Research ArticleClinical Studies

Usefulness of Prophylactic Administration of Pegfilgrastim for Esophageal Cancer Chemotherapy: A Single-center Retrospective Study

KOICHI OKAMOTO, ITASU NINOMIYA, HIROTO SAITO, MARI SHIMADA, TAKAHISA YAMAGUCHI, SHIRO TERAI, HIDEKI MORIYAMA, JUN KINOSHITA, KEISHI NAKAMURA and NORIYUKI INAKI
Anticancer Research May 2022, 42 (5) 2783-2790; DOI: https://doi.org/10.21873/anticanres.15758

Abstract

Background/Aim: To evaluate the impact of prophylactic administration of pegfilgrastim in esophageal cancer (EC) patients treated with chemotherapy consisted of docetaxel, cisplatin, and fluorouracil (DCF). Patients and Methods: Among 102 patients who received neoadjuvant or induction DCF for primary advanced EC, 65 received prophylactic pegfilgrastim and 37 did not. The association of pegfilgrastim with adverse events and clinicopathological outcomes was retrospectively analyzed. Results: In the pegfilgrastim group, the incidence of grade >3 neutropenia was lower (30.8% vs. 62.2%) and more patients avoided dose reduction or discontinuation of chemotherapy (32.3% vs. 70.3%). The radiological (PR≤) and histopathological (grade 1b≤) response rates were significantly higher (69.2% vs. 43.2% and 59.2% vs. 35.7%). Three-year overall survival and progression-free survival rates were significantly higher (65.0% vs. 48.6%, p=0.033; 56.1% vs. 35.1%, p=0.007, respectively). Conclusion: Prophylactic pegfilgrastim in DCF may relieve adverse events and improve the oncologic outcome of EC patients.

Key Words:

Chemotherapy plays a pivotal role in the treatment of advanced esophageal cancer (EC). The Japan Clinical Oncology Group 9907 study demonstrated the effectiveness of resection after neoadjuvant chemotherapy using cisplatin (CDDP) plus fluorouracil (CF) for patients with resectable esophageal squamous cell carcinoma (ESCC) (1, 2). Recent studies into the efficacy of preoperative or induction therapy using the more powerful triplet chemotherapy comprising docetaxel, cisplatin, and fluorouracil (DCF) has been increasingly selected for further improvement of the oncologic outcome of advanced ESCC (3-7). Despite the powerful antitumor effects of DCF, the severity and frequency of adverse events (AEs) including bone marrow suppression (BMS) and febrile neutropenia (FN) can exceed those of CF, docetaxel, and paclitaxel regimens. The incidence of FN in each EC chemotherapy regimen is reported to be 0.8% for CF, 18%-32% for docetaxel, and 3.8% for paclitaxel (2, 8, 9). The incidence of neutropenia caused by DCF is reported to be 62.5-76.9%, which is far higher than that caused by CF and DCF-induced serious AEs disturb the continuation of chemotherapy and reduced treatment intensity may result in poor antitumor effects (2, 4-7). Therefore, it is necessary to take preventive measures to suppress the occurrence of AEs and maintain the safely subsequent chemotherapy with enough dose intensity of anticancer drug.

The American Society of Clinical Oncology (ASCO), European Organization for research and Treatment of Cancer (EORTC), and National Comprehensive Cancer Network (NCCN) guidelines recommended the administration of primary prophylactic granulocyte colony-stimulating factor (G-CSF) when using a regimen with an FN incidence ≥20% (10-12). Pegfilgrastim is a long-acting G-CSF agent in which polyethylene glycol is chemically bonded to the N-terminus of filgrastim. The effectiveness of pegfilgrastim administration for preventing chemotherapy-induced BMS and FN has been investigated in clinical trials on chemotherapy for breast cancer, malignant lymphoma, gastrointestinal cancer, and lung cancer (13-18). Some studies have shown that use of G-CSF may not only be a supportive treatment in chemotherapy, but may have a potential direct impact on therapeutic efficacy and survival by increasing the intensity of the treatment, such as a dose-intense regimen with increased dose of anticancer drug per course (16, 17). The efficacy and the impact on oncological outcome of pegfilgrastim administration during DCF in patients with EC is not well documented. This study investigated the effectiveness of pegfilgrastim for the prophylaxis of DCF-induced BMS and assessed the impact of pegfilgrastim used in the initial DCF therapy on subsequent therapeutic strategies and patient outcomes.

