Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: A systematic review and meta-analysis from Clinical Practice Guidelines for the Use of G-CSF 2022

Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: A systematic review and meta-analysis from Clinical Practice Guidelines for the Use of G-CSF 2022 | 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 Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: A systematic review and meta-analysis from Clinical Practice Guidelines for the Use of G-CSF 2022 Tetsuhiro Yoshinami, Kazuki Nozawa, Takamichi Yokoe, Yukinori Ozaki, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3812794/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Apr, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain, were not apparent. Therefore, a single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN. PEG G-CSF single dose non-PEG G-CSF multiple doses Meta-analysis Figures Figure 1 Figure 2 Figure 3 Introduction Granulocyte colony-stimulating factor (G-CSF) is used in the primary prophylaxis of febrile neutropenia (FN) to improve the safety of chemotherapy, and it is recommended in some guidelines [ 1 – 4 ]. In Japan, two types of G-CSF are available. One is G-CSF chemically bound to polyethylene glycol (PEG G-CSF) to inhibit its degradation and delay its excretion [ 5 ]. PEG G-CSF can remain in blood for a long time, and a single dose is administered in each cycle. PEG G-CSF was approved in 2014 in Japan. The other option is normal G-CSF not bound to polyethylene glycol (non-PEG G-CSF), and it should be administered daily for several days for primary prophylaxis. Clinically, it has been debated whether single-dose PEG G-CSF is more useful for primary prophylaxis than multiple-dose non-PEG G-CSF. This clinical question must be answered in an evidence-based manner. Therefore, we conducted a systematic literature review to compare the benefits and harms of a single dose of PEG G-CSF with those of multiple doses of non-PEG G-CSF. This study was conducted as part of efforts to update Japanese practice guidelines. Materials and methods Search strategy The literature search was performed according to the “Medical information network distribution service (Minds) Handbook for Clinical Practice Guideline Development 2014” [ 6 ] and “Minds Clinical Practice Guideline Development Guide 2017” [ 7 ] using PubMed, Ichushi-Web (Japanese medical bibliographic database), and the Cochrane Library. The search terms included combinations of MeSH terms and keywords as follows: “pegfilgrastim,” “filgrastim,” “drug administration schedule,” and “administration and dosage.” No restriction regarding cancer types was implemented. The target period for screening spanned from January 1, 1999 to December 31, 2019. The initial screening was independently performed by two reviewers ( K.N. and Y.O. ) by reviewing the titles and abstracts of all articles to eliminate ineligible reports, followed by full-text screening according to the selection criteria pre-determined by the committee as inclusion of studies designed as randomized controlled trials (RCTs), non-RCTs, cohort or case-control studies, and as exclusion of guidelines, reviews, letters, abstracts without an article, laboratory studies, systematic reviews, and meta-analyses. The reasons for exclusion were recorded, and duplicates were removed. Disagreements were resolved via consensus with the co-authors ( TE.Y ., K.N. , TA.Y. , Y.O ., and T.T. ). Selection criteria were pre-determined by the committee Systematic review Outcomes on both the benefits and harms of single-dose PEG G-CSF were considered by the authors. The selected outcomes were overall survival (OS), the incidence of FN, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain. The certainty of each study selected via the screening procedure was individually assessed using the risk of bias, indirectness, imprecision, inconsistency, and others. Qualitative synthesis or meta-analysis with evidence from the literature was performed for each outcome, and the results were summarized in the systematic review reports. Considering the literature quality, the level of evidence was evaluated for each outcome and then classified into four levels: “strong,” “medium,” “weak,” and “very weak.” Statistical methodology For outcomes in which a sufficient number of studies were selected for evaluation, meta-analyses were performed using Review Manager version 5.41 (The Cochrane Collaboration, London, UK). The risk ratio (RR) was calculated, and the effect size was