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

Clinical utility of pegfilgrastim on day 3 of preoperative docetaxel, cisplatin and 5-fluorouracil chemotherapy in elderly patients with resectable esophageal cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical utility of pegfilgrastim on day 3 of preoperative docetaxel, cisplatin and 5-fluorouracil chemotherapy in elderly patients with resectable esophageal cancer Go Ikeda, Shun Yamamoto, Ikuko Azuma, Toru Kadono, Akihiro Ohara, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3841545/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Preoperative docetaxel, cisplatin, and 5-fluorouracil (DCF) has become the standard treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 trial. However, preoperative DCF is associated with a high frequency of febrile neutropenia (FN), especially in elderly patients with risk factors for FN. The utility of primary prophylactic pegfilgrastim (PPP) on day 3 of preoperative DCF for preventing FN was demonstrated in a Phase II study, but it did report comparison data in elderly ESCC patients. We aimed to evaluate the utility of PPP in these patients. Methods We retrospectively evaluated the clinical utility of PPP on day 3 of preoperative DCF in elderly patients with resectable ESCC. The patients were divided into a day 3 pegfilgrastim group (D3PG) and a no pegfilgrastim group (NPG). The incidence of FN and grade ≥ 3 neutropenia, histopathological effects, and relapse-free survival (RFS) were compared between the groups. Results Thirty patients were enrolled in each group. FN was observed in 3.3% of patients in the D3PG and 26.6% of those in the NPG ( p = 0.026), and grade ≥ 3 neutropenia was observed in 10% and 70%, respectively ( p < 0.001). The pathological complete response rate was 24.1% in the D3PG and 33.3% in the NPG ( p = 0.436); the respective 3-year RFS rates were 70.1% and 57.1% ( p = 0.304). Conclusion PPP on day 3 of preoperative DCF significantly reduced the risks of FN and grade ≥ 3 neutropenia in elderly patients with ESCC. There was no significant difference between the groups in histological effects or RFS. Esophageal cancer Pegfilgrastim Febrile neutropenia Preoperative chemotherapy DCF Figures Figure 1 Figure 2 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 CF plus docetaxel (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 (PPP) 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 PPP on day 3 is beneficial in elderly patients with locally advanced ESCC. The aim of this study was to evaluate the clinical utility of PPP administered on day 3 of preoperative DCF in elderly patients with resectable ESCC. Methods Study design and patients This retrospective study included elderly patients (aged ≥ 70 years) 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); renal and liver function within normal limits on blood tests; creatinine clearance ≥ 60 mL/min and aspartate aminotransferase and alanine aminotransferase levels ≤ 100 IU/L; and no previous treatment for EC. Pegfilgrastim (3.6 mg) was administered subcutaneously on day 3 after initiation of DCF as primary prophylaxis. Patients who received pegfilgrastim for secondary prophylaxis were excluded. 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. Chemotherapy consisted of infusion of docetaxel (70 mg/m 2 /day) and cisplatin (70 mg/m 2 /day) on day 1 and continuous infusion of 5-fluorouracil (750 mg/m 2 /day) on days 1–5. 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. The study was approved by the Clinical Trial Review Committee of the National Cancer Center (approval number: 2020 − 287) and was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The requirement for informed consent was waived in view of the retrospective observational nature of the research. Patient consent was obtained by the opt-out route. Assessments CT imaging was generally performed before and after completion of 1 and 3 courses of chemotherapy to assess the response. 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, recurrence-free survival (RFS), and factors associated with RFS. 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 for patients who received 3 cycles was 9 weeks. 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. 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 Fig. 1. Thirty patients received pegfilgrastim on day 3 of each DCF cycle (D3PG) and the remaining 30 did not receive pegfilgrastim (NPG). Table 1 Patient demographic and clinical characteristics D3PG (%) n = 30 NPG (%) n = 30 p - value Age (years) Median (range) 73 (70–80) 72 (70–78) 0.188 Sex Male/Female 23 (77)/7 (23) 26 (87)/4(13) 0.505 ECOG PS 0/1/2 17 (57)/11 (36)/2 (7) 15 (50)/15 (50)/ 0 0.312 Site of primary tumor Ut/Mt/Lt 5 (17)/18 (60)/7 (23) 4 (13)/17 (57)/9 (30) 0.876 cT stage T1/T2/T3 0/3 (10)/27 (90) 2 (7)/3 (10)/25 (83) 0.590 cN stage N0/N1/N2/N3 1 (3)/7 (23)/14 (47)/8 (27) 5 (17)/18 (60)/5 (16)/2 (7) 0.001 cStage (TNM 8th) IB/II/III/IVA/IVB 0/1 (3)/16 (54)/4 (13)/9 (30) 2 (7) /5 (17)/20 (66)/2 (7)/ 1(3) 0.009 D3PG, day 3 pegfilgrastim group; DCF, docetaxel, cisplatin, and 5-fluorouracil; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Lt, lower thoracic; Mt, middle thoracic; NPG, no pegfilgrastim group; Ut, upper thoracic The treatment profiles are shown in Table 2 . Three courses of preoperative DCF were completed by 80% of patients (24/30) in the D3PG and 93% (28/30) in the NPG ( p = 0.254). 