Patients and Methods

Patients. A total of 102 patients were initially treated with DCF as a preoperative chemotherapy for resectable cStage II/III ESCC or induction chemotherapy for cStage IVa locally advanced unresectable ESCC at Kanazawa University Hospital between September 2012 and May 2020. After completing DCF, the patients’ general condition, therapeutic effect of DCF and resectability of EC were re-evaluated. We selected radical esophagectomy or definitive chemoradiotherapy (dCRT) with the aim of radical cure (Figure 1). Our basic surgical strategy is thoracoscopic esophagectomy; however, patients with unfavorable systemic conditions underwent transhiatal blunt esophagectomy. Patients with apparent T4b and/or serious systemic condition after induction therapy were not candidates for surgery and instead underwent dCRT. All patients were staged according to the 11th edition of the Japanese classification of EC (19). Data were collected and analyzed retrospectively.

Figure 1.
Figure 1.

Diagram of patient flow through the study.

Methods of chemotherapy and use of a long-acting G-CSF agent. From September 2012 to May 2020, DCF consisted of docetaxel (60-70 mg/m2, on day 1), CDDP (60-70 mg/m2, on day 1), and 5-fluorouracil (5-FU; 750-800 mg/m2, on days 1-5), repeated every 4 weeks (6, 7). Each regimen was basically administered for one to three courses according to cancer progression status and degree of AEs. Patients presenting with grade 3 or higher hematological toxicity mainly restarted 5-FU treatment at 20% dose reduction. Patients presenting with grade 3 or higher renal dysfunction or hyponatremia mainly restarted CDDP treatment at 20% dose reduction. Administration was stopped under the following conditions: manifestation of serious AEs or based on physician’s judgment. From January 2015, patients were routinely administered pegfilgrastim 24 h after the end of 5-FU administration of each course of DCF. In this study, we defined the patients treated with prophylactic pegfilgrastim administration as the pegfilgrastim group and the patients treated without pegfilgrastim as the control group. A steroid, 5-hydroxytryptamine 3 receptor blocker, and neurokinin 1 receptor blocker were administered routinely as prophylaxis for chemotherapy-induced nausea and vomiting, according to the NCCN guidelines in both the groups (20).

Assessment of chemotherapy-induced AEs. All AEs were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The incidence and severity of chemotherapy-induced AEs in all patients were investigated retrospectively from patient interviews and clinical examinations. The maximal severity of AEs during all the courses of chemotherapy in each patient were compared between both the groups retrospectively.

Evaluation of clinical and histological response to chemotherapy. The clinical response of measurable lesions was evaluated according to the Response Evaluation Criteria in Solid Tumors (21). The treatment response of each primary esophageal lesion was evaluated endoscopically in patients without measurable disease and categorized as follows: complete response (CR), partial response (PR), stable disease, or progressive disease. PR was defined as obvious morphological improvements, such as the flattening of the elevated or ulcerative lesions. The histopathological response was diagnosed according to the evaluation criteria of the Japan Esophageal Society (19) using a 5-grade scale as follows: grade 0, no recognizable cytological or histological therapeutic effect; grade 1a, viable cancer cells accounting for two-thirds or more of the tumor tissue; grade 1b, viable cancer cells accounting for one-third or more but less than two-thirds of the tumor tissue; grade 2, viable cancer cells accounting for less than one-third of the tumor tissue; and grade 3, no viable cancer cells.

Statistical analysis. The incidences of AEs and clinicopathological variables were analyzed using χ2, Fisher’s exact, Mann–Whitney U, and Student’s t-tests as appropriate. The Kaplan–Meier method was used to analyze survival, and log rank test was used to estimate differences in survival. We calculated the hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) using univariate and multivariate Cox proportional hazards regression model. Statistical significance was assumed for a two-sided p<0.05. All analyses were performed using SPSS [IBM Statistics version 25 (IBM, Armonk, NY, USA)].

