Clinical utility of pegfilgrastim on day 3 of preoperative docetaxel, cisplatin and 5-fluorouracil chemotherapy in elderly patients with resectable esophageal cancer

Introduction

Background

Esophageal cancer (EC) has the sixth highest cancer mortality rate worldwide (1). Its major histological subtypes are squamous cell carcinoma and adenocarcinoma. Esophageal squamous cell carcinoma (ESCC) accounts for 87% of ECs worldwide and is the more common histological subtype in East Asia and East Africa (2,3). Although multimodal treatments are used for locally advanced ESCC, prognosis remains poor. In Japan, preoperative chemotherapy with cisplatin and 5-fluorouracil (CF) was the standard treatment for resectable ESCC based on the results of the JCOG9907 trial (4). However, in Western countries, preoperative chemoradiation with carboplatin or paclitaxel, for example, is the standard treatment for resectable EC (5). The results of the JCOG1109 trial demonstrated the superiority of docetaxel, cisplatin, and 5-fluorouracil (DCF) over CF in terms of overall survival (OS), making DCF the new standard treatment for resectable ESCC (6).

However, preoperative DCF has been associated with high rates of hematological and non-hematological adverse events, including loss of appetite, neutropenia, and febrile neutropenia (FN). FN is sometimes fatal and occurred in 16.3% of all patients who received preoperative DCF in the JCOG1109 trial. The American Society of Clinical Oncology guidelines recommend primary prophylactic granulocyte colony-stimulating factor (G-CSF) for regimens with a high incidence of FN (≥20%) and in patients considered to be at high risk of FN, including elderly patients. In Japanese guidelines, however, there are no recommendations regarding the utility of prophylactic G-CSF in preoperative DCF for EC patients because of a lack of data (7). Primary prophylactic pegfilgrastim, long-acting G-CSF product, has been administered during or after preoperative DCF to reduce the risk of FN.

The incidence of FN was 29.7% in a phase II trial in which pegfilgrastim was administered on day 7 of preoperative DCF for ESCC (8), indicating that FN could not be prevented. However, FN was effectively prevented in a Phase II trial in which pegfilgrastim was administered on day 3 after preoperative DCF for ESCC (9,10), suggesting that pegfilgrastim administered on day 3 after DCF could reduce the incidence of FN. However, that study did not report comparison data in elderly patients with ESCC, and it remains unclear whether administering primary prophylactic pegfilgrastim on day 3 is beneficial in elderly patients with locally advanced ESCC.

The aim of this study was to evaluate the clinical utility of primary prophylactic pegfilgrastim administered on day 3 of preoperative DCF in elderly patients with resectable ESCC. We present this article in accordance with the STROBEreporting checklist (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-20/rc).

Methods

Study design and patients

This retrospective study included elderly patients with advanced EC who received preoperative DCF at the National Cancer Center Hospital in Japan between 2009 and 2022. Inclusion criteria were as follows: resectable stage II, III, or IVb EC with histologically proven squamous cell carcinoma; cT1N1–3M0, cT2–3N0–3M0, or cT1–3N0–3M1 (M1 disease limited to supraclavicular lymph node metastasis) (Union for International Cancer Control, TNM Classification of Malignant Tumors, 8th edition); patients aged 70 years and older; no prior history of systemic chemotherapy or radiotherapy; ECOG performance status 0 or 1; and organ functions are adequate [neutrophil count ≥1,500/µL, hemoglobin level ≥9.0 g/dL, platelet count ≥10⁵/µL, aspartate aminotransferase and alanine aminotransferase levels ≤100 IU/L, creatinine clearance (CCr) ≥60 mL/min]. We initiated the use of pegfilgrastim after recognizing its usefulness. Therefore, the no pegfilgrastim group (NPG) is more common in the first half of the observation period and the D3PG group in the second half.

Preoperetive DCF consisted of infusion of docetaxel (70 mg/m²/day) and cisplatin (70 mg/m²/day) on day 1 and continuous infusion of 5-fluorouracil (750 mg/m²/day) on days 1–5. Preoperative DCF was administered intravenously at 3-week intervals for up to 3 courses at the discretion of the attending physician based on the patient’s general condition and the effectiveness of treatment. Patients aged 75 years and older with PS 1 were allowed to reduce the dose of DCF by 20% from the first course. The dose of cisplatin was reduced by 20% in the subsequent cycle if CCr was 45≤ CCr <60 mL/min, reduced by 50% if CCr was 30≤ CCr <45 mL/min or stopped if CCr was <30 mL/min. The doses of 5-fluorouracil and docetaxel were reduced by 20% in the subsequent cycle if ≥ grade 3 diarrhea or mucositis were observed. The dose of DCF were reduced by 20% in the subsequent cycle if grade 4 neutropenia or ≥ grade 3 fatigue, anorexia or nausea were observed. If any adverse events did not recover to ≤ grade 2, the subsequent course was considered to be reduced or discontinued. Pegfilgrastim (3.6 mg) was administered subcutaneously on day 3 after initiation of DCF as primary prophylaxis. Patients who received G-CSF such as filgrastim and lenograstim for secondary prophylaxis were excluded. Instead of secondary prophylaxis, the dosage of DCF therapy for next course was reduced. The use of G-CSF was permitted as therapeutic use. Prophylactic antibiotic therapy (levofloxacin 500 mg/day or ciprofloxacin 600 mg/day) was administered during the first 5–15 days of each course of preoperative DCF.