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 2 patients. The remaining 24 patients received a third course of preoperative DCF. All these patients proceeded to the planned surgery, but 1 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. The RDIs for patients who received 3 courses were compared between the groups. The RDI was 0.914 in the D3PG and 0.850 in the NPG for docetaxel ( p = 0.013), 0.858 and 0.844, respectively, for cisplatin ( p = 0.445), and 0.916 and 0.846 for 5-FU ( p = 0.011), with significant differences between the groups for docetaxel and 5-FU. Table 2 Treatment profiles D3PG (%) n = 30 NPG (%) n = 30 p -value Treatment completion rate for 3 DCF cycles 24/30 (80) 28/30 (93) 0.254 RDI for patients who completed three DCF cycles Docetaxel 0.914 0.850 0.013 Cisplatin 0.858 0.844 0.445 5-Fluorouracil 0.916 0.846 0.011 D3PG, day 3 pegfilgrastim group; DCF, docetaxel, cisplatin, and 5-fluorouracil; NPG, no pegfilgrastim group; RDI, relative dose intensity 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 = 0.026), 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, including pegfilgrastim-related adverse events, such as bone pain, back pain, headache, arthralgia, and rash, and no pegfilgrastim-related adverse events were observed. Table 3 Adverse events D3PG (%) n = 30 NPG (%) n = 30 p -value Grade All 1 2 3 4 ≥ 3 (%) All 1 2 3 4 ≥ 3 (%) Leukopenia 4 0 0 2 2 4 (13) 23 0 8 14 1 15 (50) 0.005 Neutropenia 5 1 1 0 3 3 (10) 28 2 5 9 12 21 (70) < 0.001 Leukocytosis 22 - - 22 - 22 (73) 0 - - 0 0 0 < 0.001 Thrombocytopenia 17 9 3 5 0 5 (17) 29 28 1 0 0 0 0.052 Anemia 29 21 7 1 0 1 (3) 27 23 4 0 0 0 1 Fatigue 23 22 1 0 0 0 18 11 5 2 0 2 (7) 0.492 Anorexia 22 13 8 1 0 1 (3) 26 13 12 1 0 1 (3) 1 Nausea 13 9 4 0 0 0 16 10 4 2 0 2 (7) 0.492 Mucositis 15 10 5 0 0 0 15 8 7 0 0 Diarrhea 7 5 2 0 0 0 10 4 4 2 0 2 (7) 0.492 Creatinine increased 6 3 3 0 0 0 4 1 3 0 0 0 - Febrile neutropenia 1 - - 1 0 1 (3) 8 - - 8 0 8 (27) 0.026 D3PG, day 3 pegfilgrastim group; NPG, no pegfilgrastim group R0 resection was achieved in the 29 patients (100%) who underwent surgery in the D3PG and in 28 (93%) in the NPG, with R1 resection achieved in the remaining 2 (7%) in the NPG ( p = 0.492). 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% (5/29) 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 ). Table 4 Surgical outcomes D3PG group (%) n = 30 NPG group (%) n = 30 p -value Surgical curability R0 29 (100) 28 (93) 0.492 R1 0 2 (7) R2 0 0 Histopathological response Grade 3 7 (24) 10 (33) 0.775 Grade 2 10 (35) 7 (23) Grade 1b 5 (17) 5 (17) Grade 1a 7 (24) 8 (27) D3PG, day 3 pegfilgrastim group; NPG, no pegfilgrastim group 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 = 0.304; Fig. 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 = 0.015) but pegfilgrastim was not ( p = 0.067; Table 5 ). Table 5 Multivariate analysis for relapse-free survival Factor Hazard ratio (95% confidence interval) p -value Pegfilgrastim D3PG/NPG 0.325 (0.098–1.082) 0.067 cN stage N ≥ 2/N < 2 4.278 (1.323–13.830) 0.015 ECOG PS 0/1–2 1.892 (0.654–5.475) 0.240 Age, years ≥ 72/<72 0.655 (0.239–1.797) 0.412 Sex Male/Female 0.431 (0.141–1.314) 0.139 D3PG, day 3 pegfilgrastim group; DCF, docetaxel, cisplatin, and 5-fluorouracil; ECOG PS, Eastern Cooperative Oncology Group Performance Status; NPG, no pegfilgrastim group 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 PPP during preoperative DCF by comparing patients who did and did not receive pegfilgrastim. Preoperative DCF is reported to be associated with a high incidence of FN, which ranges from 3.1–22.9% [ 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. 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. Furthermore, in terms of short-term efficacy, we found statistically significant reductions in hematological toxicity, RDI, and frequency of FN in the D3PG. RFS as a long-term endpoint tended to be better in the D3PG than in the NPG, although no significant difference could be demonstrated. 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 PPP may have been harder to demonstrate. 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. 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. In conclusion, PPP 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. Declarations Acknowledgements We would like to thank the members of the National Cancer Center Hospital Japan for their support of this work. References Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. 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Support Care Cancer 28:1849–1854 Linot B, Augereau P, Breheret R et al (2014) 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 22:2831–2837 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Byoin","correspondingAuthor":false,"prefix":"","firstName":"Shigeki","middleName":"","lastName":"Sekine","suffix":""},{"id":268399212,"identity":"9614abcc-b44a-4737-bd84-95eb14858145","order_by":11,"name":"Koshiro Ishiyama","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Koshiro","middleName":"","lastName":"Ishiyama","suffix":""},{"id":268399213,"identity":"c720917f-d8d4-4432-adf5-855f2b880cb1","order_by":12,"name":"Junya Oguma","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Junya","middleName":"","lastName":"Oguma","suffix":""},{"id":268399214,"identity":"728f4426-572e-4368-914e-90bba98a1491","order_by":13,"name":"Hiroyuki Daiko","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Daiko","suffix":""},{"id":268399215,"identity":"74e17bcb-7fc8-4b39-b05e-c67512bff25a","order_by":14,"name":"Katsuhiko Iwakiri","email":"","orcid":"","institution":"Nippon Medical School Hospital: Nihon Ika Daigaku Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Katsuhiko","middleName":"","lastName":"Iwakiri","suffix":""},{"id":268399216,"identity":"ea23b48f-bed4-4138-b2b2-e12c6eea9407","order_by":15,"name":"Ken Kato","email":"","orcid":"https://orcid.org/0000-0002-1733-5072","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Ken","middleName":"","lastName":"Kato","suffix":""}],"badges":[],"createdAt":"2024-01-07 05:53:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3841545/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3841545/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50116542,"identity":"b4169bfb-e268-4b7e-a846-ac2f1e007fd5","added_by":"auto","created_at":"2024-01-24 18:51:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47914,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment flow chart for all patients who received preoperative DCF therapy.