Results

Demographic and clinical characteristics of EC patients treated with DCF. The clinical characteristics and a diagram of patient flow of the study population are shown in Table I and Figure 1, respectively. Surgery was performed in 77 of 102 cases (75.5%), and 62 out of 77 surgically resected cases (80.5%) received curative resection. Surgical T4b cases with unresectable invasion to the aorta, trachea, or bronchus resulted in noncurative resection. Between September 2012 and January 2015, 37 patients received DCF without pegfilgrastim as a historical control. After January 2015, prophylactic pegfilgrastim administration was performed in 65 patients during DCF therapy. There was no significant difference for any clinical characteristics examined, except for tumor length in the major axis and degree of differentiation, between the groups.

View this table:
Table I.

Characteristics of patients treated with or without prophylactic G-CSF agent.

Incidence and severity of chemotherapy-induced BMS and FN with and without pegfilgrastim. The incidences of chemotherapy-induced AEs of grade ≥3 and the severity of chemotherapy-induced leukopenia, neutropenia, and FN are shown in Table II. The incidence of leukopenia and neutropenia of all grades was significantly lower in the pegfilgrastim group compared with the control group (44.6% vs. 70.3%, p=0.026 and 49.2% vs. 73.0%, p=0.030, respectively). The incidences of leukopenia and neutropenia of grade ≥3 were also significantly lower in the pegfilgrastim group (27.7% vs. 51.4%, p=0.017 and 30.8% vs. 62.2%, p=0.002, respectively). The incidence of FN tended to be lower in the pegfilgrastim group than in the control group (12.3% vs. 18.9%, p=0.365). Patients in both groups with chemotherapy-induced severe BMS and FN were treated with antibiotics and additional G-CSF administration as appropriate. Significantly fewer patients were forced to discontinue or reduce 5-FU dose after the second chemotherapy due to DCF-induced BMS or FN (32.3% vs. 70.3%, p<0.001). As a result, the average number of chemotherapy courses performed was significantly higher in the pegfilgrastim group than in the control group (2.40±0.68 vs. 1.86±0.35, p<0.001). Furthermore, the average relative dose intensity of 5-FU could be maintained significantly higher in the pegfilgrastim group than in the control group (5-FU: 95.4±8.5% vs. 84.3±15.4%, p<0.001; CDDP: 97.0±8.6% vs. 95.7±13.9%, p=0.545; docetaxel: 97.5±8.0% vs. 94.6±15.7%, p=0.221).

View this table:
Table II.

Incidence and severity of adverse events induced by docetaxel, cisplatin, and fluorouracil therapy (CTCAE Grade ≥3).

Clinical response after chemotherapy. The response rates (CR+PR) of DCF in endoscopic and clinical overall response were significantly higher in the pegfilgrastim group than in the control group (78.5% vs. 59.5%, p=0.041 and 69.2% vs. 43.2%, p=0.010, respectively). The histopathological response rates in 49 surgically resected cases in the pegfilgrastim group were also higher than those in 28 resected cases in the control group (grade ≥1b, 55.1% vs. 35.7%, p=0.048) (Table III).

View this table:
Table III.

Clinicopathological anti-tumor effects induced by DCF therapy.

Survival. The median follow-up period for all patients who received DCF was 27.1 months (range=1.4-122.3 months). The 3-year overall survival rates of each EC cStage that received DCF were 100% in cStage II, 62.1% in cStage III, and 44.1% in cStage IVA (p=0.007). The survival curves of all cStages showed significantly better 3-year OS in the pegfilgrastim group than in the control group (65.0% vs. 48.6%, p=0.033) (Figure 2A). The 3-year survival rates in surgically resected cases were superior in the pegfilgrastim group than in the control group (71.2% vs. 57.1%, p=0.075) (Figure 2B). There were no significant differences between the two groups in terms of 3-year OS according to cStages (cStage II, 100% vs. 100%, p=0.248; cStage III, 78% vs. 50%, p=0.150; cStage IVa, 43.6% vs. 35.7%, p=0.405). The tumor recurrence rate in surgically resected cases tended to be lower in the pegfilgrastim group (36.7% vs. 57.1%, p=0.083). With respect to the recurrence patterns, the recurrence rate of hematogenous metastases in surgically resected cases tended to be lower in the pegfilgrastim group (16.3% vs. 35.7%, p=0.053). The 3-year PFS rate was higher in the pegfilgrastim group than in the control group (56.1% vs. 35.1%, p=0.007) (Figure 2C).