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Clinical Trial Review Committee of the National Cancer Center (approval No. 2020-287). The requirement for informed consent was waived in view of the retrospective observational nature of the research.

Assessments

The primary endpoint was the incidence of FN associated with up to 3 cycles of preoperative DCF. Secondary endpoints were grade ≥3 neutropenia, non-hematological toxicity, relative dose intensity (RDI) of DCF, postoperative histological response, relapse-free survival (RFS), and factors associated with RFS. As nadir is reported to be more common on days 7–8 after initiation of DCF therapy, the first blood test was performed 6–9 days and the second on 12–15 days (9). CT imaging was generally performed before and after completion of 1 and 3 courses of chemotherapy to assess the response. The severity of adverse events was assessed according to Common Terminology Criteria for Adverse Events version 5.0. RDI was calculated by dividing the scheduled dose by the actual dose administered. The scheduled duration of each cycle was 3 weeks and up to 3 cycles were evaluated; the RDI was evaluated in 3 weeks if DCF was completed in 1 cycle, the RDI was evaluated in 6 weeks if DCF was completed in 2 cycles, the RDI was evaluated in 9 weeks if DCF was completed in 3 cycles. Histopathological response was classified according to the proportion of tumor tissue that degenerated or became necrotic using the following grading system according to the Japanese Classification of Esophageal Cancer, 11th edition (11): grade 0, no part of tumor affected; grade 1a, less than one-third affected; grade 1b, between one-third and two-thirds affected; grade 2, between two-thirds and entire tumor affected; and grade 3, no residual tumor. RFS was defined as the time from the start of preoperative DCF to progression, presence of new lesions, or death in cases that underwent surgery and was censored in survival cases without progression.

Statistical analysis

Patient characteristics and toxicity were compared between groups using the chi-squared test or Fisher’s exact test. Survival curves was estimated using the Kaplan-Meier method and were compared using the log-rank test. Factors related to RFS were assessed by Cox hazard regression analysis.

Results

Patient characteristics and treatment procedure

Patient characteristics are shown in Table 1 and the treatment flow chart for all 60 patients who received preoperative DCF is presented in Figure 1. Thirty patients received pegfilgrastim on day 3 of each DCF cycle and the remaining 30 did not receive pegfilgrastim. There was a significant difference in clinical N stage between the two groups. For other characteristics, there were no significant differences.

Figure 1 Treatment flow chart for all patients who received preoperative DCF therapy. D3PG, day 3 pegfilgrastim group; NPG, no pegfilgrastim group; PD, progressive disease; FN, febrile neutropenia.

The treatment profiles are shown in Table 2. Three courses of preoperative DCF were completed by 80% of patients (24/30) in the day 3 pegfilgrastim group (D3PG) and 93% (28/30) in the NPG (P=0.25). Two patients in the D3PG developed progressive disease, 1 developed FN, and 1 developed delirium during the first course of DCF; all 4 of these patients proceeded to surgery after the end of the first course. The remaining 26 patients in the D3PG received a second course of DCF, which was discontinued in 2 patients because of grade 2 nausea. Surgery was subsequently performed in these two patients. The remaining 24 patients received a third course of preoperative DCF. All these patients proceeded to the planned surgery, but one was found to be inoperable because of intraoperative peritoneal dissemination. Therefore, only 29 of the 30 patients ultimately underwent surgery. One patient in the NPG discontinued treatment after 1 course of DCF because of FN and proceeded to surgery. One of the remaining 29 patients developed progressive disease after 2 courses and proceeded to surgery. Twenty-eight patients underwent 3 courses of preoperative DCF, and ultimately all 30 patients underwent surgery. There were no patients who received postoperative adjuvant therapy.

Safety and efficacy

Adverse events during DCF are shown in Table 3. FN occurred in 3.3% of patients in the D3PG and 26.6% of those in the NPG (P=0.02), grade ≥3 neutropenia occurred in 10% and 70% (P<0.001), and leukocytosis in 73% and 0% (P<0.001), respectively. There were no significant differences between the groups in non-hematological adverse events, and no pegfilgrastim-related adverse events were observed such as bone pain, back pain, headache, arthralgia, and rash, and no pegfilgrastim-related adverse events were observed.