expressed as the 95% confidence interval (CI) for each study. They were calculated using random-effects models. A forest plot was used to graphically represent the calculated RR for individual studies and overall meta-analyses. To assess heterogeneity, the I 2 test and chi-square–based Q test were used. Statistically significant heterogeneity was defined as I 2 > 50% or P < 0.1. A funnel plot was applied to graphically investigate the potential for publication bias. When the number of studies was insufficient for meta-analysis, only qualitative synthesis was performed to evaluate outcomes. Results Literature search The initial search yielded 452 results as follows: PubMed, 339; the Cochrane Library, 1; and Ichushi-Web, 112 (Date of the search: May 27, 2020). No studies were added by hand searching. Among the 452 articles, 402 were excluded in the first screening. The remaining 50 studies were included in the second screening, and 27 were excluded. Twenty-three articles were available for qualitative synthesis, and 18 were available for meta-analysis (Fig. 1 ). Benefits and harms of single-dose PEG G-CSF compared with multiple-dose non-PEG G-CSF Relationship between OS and the type of G-CSF Only one RCT was available for this outcome, and meta-analysis was not performed. In the RCT targeting pediatric patients after autologous peripheral blood stem cell transplantation [ 8 ], the 1-year OS rate was 74.5% in 21 patients who received a single dose of PEG G-CSF, versus 84.1% in 29 patients who received multiple doses of non-PEG G-CSF, revealing no statistical difference. The quality/certainty of evidence for this outcome was weak because of the small sample size from a single RCT. Relationship between the incidence of FN and the type of G-CSF In total, 12 RCTs [ 9 – 20 ] and 6 non-RCTs [ 21 – 26 ] compared the incidence of FN between single-dose PEG G-CSF and multiple-dose non-PEG G-CSF. The meta-analysis using 12 RCTs revealed a significant decrease in the incidence of FN in patients who received a single dose of PEG G-CSF (RR = 1.18, 95% CI = 1.03–1.34, P = 0.01, Fig. 2 ). The quality/certainty of evidence for this outcome was strong because multiple RCTs were available without any inconsistency or any publication bias. Relationship between infection-related mortality and the type of G-CSF Among 288 patients from three RCTs [ 15 , 17 , 20 ] available to compare infection-related mortality between single-dose PEG G-CSF and multiple-dose non-PEG G-CSF, there was only one event in the PEG G-CSF group, and meta-analysis was not performed. Qualitative synthesis revealed no apparent difference. The quality/certainty of evidence for this outcome was weak because of the absence of events. Relationship between the duration of neutropenia (less than 500/µL) and the type of G-CSF Data from a total of 18,165 patients, including 16,223 patients [ 9 – 12 , 14 – 20 , 27 , 28 ] who received a single dose of PEG G-CSF from 13 RCTs and patients from four non-RCTs [ 21 , 22 , 26 , 29 ], were used to evaluate the outcome. The duration of neutropenia (less than 500/µL) ranged from 1.3 to 10.4 days in the PEG G-CSF group and from 1.9 to 9.8 days in the non-PEG G-CSF group, highlighting the large heterogeneity in each group. In addition, selection bias was identified, and meta-analysis was considered meaningless. Qualitative synthesis indicated no apparent difference between the two arms. The quality/certainty of evidence for this outcome was weak. Relationship between quality of life and the type of G-CSF No articles were selected in the literature screening, and this outcome could not be assessed. Relationship between pain and the type of G-CSF Meta-analysis was performed using 11 RCTs [ 9 – 12 , 14 – 16 , 18 – 20 , 30 ] and 4 non-RCTs [ 21 , 22 , 25 , 26 ] comparing the incidence of pain between single-dose PEG G-CSF and multiple-dose non-PEG G-CSF. There was a numerical increase in pain in the non-PEG G-CSF group, but no significant difference was observed (RR = 0.86, 95% CI = 0.73–1.01, P = 0.06, Fig. 3 ). The quality/certainty of evidence for this outcome was strong because the meta-analysis included many RCTs with little heterogeneity in the results of each trial. Discussion G-CSF is an essential drug for patients receiving chemotherapy for various cancers. Primary prophylaxis of FN using G-CSF has been recommended in particular situations. In the present systematic review, we found a significantly lower incidence of FN for a single dose of PEG G-CSF than for multiple doses of non-PEG G-CSF. The