Figure 2.
Figure 2.

Survival curve of patients treated with or without prophylactic pegfilgrastim administration. Overall survival curves in all patients (A) and those in resected patients (B) in both groups. Progression-free survival curves in all patients treated with docetaxel, cisplatin, and fluorouracil in both groups (C). *p<0.05.

Clinicopathological factors associated with OS. Univariate analysis showed that tumor depth, pretreatment cStage, presence of surgery, and the use of pegfilgrastim were statistically significant prognostic factors for OS. Multivariate analysis revealed that tumor depth, presence of surgery, and the use of pegfilgrastim were statistically significant prognostic factors for OS (Table IV).

View this table:
Table IV.

Univariate and multivariate analyses of clinicopathological variables associated with overall survival.

Discussion

The present study provides evidence for the usefulness of pegfilgrastim (a long-acting G-CSF) on the prophylaxis of AEs and clinical outcome in patients receiving DCF for advanced EC.

The risk of occurrence and aggravation of BMS and FN depends on the type of disease, regimen of treatment, patient’s comorbidities, and purpose of treatment. The ASCO, EORTC, and NCCN guidelines list elderly patients, prior history of chemotherapy or radiotherapy, presence of infection, poor performance status, poor nutrition, renal dysfunction, liver dysfunction, chronic obstructive pulmonary disease, cardiovascular disease, and gastrointestinal mucosal damage as pivotal risk factors of developing FN (10-12). Conventionally, the risk may be reduced by decreasing the intensity of treatment in high-risk cases. In clinical practice, initial chemotherapy with prophylactic G-CSF to maintain treatment intensity is recommended in chemotherapy aimed at curing the disease or prolonging survival and in cases predicted to have a poor prognosis if treatment intensity is reduced (13, 14). Improvements in the safety of DCF by the usage of prophylactic pegfilgrastim are expected to concurrently prevent the deterioration of the patient’s general condition, cancer resistance, immune exhaustion, and quality of life caused by infectious diseases and malnutrition, thereby enabling the continuation of adequate chemotherapy and maintaining antitumor activity. Our results show improvements in clinical and histopathological responses by pegfilgrastim administration in resected cases. Since significant differences were observed in 3-year OS and PFS, this suggests that the use of pegfilgrastim contributes to a reductive effect of cancer tissue and a suppressive effect on circulating tumor cells rather than improving the resection rate. By contrast, the resection rate in cStage IVa borderline resectable cases did not improve despite maintaining relative dose intensity.

The disadvantages of using a G-CSF include the risk of serious AEs, such as anaphylactic shock, splenic rupture, and malignant changes in BMS due to bone marrow overstimulation. A meta-analysis reported that the incidence of secondary acute myeloid leukemia or myelodysplastic syndrome in patients supported by G-CSF increased from 0.36% to 0.79% in solid tumor and malignant lymphoma chemotherapy (22). Furthermore, the safety of simultaneous administration of G-CSF and anticancer drugs has not yet been established. Pegfilgrastim did not cause serious AEs in this study; however, more efficient administration methods, optimal timing, and more appropriate indications for pegfilgrastim usage are needed to avoid the onset of neutropenia, as pegfilgrastim does not prevent neutropenia in all cases.

The current study has several limitations. First, this was a retrospective analysis performed at a single institution. Additionally, the groups were treated at different time periods, and a relatively large number of cases with a short observation period were included.

In conclusion, this study shows that pegfilgrastim (a long-acting G-CSF) is effective in preventing AEs and improving clinical outcomes in patients receiving DCF for advanced EC.

Acknowledgements

The Authors are grateful to the nurses and pharmacists involved in the study. The Authors also thank Enago (www.enago.jp) for editing a draft of this manuscript.

Footnotes

  • Authors’ Contributions

    K.O. contributed to the study conception and design. H.S., M.S., T.Y., S.T., H.M., J.K, and K.N. contributed to the treatment of the patients and data acquisition. K.O. and I.N. contributed to the analysis of the data, interpretation of the outcomes, and writing of the report. N.I. contributed to editing, reviewing, and the final approval of the report. All Authors have read and approved the final manuscript.

  • Conflicts of Interest

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

  • Received March 4, 2022.
  • Revision received March 25, 2022.
  • Accepted March 28, 2022.

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