The RDI was 0.914 in the D3PG and 0.850 in the NPG for docetaxel (P=0.01), 0.858 and 0.844, respectively, for cisplatin (P=0.45), and 0.916 and 0.846 for 5-fluorouracil (P=0.01), with significant differences between the groups for docetaxel and 5-fluorouracil. Including patients whose admission was delayed by a few days due to the timing of admission, 70% completed the planned 9-week treatment schedule in D3PG, and 53.3% completed it in NPG. R0 resection was achieved in the 29 patients (100%) who underwent surgery in the D3PG and in 28 (93.3%) in the NPG, with R1 resection achieved in the remaining 2 (6.6%) in the NPG (P=0.49). In the D3PG, the histopathological response rate was 0% for grade 0, 24.1% (7/29) for grade 1a, 17.2% (5/29) for grade 1b, 34.5% (10/29) for grade 2, and 24.1% (7/29) for grade 3; the respective histopathological response rates in the NPG were 0% 0, 26.6% (8/30), 16.7% (5/30), 23.3% (7/30), and 33.3% (10/30). Histological response did not significantly differ between the groups (Table 4).

The 3-year RFS rate was 70.1% in the D3PG and 57.1% in the NPG (hazard ratio 0.58, 95% confidence interval: 0.206–1.661, P=0.30; Figure 2). The median follow-up period was 17.8 months in the D3PG and 62.8 months in the NPG. Multivariate analysis of factors associated with RFS showed that an N stage higher than N2 was a significant risk factor (P=0.01) but pegfilgrastim was not (P=0.07; Table 5).

Figure 2 Kaplan-Meier curves for RFS. The 3-year RFS was 70.1% in the D3PG and 57.1% in the NPG (hazard ratio =0.58, 95% confidential interval: 0.206–1.661, P=0.30). Median follow-up period was 17.8 months in the D3PG and 62.8 months in the NPG. D3PG, day 3 pegfilgrastim group; NPG, no pegfilgrastim group; RFS, relapse-free survival.

Discussion

This retrospective parallel-group comparative observational study demonstrated the clinical utility of pegfilgrastim administration on day 3 after initiation of preoperative DCF for preventing FN and maintaining treatment dose intensity in elderly patients with resectable ESCC. This study is also the first to demonstrate the clinical benefit of primary prophylactic pegfilgrastim during preoperative DCF by comparing elderly patients with resectable ESCC who did and did not receive pegfilgrastim.

Preoperative DCF is reported to be associated with a high incidence of FN, which ranges from 3.1% to 22.9% (6,12-14). In this study, FN developed in 26.6% of patients in the NPG but in only 3.3% of those in the D3PG. In a prospective study with the same subjects as the present study except for age, there was no incidence of FN at all (9). However, in that prospective phase 2 study, the age of eligible patients was 62 years (range, 44–75 years), which was younger than in the present study. Therefore, primary prophylactic G-CSF might not necessary for all patients receiving DCF, but it is recommended for those with higher risk factors for FN such as elderly patients and those with repeated aspiration.Therefore, primary prophylactic G-CSF might not necessarily be required in all patients receiving DCF but is recommended for patients with risk factors for FN such as the elderly. Furthermore, in terms of short-term efficacy, we found not only a significant reduction in frequency of FN and hematological toxicity but also a significant increase in RDI in the D3PG. Higher RDI of D3PG may lead to a numerically higher histopathologic response and longer RFS in D3PG, although no significant difference could be demonstrated due to the small sample size. In a study of patients with head and neck cancer, there were significantly fewer cases of FN and delays in administration of chemotherapy in the group that received G-CSF during administration of DCF than in the group that received pegfilgrastim on day 7. Furthermore, OS was significantly shorter in the group at high risk of infection (≥ grade 3 neutropenia and FN) than in the group at low risk. Therefore, administration of G-CSF during DCF could be expected to prevent delays in administration of chemotherapy because of neutropenia and infection, thereby maintaining treatment intensity and improving prognosis (15). In our study, patient background characteristics differed between the groups, with the D3PG including patients with more advanced disease, in whom a significant prognostic impact of primary prophylactic pegfilgrastim may have been harder to demonstrate. There are several reports on the prophylactic administration of pegfilgrastim on day 7 in DCF therapy for EC (10,16). According to them, its benefit is debatable.