quality/certainty of evidence for this outcome was strong, and single-dose PEG G-CSF was demonstrated to have an apparent benefit. The difference in other outcomes associated with benefit, such as OS, infection-related mortality, the duration of neutropenia (less than 500/µL), and quality of life, were not apparent, but the quality/certainty of evidence for these outcomes was weak. The evaluation of pain, which was the only outcome assessing harm, revealed no difference between the groups with strong quality/certainty of evidence. Consequently, we concluded that a single dose of PEG G-CSF has more benefit than harm compared with multiple doses of non-PEG-GCSF. On the basis of “Minds Handbook for Clinical Practice Guideline Development 2014” [ 6 ] and “Minds Clinical Practice Guideline Development Guide 2017,” we had to assess both the balance between harm and benefit and patients’ preference and financial burden. We thought that most patients prefer the single dose of PEG G-CSF to the multiple doses of non-PEG G-CSF because the former had distinct advantages such as decreasing the incidence of FN and pain without any increase of adverse events. Moreover, as an apparent benefit of PEG G-CSF, patients only have to visit hospital on 1 day, whereas several days are required to receive non-PEG G-CSF, which could also explain patients’ preference for PEG G-CSF. There were no data regarding the financial burden, and we could not judge which treatment was better. Based on this systematic review, Clinical Practice Guidelines for the Use of G-CSF 2022 strongly recommend single-dose PEG G-CSF over multiple-dose non-PEG G-CSF when G-CSF is required for patients receiving chemotherapy because of the significant decrease of the incidence of FN and patients’ preferences. However, this review had several limitations. One limitation was the lack of evidence, especially for evaluating OS and quality of life, which are among the most important outcomes for patients with cancer. Another limitation was that the current systematic review included various cancer types. The situations are possibly different between patients receiving chemotherapy with severe myelosuppression such as auto-PBCST and regular chemotherapy for solid tumors. The final limitation was that the type and duration of non-PEG G-CSF were not standardized. Conclusions For the primary prophylaxis of FN with G-CSF, a single dose of PEG G-CSF is strongly recommended over multiple doses of non-PEG G-CSF. This systematic review of the literature demonstrated that a single dose of PEG G-CSF better prevents FN than multiple doses of non-PEG G-CSF. We should consider single-dose PEG G-CSF as the first choice if G-CSF is necessary for the primary prophylaxis of FN. Declarations Acknowledgments We are grateful to Mr. Naohiko Yamaguchi for his contribution to the initial literature search. We would also like to thank Ms. Natsuki Fukuda for their valuable comments and suggestions. We additionally thank Joe Barber Jr., PhD, from Edanz (www.edanz.com/ac) for editing a draft of this manuscript.. Funding The present study did not receive any funding. Author information Authors and Affiliations Tetsuhiro Yoshinami Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan Kazuki Nozawa Department of Center for Cancer Genomics and Advanced Therapeutics, Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan Takamichi Yokoe Department of Surgery, Keio University School of Medicine, Tokyo, Japan Yukinori Ozaki Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Hiroshi Nishio Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan Kenji Tsuchihashi Department of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan Eiki Ichihara Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan Yuji Miura Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan Makoto Endo Department of Orthopaedic Surgery, Kyushu University, Fukuoka, Japan Shingo Yano Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan Dai Maruyama Department of Hematology Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Nobuyuki Susumu Department of Obstetrics and Gynecology, International University of Health and Welfare Narita Hospital, Chiba, Japan Munetaka Takekuma Deparment of Gynecology, Shizuoka Cancer Center, Shizuoka, Japan Takashi Motohashi Department of Obstetrics and Gynecology, Tokyo Women's Medical University Hospital, Tokyo, Japan Mamoru Ito Department of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan Eishi Baba Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University,Fukuoka, Japan