\u003c/p\u003e\n\u003cp\u003eD3PG, day 3 pegfilgrastim group; FN, febrile neutropenia; NPG, no pegfilgrastim group; PD, progressive disease.\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-3841545/v1/c2c7f121c8707e7cc34462d1.png"},{"id":50116543,"identity":"5c6c5bb8-1908-421c-8b45-e0ed23747918","added_by":"auto","created_at":"2024-01-24 18:51:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14125,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for RFS.\u003c/p\u003e\n\u003cp\u003eThe 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, \u003cem\u003ep\u003c/em\u003e=0.304). 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.\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-3841545/v1/f7a7319565982b005ea5e916.png"},{"id":51290400,"identity":"a702f986-a605-4365-a685-8fd65b6261cd","added_by":"auto","created_at":"2024-02-18 20:54:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":354086,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3841545/v1/23105284-6eed-442b-8d71-ec8f6135ce05.pdf"}],"financialInterests":"","formattedTitle":"Clinical utility of pegfilgrastim on day 3 of preoperative docetaxel, cisplatin and 5-fluorouracil chemotherapy in elderly patients with resectable esophageal cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eEsophageal cancer (EC) has the sixth highest cancer mortality rate worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, in Western countries, preoperative chemoradiation with carboplatin or paclitaxel, for example, is the standard treatment for resectable EC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The results of the JCOG1109 trial demonstrated the superiority of CF plus docetaxel (DCF) over CF in terms of overall survival (OS), making DCF the new standard treatment for resectable ESCC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, 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 (\u0026ge;\u0026thinsp;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. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Primary prophylactic pegfilgrastim (PPP) has been administered during or after preoperative DCF to reduce the risk of FN.\u003c/p\u003e \u003cp\u003eThe incidence of FN was 29.7% in a Phase II trial in which pegfilgrastim was administered on day 7 of preoperative DCF for ESCC [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], 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 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], 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 PPP on day 3 is beneficial in elderly patients with locally advanced ESCC.\u003c/p\u003e \u003cp\u003eThe aim of this study was to evaluate the clinical utility of PPP administered on day 3 of preoperative DCF in elderly patients with resectable ESCC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis retrospective study included elderly patients (aged\u0026thinsp;\u0026ge;\u0026thinsp;70 years) 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); renal and liver function within normal limits on blood tests; creatinine clearance\u0026thinsp;\u0026ge;\u0026thinsp;60 mL/min and aspartate aminotransferase and alanine aminotransferase levels\u0026thinsp;\u0026le;\u0026thinsp;100 IU/L; and no previous treatment for EC. Pegfilgrastim (3.6 mg) was administered subcutaneously on day 3 after initiation of DCF as primary prophylaxis. Patients who received pegfilgrastim for secondary prophylaxis were excluded. 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. Chemotherapy consisted of infusion of docetaxel (70 mg/m\u003csup\u003e2\u003c/sup\u003e/day) and cisplatin (70 mg/m\u003csup\u003e2\u003c/sup\u003e/day) on day 1 and continuous infusion of 5-fluorouracil (750 mg/m\u003csup\u003e2\u003c/sup\u003e/day) on days 1\u0026ndash;5. Prophylactic antibiotic therapy (levofloxacin 500 mg/day or ciprofloxacin 600 mg/day) was administered during the first 5\u0026ndash;15 days of each course of preoperative DCF.\u003c/p\u003e \u003cp\u003e The study was approved by the Clinical Trial Review Committee of the National Cancer Center (approval number: 2020\u0026thinsp;\u0026minus;\u0026thinsp;287) and was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The requirement for informed consent was waived in view of the retrospective observational nature of the research. Patient consent was obtained by the opt-out route.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAssessments\u003c/h2\u003e \u003cp\u003eCT imaging was generally performed before and after completion of 1 and 3 courses of chemotherapy to assess the response. The primary endpoint was the incidence of FN associated with up to 3 cycles of preoperative DCF. Secondary endpoints were grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia, non-hematological toxicity, relative dose intensity (RDI) of DCF, postoperative histological response, recurrence-free survival (RFS), and factors associated with RFS. 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 for patients who received 3 cycles was 9 weeks. 