 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 the 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 the 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, ≥1,600; 1, 1,200-1,599; 2, 800-1,199; 3, <800), and T-cho (0, ≥180; 1, 140-179; 2, 100-139; 3, <100) (27). The CONUT score was defined based on the total scores for these points. NLR was calculated as neutrophil count/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 the COP-NLR score of 2. Patients with one or no abnormal values were assigned the COP-NLR score of 1 or 0, respectively (28). 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 (29).

Outcome. The primary outcome was the incidence of FN in cycle 1 of DCF chemotherapy. FN was defined as having an axillary temperature of ≥37.5°C and neutropenia with a neutrophil count of <500/mm3 or neutrophil count of <1,000/mm3 that was 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 recorded from pre-treatment to day 21.

RDI. We examined the completion rate, % dose, duration of administration, and RDI of DCF chemotherapy until three cycles. The RDI was calculated for each patient as the actual dose divided by the standard dose. The RDI of DCF chemotherapy was represented as the average RDI, which was calculated as follows: the sum of RDI for docetaxel, cisplatin, and 5-fluorouracil divided by the number of drugs in the DCF regimen. If treatment was withdrawn due to adverse effects, the RDI for the next cycle was calculated as 0. In contrast, if treatment was discontinued due to progressive disease or loss to follow-up by changing hospitals, the RDI was calculated until the cycle up to the observation period.

Statistical analysis. We compared the baseline characteristics of the FN and non-FN groups. Univariate analysis was performed using the chi-squared test or Fisher’s exact test for categorical variables. Significant variables (p<0.05) extracted using univariate analysis were entered into the multivariate analysis after excluding correlated factors. The multivariate analysis was performed using logistic regression analysis. Significant independent variables contributing to the incidence of DCF chemotherapy-induced FN were extracted using a stepwise selection method by adding cStage and prior neoadjuvant chemotherapy. p-Values <0.05 were considered statistically significant. All statistical analyses were performed using SPSS version 25 (IBM, Tokyo, Japan).

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

We compared % dose, duration of administration (day), RDI (%) of each cycle, and total RDI (%) of the FN and non-FN groups using Mann–Whitney U-test. In addition, we compared the completion rates of each cycle and the proportion of patients with total RDI ≥85% in the FN and non-FN groups using the chi-squared test or Fisher’s exact test.

Results

Patient characteristics. Table I shows the characteristics of the 100 patients. The median age was 66 years (range=43-78 years), and 82 patients (82%) were men. The median BMI was 20.4 kg/m2 (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 in cycle 1 was administered 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.

View this table:
Table I.

Patient characteristics (n=100).

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

Univariate analysis. In the FN group, age ≥65 years, neutrophil counts <2,000/mm3, anemia, Alb <3.5 g/dl, T-cho <180 mg/dl, PNI <45, GNRI <92, CONUT score ≥4, and COP-NLR score of 0 were significantly higher than those in the non-FN group (Table II).

View this table:
Table II.

Univariate analysis of predictors of febrile neutropenia (FN) after the administration of pegfilgrastim as primary prophylaxis in patients with esophageal cancer treated with docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy.

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 III).

View this table:
Table III.

Multivariate analysis of predictors for febrile neutropenia (FN) incidence after pegfilgrastim as primary prophylaxis in patients with esophageal cancer treated with docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy.

Changes in neutrophil counts. Figure 1 shows the changes in the neutrophil counts between the FN and non-FN groups. In the FN group, day 7-10 neutrophil counts were 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, the neutrophil counts on days 11-21 were not significantly different from those in the non-FN group.

Figure 1.
Figure 1.

Changes in the neutrophil count between the febrile neutropenia (FN) and non-FN groups in cycle 1 of docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy.

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

View this table:
Table IV.

Completion rate, % dose, duration of administration and relative dose intensity (RDI) of docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy.

The % dose of DCF chemotherapy in the FN group in cycles 2 and 3 was significantly lower 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 those in the non-FN group were 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 that in the non-FN group.