Nobuaki Ochi Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan Toshio Kubo Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan Keita Uchino Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo, Japan Takahiro Kimura Department of Urology, The Jikei University School of Medicine, Tokyo, Japan Yutaro Kamiyama Department of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan Shinji Nakao Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences,Kanazawa University, Ishikawa, Japan Shinobu Tamura Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan Hitomi Nishimoto Department of Nursing, Okayama University Hospital, Okayama, Japan Yasuhisa Kato Department of Drug Information, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, Kanagawa, Japan Atsushi Sato Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Aomori, Japan Toshimi Takano Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Author c ontributions All authors contributed to the conception and design of the present study. The first draft of the manuscript was written by T.Y. , and all authors commented on the previous version of the manuscript. All authors read and gave their final approval. Corresponding author Tetsuhiro Yoshinami Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. Tel.: +81-6-6979-3772; Fax: +81-6-6879-3779 E-mail: [email protected] Data availability Data associated with this systematic review can be accessed from the corresponding author upon reasonable request. Ethics declarations Conflicts of interest TE . Y . received honoraria from Kyowa-Kirin, Pfizer, Chugai, Eli Lilly, MSD, Astra Zeneca and Eisai. Y . O . received honoraria from Daiichi-Sankyo, Pfizer, Chugai, Lilly and Kyowa Kirin. K . T . received honoraria from Ono, Chugai, Taiho and Novartis. E . I . received honoraria from Eli Lilly, and research funding from MSD, Ono, Janssen Pharma and Takeda. Y . M . received honoraria from Ono, MSD, Takeda, Eisai and Bristol Myers Squibb, and research funding from MSD and Ono. S . Y . received research funding from Otsuka. D . M . received honoraria from Janssen, Nippon Shinyaku, Eisai, Mundipharma, Kyowa Kirin, Chugai, Zenyaku, MSD, SymBio, Sanofi, AbbVie, Takeda, Astra Zeneca and Bristol Myers Squibb, and research funding from Biopharma, Novartis, Kyowa Kirin, Ono, Chugai, Janssen, Takeda, Otsuka, Sanofi, Astellas, Bristol Myers Squibb, AbbVie, Eisai, MSD, Taiho and Astra Zeneca. T . M . received honoraria from Astra Zeneca, Chugai and Myriadgenetics. E . B . received honoraria from Chugai, and Daiichi-Sankyo, and research funding from Taiho and Chugai. T . KU . received honoraria from Chugai. T . KI . received honoraria from Sanofi. S . N . received honoraria from Kyowa Kirin. A . S . received honoraria and scholarship donation from Chugai and Taiho. T . T . received honoraria from Daiichi-Sankyo, Chugai and Eli Lilly. 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J Med Econ. ;16(1):160-8. 10.3111/13696998.2012.734885 . Epub 2012 Oct 11. PMID: 23016568 Kubista E, Glaspy J, Holmes FA, Green MD, Hackett J, Neumann T, Pegfilgrastim Study Group (2003) ;. Bone pain associated with once-per-cycle pegfilgrastim is similar to daily filgrastim in patients with breast cancer. Clin Breast Cancer. ;3(6):391-8. 10.3816/cbc.2003.n.003 . PMID: 12636878 Cite Share Download PDF Status: Published Journal Publication published 23 Apr, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 11 Feb, 2024 Reviewers agreed at journal 16 Jan, 2024 Reviewers invited by journal 09 Jan, 2024 Editor assigned by journal 05 Jan, 2024 First submitted to journal 03 Jan, 2024 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3812794","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266294566,"identity":"54f705cd-acbb-45d6-8c86-32716d32057e","order_by":0,"name":"Tetsuhiro 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Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yuji","middleName":"","lastName":"Miura","suffix":""},{"id":266294574,"identity":"31f592e5-3987-49bd-beff-d722e3d34e71","order_by":8,"name":"Makoto Endo","email":"","orcid":"","institution":"Kyushu University Hospital: Kyushu Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Endo","suffix":""},{"id":266294575,"identity":"e6be8ac4-63d6-40be-b3ad-e49de3f07c17","order_by":9,"name":"Shingo Yano","email":"","orcid":"","institution":"Jikei University School of Medicine: Tokyo Jikeikai Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Yano","suffix":""},{"id":266294576,"identity":"230aa4c1-ef56-4866-9a94-1b6c27d11485","order_by":10,"name":"Dai