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 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]: 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. Patient characteristics and toxicity were compared between groups using the chi-squared test or Fisher\u0026rsquo;s exact test. Survival curves was estimated using the Kaplan\u0026ndash;Meier method and were compared using the log-rank test. Factors related to RFS were assessed by Cox hazard regression analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics and treatment procedure\u003c/h2\u003e \u003cp\u003ePatient characteristics are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and the treatment flow chart for all 60 patients who received preoperative DCF is presented in Fig.\u0026nbsp;1. Thirty patients received pegfilgrastim on day 3 of each DCF cycle (D3PG) and the remaining 30 did not receive pegfilgrastim (NPG).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient demographic and clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eD3PG (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNPG (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e- value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (70\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 (70\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.188\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003eMale/Female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (77)/7 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (87)/4(13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003cp\u003e0/1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (57)/11 (36)/2 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (50)/15 (50)/ 0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.312\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite of primary tumor\u003c/p\u003e \u003cp\u003eUt/Mt/Lt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (17)/18 (60)/7 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (13)/17 (57)/9 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.876\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecT stage\u003c/p\u003e \u003cp\u003eT1/T2/T3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/3 (10)/27 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7)/3 (10)/25 (83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.590\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN stage\u003c/p\u003e \u003cp\u003eN0/N1/N2/N3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3)/7 (23)/14 (47)/8 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (17)/18 (60)/5 (16)/2 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecStage (TNM 8th)\u003c/p\u003e \u003cp\u003eIB/II/III/IVA/IVB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/1 (3)/16 (54)/4 (13)/9 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7) /5 (17)/20 (66)/2 (7)/ 1(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eD3PG, day 3 pegfilgrastim group; DCF, docetaxel, cisplatin, and 5-fluorouracil; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Lt, lower thoracic; Mt, middle thoracic; NPG, no pegfilgrastim group; Ut, upper thoracic\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe treatment profiles are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Three courses of preoperative DCF were completed by 80% of patients (24/30) in the D3PG and 93% (28/30) in the NPG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.254). 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 2 patients. The remaining 24 patients received a third course of preoperative DCF. All these patients proceeded to the planned surgery, but 1 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. The RDIs for patients who received 3 courses were compared between the groups. The RDI was 0.914 in the D3PG and 0.850 in the NPG for docetaxel (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013), 0.858 and 0.844, respectively, for cisplatin (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.445), and 0.916 and 0.846 for 5-FU (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011), with significant differences between the groups for docetaxel and 5-FU.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment profiles\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eD3PG (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNPG (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment completion rate for 3 DCF cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24/30 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28/30 (93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eRDI for patients who completed three DCF cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDocetaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.914\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.850\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCisplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.858\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.844\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5-Fluorouracil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.916\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eD3PG, day 3 pegfilgrastim group; DCF, docetaxel, cisplatin, and 5-fluorouracil; NPG, no pegfilgrastim group; RDI, relative dose intensity\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSafety and efficacy\u003c/h3\u003e\n\u003cp\u003eAdverse events during DCF are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. FN occurred in 3.3% of patients in the D3PG and 26.6% of those in the NPG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026), grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia occurred in 10% and 70% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and leukocytosis in 73% and 0% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), respectively. There were no significant differences between the groups in non-hematological adverse events, including pegfilgrastim-related adverse events, such as bone pain, back