Proportion of patients with total RDI ≥85%. The proportion of patients with total RDI ≥85% in the FN group was lower than that 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 that in the non-FN group (Figure 2).

Figure 2.
Figure 2.

Proportion of patients with total relative dose intensity (RDI) ≥85% of docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy. FN: Febrile neutropenia.

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 a 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. On the basis of the results, GNRI and COP-NLR are useful indicators for determining appropriate early management strategies for patients at a high risk of FN when commencing DCF chemotherapy.

The FN group had significantly low neutrophil counts at the time of pegfilgrastim administration (median day 7) and delayed neutrophil recovery compared with 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 a total RDI <85%. There have been a few reports on the clinical effect of FN on the changes in neutrophil counts and RDI of DCF chemotherapy. Therefore, our findings demonstrate that early administration of pegfilgrastim for FN might lead to the maintenance of a high RDI.

GNRI is a nutrition-related parameter consisting of Alb and ideal body weight ratio. Many patients with esophageal cancer have a poor nutritional status because of the accompanying esophageal obstruction (30). According to the ASCO guidelines, a poor nutritional status has been reported as a predictor of FN (12). Nevertheless, the association between FN and poor nutritional status in esophageal cancer is not clear. We investigated the association of FN with a poor nutritional status using various nutrition-related parameters. 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 consists of ideal body weight ratio as a constituent factor, was considered to be a nutritional indicator reflecting a poor nutritional status that could not be assessed by Alb alone.

A poor nutrition status has an influence on the reduction in neutrophil function (31). It is known that a 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 a poor nutrition status related to a low Alb level and BMI (31, 32). Additionally, the increase in IL-6 level has been reported as a predictor of FN in patients with breast cancer (33). 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. Studies have reported that low levels of neutrophils, TLC, NLR, and Plt before treatment were predictors of neutropenia and FN (34-36). Therefore, we investigated predictive factors of FN using various immune-related parameters. The findings showed that the COP-NLR score of 0 had a greater effect on FN incidence 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. The COP-NLR score, which consists of three components, of 0 may reflect a decrease in the bone marrow function before chemotherapy rather than a single component. In other words, the 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.

Here, we evaluated the effect of FN on changes in the 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 its administration (37); 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 could not reduce the incidence of FN (38). 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 (39). 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 (40). Therefore, pegfilgrastim should be administered to patients at a high risk of FN within 7 days of the first cycle of DCF chemotherapy to prevent FN.

In this study, the proportion of patients with total RDI <85% was as high as 81% in the FN group. A prospective observational study also reported that RDI <85% was associated with shorter progression-free survival than RDI ≥85% (41). Therefore, patients at a high risk of FN with DCF chemotherapy may not be able to maintain RDI ≥85% despite the administration of pegfilgrastim on day 7. Additionally, it may lead to a lack of antitumor effect and poor prognosis after surgery; hence, it is critical to maintain a high RDI.

Limitations. 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 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 of 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 a high risk of DCF chemotherapy-induced FN. Furthermore, FN incidence after pegfilgrastim administration had a strong effect 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 in patients at a high risk of FN.

Footnotes

  • Author’s Contributions

    All Authors contributed to the study conception and design. Data collection was performed by T.I., M.Ki., 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.

  • Conflicts of Interest

    The Authors declare no conflicts of interest related to this study.

  • Received October 13, 2022.
  • Revision received October 22, 2022.
  • Accepted October 24, 2022.

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Predictive Factors of Febrile Neutropenia After Primary Prophylactic Pegfilgrastim With DCF Chemotherapy for Esophageal Cancer
TAKAHITO INAGAKI, MIKI SATO, MASAOKI KIN, KOJI OTSUKA, MASAHIKO MURAKAMI, MARI KOGO
Anticancer Research Dec 2022, 42 (12) 6071-6081; DOI: 10.21873/anticanres.16119
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