Maruyama","email":"","orcid":"","institution":"Cancer institute hosptital","correspondingAuthor":false,"prefix":"","firstName":"Dai","middleName":"","lastName":"Maruyama","suffix":""},{"id":266294577,"identity":"094fc567-e363-4e10-be12-d7262c8b569f","order_by":11,"name":"Nobuyuki Susumu","email":"","orcid":"","institution":"International University of Health and Welfare: Kokusai Iryo Fukushi Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Nobuyuki","middleName":"","lastName":"Susumu","suffix":""},{"id":266294578,"identity":"5a399478-c2d0-46fa-9a30-b97e8d6a9168","order_by":12,"name":"Munetaka Takekuma","email":"","orcid":"","institution":"Shizuoka Cancer Center: Shizuoka Kenritsu Shizuoka Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Munetaka","middleName":"","lastName":"Takekuma","suffix":""},{"id":266294579,"identity":"a2a21b2f-422a-46ed-bb9f-b5026f31b5d3","order_by":13,"name":"Takashi Motohashi","email":"","orcid":"","institution":"Tokyo Women's Medical University: Tokyo Joshi Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Motohashi","suffix":""},{"id":266294580,"identity":"20f66cdf-988f-4f60-a768-ad1a4db13e83","order_by":14,"name":"Mamoru Ito","email":"","orcid":"","institution":"Kyushu University Hospital: Kyushu Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Mamoru","middleName":"","lastName":"Ito","suffix":""},{"id":266294581,"identity":"989b4c2a-1a87-4b50-a003-3de05004bb58","order_by":15,"name":"Eishi Baba","email":"","orcid":"","institution":"Kyushu University Faculty of Medicine Graduate School of Medical Science: Kyushu Daigaku Igakubu Daigakuin Igakukei Gakufu Daigakuin Igaku Kenkyuin","correspondingAuthor":false,"prefix":"","firstName":"Eishi","middleName":"","lastName":"Baba","suffix":""},{"id":266294582,"identity":"0e6bef4b-bfbe-45bf-a320-adcbe5c5187f","order_by":16,"name":"Nobuaki Ochi","email":"","orcid":"","institution":"Kawasaki Medical School: Kawasaki Ika 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Byoin","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Kimura","suffix":""},{"id":266294586,"identity":"09a6fd86-bce0-4236-8b81-9a1c10684bdc","order_by":20,"name":"Yutaro Kamiyama","email":"","orcid":"","institution":"Jikei University School of Medicine: Tokyo Jikeikai Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yutaro","middleName":"","lastName":"Kamiyama","suffix":""},{"id":266294587,"identity":"3bec65c6-656d-497a-8df3-71ef86a7aa4c","order_by":21,"name":"Shinji Nakao","email":"","orcid":"","institution":"Kanazawa University: Kanazawa Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Shinji","middleName":"","lastName":"Nakao","suffix":""},{"id":266294588,"identity":"4c2b2139-f5a8-4af4-a773-a2d8607693fc","order_by":22,"name":"Hitomi Nishimoto","email":"","orcid":"","institution":"Okayama University: Okayama Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hitomi","middleName":"","lastName":"Nishimoto","suffix":""},{"id":266294589,"identity":"7c06546f-7dce-4370-b3a5-8bd7a8e7b6eb","order_by":23,"name":"Yasuhisa Kato","email":"","orcid":"","institution":"Shonan University of Medical Sciences: Shonan Iryo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yasuhisa","middleName":"","lastName":"Kato","suffix":""},{"id":266294590,"identity":"7e264d9a-0631-49f2-9f3e-30cec844064c","order_by":24,"name":"Atsushi Sato","email":"","orcid":"","institution":"Hirosaki University: Hirosaki Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Sato","suffix":""},{"id":266294591,"identity":"b7c07ac2-aeff-4bd2-ae4b-e3b1105bc8b8","order_by":25,"name":"Toshimi Takano","email":"","orcid":"","institution":"Cancer insutitute hospital of Japanses Foundation for research","correspondingAuthor":false,"prefix":"","firstName":"Toshimi","middleName":"","lastName":"Takano","suffix":""}],"badges":[],"createdAt":"2023-12-27 15:12:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3812794/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3812794/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-024-02504-4","type":"published","date":"2024-04-23T22:26:41+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49539069,"identity":"659a3e53-b649-4266-b736-1d5242e45eb1","added_by":"auto","created_at":"2024-01-12 17:02:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":17139,"visible":true,"origin":"","legend":"\u003cp\u003eModified PRISMA flow diagram of the literature search process.\u003c/p\u003e\n\u003cp\u003eIn total, 452 studies were identified through searchingthree literature databases using keywords. After the first and second screenings, 23 studies were included in the qualitative synthesis, and 18 were available for the quantitative synthesis.