pain, headache, arthralgia, and rash, and no pegfilgrastim-related adverse events were observed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eD3PG (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c13\" namest=\"c8\"\u003e \u003cp\u003eNPG (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e(13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e15\u003c/p\u003e \u003cp\u003e(50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e21\u003c/p\u003e \u003cp\u003e(70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukocytosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22\u003c/p\u003e \u003cp\u003e(73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e(17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.492\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.492\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucositis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.492\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine\u003c/p\u003e \u003cp\u003eincreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFebrile\u003c/p\u003e \u003cp\u003eneutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e8\u003c/p\u003e \u003cp\u003e(27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003eD3PG, day 3 pegfilgrastim group; NPG, no pegfilgrastim group\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eR0 resection was achieved in the 29 patients (100%) who underwent surgery in the D3PG and in 28 (93%) in the NPG, with R1 resection achieved in the remaining 2 (7%) in the NPG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.492). 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% (5/29) 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\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurgical outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eD3PG group (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNPG group (%)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eSurgical curability\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.492\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eHistopathological response\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.775\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eD3PG, day 3 pegfilgrastim group; NPG, no pegfilgrastim group\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe 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\u0026ndash;1.661, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.304; Fig.\u0026nbsp;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 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) but pegfilgrastim was not (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.067; Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis for relapse-free survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio (95% confidence interval)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePegfilgrastim\u003c/p\u003e \u003cp\u003eD3PG/NPG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.325 (0.098\u0026ndash;1.082)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN stage\u003c/p\u003e \u003cp\u003eN\u0026thinsp;\u0026ge;\u0026thinsp;2/N\u0026thinsp;\u0026lt;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.278 (1.323\u0026ndash;13.830)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003cp\u003e0/1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.892 (0.654\u0026ndash;5.475)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;72/\u0026lt;72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.655 (0.239\u0026ndash;1.797)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.412\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003eMale/Female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.431 (0.141\u0026ndash;1.314)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eD3PG, day 3 pegfilgrastim group; DCF, docetaxel, cisplatin, and 5-fluorouracil; ECOG PS, Eastern Cooperative Oncology Group Performance Status; NPG, no pegfilgrastim group\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis 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 PPP during preoperative DCF by comparing patients who did and did not receive pegfilgrastim.\u003c/p\u003e \u003cp\u003ePreoperative DCF is reported to be associated with a high incidence of FN, which ranges from 3.1\u0026ndash;22.9% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In this study, FN developed in 26.6% of patients in the NPG but in only 3.3% of those in the D3PG. 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. Furthermore, in terms of short-term efficacy, we found statistically significant reductions in hematological toxicity, RDI, and frequency of FN in the D3PG. RFS as a long-term endpoint tended to be better in the D3PG than in the NPG, although no significant difference could be demonstrated. 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\u0026thinsp;\u0026ge;\u0026thinsp;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 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. 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 PPP may have been harder to demonstrate.\u003c/p\u003e \u003cp\u003eAlthough 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.\u003c/p\u003e \u003cp\u003eThis 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. 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.