Although pegfilgrastim-related adverse events have been reported, none were observed in our patients. One patient in the D3PG had grade 2 hepatic dysfunction possibly due to DCF. There is concern that administration of G-CSF during chemotherapy may exacerbate neutropenia by inducing proliferation of immature neutrophils. However, leukopenia and neutropenia were not more common in the D3PG compared with the NPG. Therefore, DCF chemotherapy may be safely administered without an increase in FN during treatment with pegfilgrastim. In this study, there was no significant differences between the groups in either hematological toxicity or nonhematologic toxicity except for FN, indicating that pegfilgrastim is safe in elderly patients with ESCC.

This study had some limitations. First, it had a single-center, retrospective design, and the impact of pegfilgrastim on prognosis could not be fully investigated because of differences in patient background characteristics between the D3PG and NPG. The safety of pegfilgrastim in DCF should be thoroughly examined as well as efficacy. Prospective parallel-group studies on the utility of G-CSF are warranted, as the need for G-CSF might increase with increasing therapeutic intensity to improve the clinical outcomes of EC. Second, prophylactic antibiotic therapy was administered in all patients. Therefore, we could not evaluate the impact of pegfilgrastim alone on the risk of FN. Third, given that the dose of pegfilgrastim in Japan is 3.6 mg, the 6.0 mg dose used in other countries was not examined.

Conclusions

Primary prophylactic pegfilgrastim on day 3 after initiation of preoperative DCF significantly reduced the risks of FN and ≥ grade 3 neutropenia during 3 courses of preoperative DCF in elderly patients with ESCC.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-20/rc

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-20/prf

Data Sharing Statement: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-20/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-20/coif). K.K. serves as an unpaid editorial board member of Annals of Esophagus from December 2023 to November 2025. K.K. reports funding to the institution from Merck Sharp & Dohme Corp (MSD), Ono Pharmaceuticals, Bristol Myers Squibb (BMS), Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Clinical Trial Review Committee of the National Cancer Center (approval No. 2020-287). The requirement for informed consent was waived in view of the retrospective observational nature of the research.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Arnold M, Ferlay J, van Berge Henegouwen MI, et al. Global burden of oesophageal and gastric cancer by histology and subsite in 2018. Gut 2020;69:1564-71. [Crossref] [PubMed]
3. Watanabe M, Tachimori Y, Oyama T, et al. Comprehensive registry of esophageal cancer in Japan, 2013. Esophagus 2021;18:1-24. [Crossref] [PubMed]
4. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012;19:68-74. [Crossref] [PubMed]
5. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 2015;16:1090-8. [Crossref] [PubMed]
6. Kato K, Machida R, Ito Y, et al. Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial. Lancet 2024;404:55-66. [Crossref] [PubMed]
7. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3199-212. [Crossref] [PubMed]
8. Maeda O, Fukaya M, Koike M, et al. Preoperative docetaxel, cisplatin, and fluorouracil treatment with pegfilgrastim on day 7 for patients with esophageal cancer: A phase II study. Asia Pac J Clin Oncol 2022;18:578-85. [Crossref] [PubMed]
9. Ishikawa T, Yasuda T, Okayama T, et al. Early administration of pegfilgrastim for esophageal cancer treated with docetaxel, cisplatin, and fluorouracil: A phase II study. Cancer Sci 2019;110:3754-60. [Crossref] [PubMed]
10. Kawahira M, Yokota T, Hamauchi S, et al. Primary prophylactic granulocyte colony-stimulating factor according to ASCO guidelines has no preventive effect on febrile neutropenia in patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy. Int J Clin Oncol 2018;23:1189-95. [Crossref] [PubMed]
11. Japanese Classification of Esophageal Cancer, 11th Edition: part I. Esophagus 2017;14:1-36.
12. Hara H, Tahara M, Daiko H, et al. Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma. Cancer Sci 2013;104:1455-60. [Crossref] [PubMed]
13. Yokota T, Kato K, Hamamoto Y, et al. Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer. Br J Cancer 2016;115:1328-34. [Crossref] [PubMed]
14. Nomura H, Hatogai K, Maki Y, et al. Risk factors for febrile neutropenia in neoadjuvant docetaxel, cisplatin, and 5-fluorouracil chemotherapy for esophageal cancer. Support Care Cancer 2020;28:1849-54. [Crossref] [PubMed]
15. Linot B, Augereau P, Breheret R, et al. Efficacy and safety of early G-CSF administration in patients with head and neck cancer treated by docetaxel-cisplatin and 5-fluorouracil (DCF protocol): a retrospective study. Support Care Cancer 2014;22:2831-7. [Crossref] [PubMed]
16. Okamoto K, Ninomiya I, Saito H, et al. Usefulness of Prophylactic Administration of Pegfilgrastim for Esophageal Cancer Chemotherapy: A Single-center Retrospective Study. Anticancer Res 2022;42:2783-90. [Crossref] [PubMed]