\u003c/p\u003e\n\u003cp\u003ePRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analysis\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-3812794/v1/3a9bb32b181cb3f405440cf3.png"},{"id":49539067,"identity":"1c0e353a-95c5-492f-ad37-5f4c8de4dc65","added_by":"auto","created_at":"2024-01-12 17:02:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":148619,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis of the incidence of febrile neutropenia (FN). A forest plot of the risk ratio (RR) of FN comparing single-dose of granulocyte colony-stimulating factor (G-CSF) bound to polyethylene glycol (PEG G-CSF) and multiple doses of G-CSF not bound to polyethylene glycol (non-PEG G-CSF).\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-3812794/v1/1b776729335f85bbee0617e6.png"},{"id":49539705,"identity":"f8cda783-1da2-4963-b45c-8a7c006597f5","added_by":"auto","created_at":"2024-01-12 17:10:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":209616,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis of pain as an adverse event of granulocyte colony-stimulating factor (G-CSF). A forest plot of the risk ratio (RR) of pain comparing a single dose of G-CSF bound to polyethylene glycol (PEG G-CSF) and multiple doses of G-CSF not bound to polyethylene glycol (non-PEG G-CSF).\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-3812794/v1/d3ea6b2b7c21332021637ee8.png"},{"id":55690287,"identity":"a328dc40-7f27-4639-a270-46d0ef72333d","added_by":"auto","created_at":"2024-05-01 22:34:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1069982,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3812794/v1/0c6078a5-f3c8-4482-aa63-7c2aa386cc97.pdf"}],"financialInterests":"","formattedTitle":"Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: A systematic review and meta-analysis from Clinical Practice Guidelines for the Use of G-CSF 2022","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGranulocyte colony-stimulating factor (G-CSF) is used in the primary prophylaxis of febrile neutropenia (FN) to improve the safety of chemotherapy, and it is recommended in some guidelines [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In Japan, two types of G-CSF are available. One is G-CSF chemically bound to polyethylene glycol (PEG G-CSF) to inhibit its degradation and delay its excretion [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. PEG G-CSF can remain in blood for a long time, and a single dose is administered in each cycle. PEG G-CSF was approved in 2014 in Japan. The other option is normal G-CSF not bound to polyethylene glycol (non-PEG G-CSF), and it should be administered daily for several days for primary prophylaxis.\u003c/p\u003e \u003cp\u003eClinically, it has been debated whether single-dose PEG G-CSF is more useful for primary prophylaxis than multiple-dose non-PEG G-CSF. This clinical question must be answered in an evidence-based manner. Therefore, we conducted a systematic literature review to compare the benefits and harms of a single dose of PEG G-CSF with those of multiple doses of non-PEG G-CSF. This study was conducted as part of efforts to update Japanese practice guidelines.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eThe literature search was performed according to the \u0026ldquo;Medical information network distribution service (Minds) Handbook for Clinical Practice Guideline Development 2014\u0026rdquo; [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and \u0026ldquo;Minds Clinical Practice Guideline Development Guide 2017\u0026rdquo; [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] using PubMed, Ichushi-Web (Japanese medical bibliographic database), and the Cochrane Library. The search terms included combinations of MeSH terms and keywords as follows: \u0026ldquo;pegfilgrastim,\u0026rdquo; \u0026ldquo;filgrastim,\u0026rdquo; \u0026ldquo;drug administration schedule,\u0026rdquo; and \u0026ldquo;administration and dosage.\u0026rdquo; No restriction regarding cancer types was implemented. The target period for screening spanned from January 1, 1999 to December 31, 2019. The initial screening was independently performed by two reviewers (\u003cem\u003eK.N.\u003c/em\u003e and \u003cem\u003eY.O.