\u003c/p\u003e \u003cp\u003eIn conclusion, PPP on day 3 after initiation of preoperative DCF significantly reduced the risks of FN and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia during 3 courses of preoperative DCF in elderly patients with ESCC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe would like to thank the members of the National Cancer Center Hospital Japan for their support of this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J Clin 71:209\u0026ndash;249\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArnold M, Ferlay J, van Berge Henegouwen MI et al (2020) Global burden of oesophageal and gastric cancer by histology and subsite in 2018. Gut 69:1564\u0026ndash;1571\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatanabe M, Tachimori Y, Oyama T et al (2021) Comprehensive registry of esophageal cancer in Japan, 2013. Esophagus 18:1\u0026ndash;24\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndo N, Kato H, Igaki H et al (2012) 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 19:68\u0026ndash;74\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShapiro J, van Lanschot JJB, Hulshof M et al (2015) Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 16:1090\u0026ndash;1098\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuko Kitagawa R, Ishihara H, Ishikawa et al (2023) Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part1. Esophagus 20:343\u0026ndash;372\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith TJ, Bohlke K, Lyman GH et al (2015) Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 33:3199\u0026ndash;3212\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaeda O, Fukaya M, Koike M et al (2022) 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 18:578\u0026ndash;585\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshikawa T, Yasuda T, Okayama T et al (2019) Early administration of pegfilgrastim for esophageal cancer treated with docetaxel, cisplatin, and fluorouracil: A phase II study. Cancer Sci 110(12):3754\u0026ndash;3760\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawahira M, Yokota T, Hamauchi S et al (2018) 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 23:1189\u0026ndash;1195\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsubara H, President F, Ando N et al (2017) Japanese Classification of Esophageal Cancer, 11th Edition: Part I. Vol 14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHara H, Tahara M, Daiko H et al (2013) Phase II feasibility study of preoperative with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma. Cancer Sci 104:1455\u0026ndash;1460\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYokota T, Kato K, Hamamoto Y et al (2016) 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 115:1328\u0026ndash;1334\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNomura H, Hatogai K, Maki Y et al (2020) Risk factors for febrile neutropenia in neoadjuvant docetaxel, cisplatin, and 5-fluorouracil chemotherapy for esophageal cancer. Support Care Cancer 28:1849\u0026ndash;1854\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLinot B, Augereau P, Breheret R et al (2014) 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 22:2831\u0026ndash;2837\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Esophageal cancer, Pegfilgrastim, Febrile neutropenia, Preoperative chemotherapy, DCF","lastPublishedDoi":"10.21203/rs.3.rs-3841545/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3841545/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePreoperative docetaxel, cisplatin, and 5-fluorouracil (DCF) has become the standard treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 trial. However, preoperative DCF is associated with a high frequency of febrile neutropenia (FN), especially in elderly patients with risk factors for FN. The utility of primary prophylactic pegfilgrastim (PPP) on day 3 of preoperative DCF for preventing FN was demonstrated in a Phase II study, but it did report comparison data in elderly ESCC patients. We aimed to evaluate the utility of PPP in these patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively evaluated the clinical utility of PPP on day 3 of preoperative DCF in elderly patients with resectable ESCC. The patients were divided into a day 3 pegfilgrastim group (D3PG) and a no pegfilgrastim group (NPG). The incidence of FN and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia, histopathological effects, and relapse-free survival (RFS) were compared between the groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThirty patients were enrolled in each group. FN was observed in 3.3% of patients in the D3PG and 26.6% of those in the NPG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026), and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia was observed in 10% and 70%, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The pathological complete response rate was 24.1% in the D3PG and 33.3% in the NPG (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.436); the respective 3-year RFS rates were 70.1% and 57.1% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.304).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePPP on day 3 of preoperative DCF significantly reduced the risks of FN and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neutropenia in elderly patients with ESCC. There was no significant difference between the groups in histological effects or RFS.\u003c/p\u003e","manuscriptTitle":"Clinical utility of pegfilgrastim on day 3 of preoperative docetaxel, cisplatin and 5-fluorouracil chemotherapy in elderly patients with resectable esophageal cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-24 18:51:21","doi":"10.21203/rs.3.rs-3841545/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"034ed7cd-aaf8-48e9-8ca7-04c75e045d46","owner":[],"postedDate":"January 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T10:26:39+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-24 18:51:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3841545","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3841545","identity":"rs-3841545","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}