\u003c/em\u003e) by reviewing the titles and abstracts of all articles to eliminate ineligible reports, followed by full-text screening according to the selection criteria pre-determined by the committee as inclusion of studies designed as randomized controlled trials (RCTs), non-RCTs, cohort or case-control studies, and as exclusion of guidelines, reviews, letters, abstracts without an article, laboratory studies, systematic reviews, and meta-analyses. The reasons for exclusion were recorded, and duplicates were removed. Disagreements were resolved via consensus with the co-authors (\u003cem\u003eTE.Y\u003c/em\u003e., \u003cem\u003eK.N.\u003c/em\u003e, \u003cem\u003eTA.Y.\u003c/em\u003e, \u003cem\u003eY.O\u003c/em\u003e., and \u003cem\u003eT.T.\u003c/em\u003e). Selection criteria were pre-determined by the committee\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSystematic review\u003c/h2\u003e \u003cp\u003eOutcomes on both the benefits and harms of single-dose PEG G-CSF were considered by the authors. The selected outcomes were overall survival (OS), the incidence of FN, infection-related mortality, the duration of neutropenia (less than 500/\u0026micro;L), quality of life, and pain. The certainty of each study selected via the screening procedure was individually assessed using the risk of bias, indirectness, imprecision, inconsistency, and others. Qualitative synthesis or meta-analysis with evidence from the literature was performed for each outcome, and the results were summarized in the systematic review reports. Considering the literature quality, the level of evidence was evaluated for each outcome and then classified into four levels: \u0026ldquo;strong,\u0026rdquo; \u0026ldquo;medium,\u0026rdquo; \u0026ldquo;weak,\u0026rdquo; and \u0026ldquo;very weak.\u0026rdquo;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methodology\u003c/h2\u003e \u003cp\u003e For outcomes in which a sufficient number of studies were selected for evaluation, meta-analyses were performed using Review Manager version 5.41 (The Cochrane Collaboration, London, UK).\u003c/p\u003e \u003cp\u003eThe risk ratio (RR) was calculated, and the effect size was expressed as the 95% confidence interval (CI) for each study. They were calculated using random-effects models. A forest plot was used to graphically represent the calculated RR for individual studies and overall meta-analyses. To assess heterogeneity, the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e test and chi-square\u0026ndash;based Q test were used. Statistically significant heterogeneity was defined as \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% or P\u0026thinsp;\u0026lt;\u0026thinsp;0.1. A funnel plot was applied to graphically investigate the potential for publication bias.\u003c/p\u003e \u003cp\u003eWhen the number of studies was insufficient for meta-analysis, only qualitative synthesis was performed to evaluate outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eLiterature search\u003c/h2\u003e \u003cp\u003eThe initial search yielded 452 results as follows: PubMed, 339; the Cochrane Library, 1; and Ichushi-Web, 112 (Date of the search: May 27, 2020). No studies were added by hand searching. Among the 452 articles, 402 were excluded in the first screening. The remaining 50 studies were included in the second screening, and 27 were excluded. Twenty-three articles were available for qualitative synthesis, and 18 were available for meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBenefits and harms of single-dose PEG G-CSF compared with multiple-dose non-PEG G-CSF\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eRelationship between OS and the type of G-CSF\u003c/h2\u003e \u003cp\u003eOnly one RCT was available for this outcome, and meta-analysis was not performed. In the RCT targeting pediatric patients after autologous peripheral blood stem cell transplantation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], the 1-year OS rate was 74.5% in 21 patients who received a single dose of PEG G-CSF, versus 84.1% in 29 patients who received multiple doses of non-PEG G-CSF, revealing no statistical difference. The quality/certainty of evidence for this outcome was weak because of the small sample size from a single RCT.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between the incidence of FN and the type of G-CSF\u003c/h2\u003e \u003cp\u003eIn total, 12 RCTs [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and 6 non-RCTs [\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] compared the incidence of FN between single-dose PEG G-CSF and multiple-dose non-PEG G-CSF. The meta-analysis using 12 RCTs revealed a significant decrease in the incidence of FN in patients who received a single dose of PEG G-CSF (RR\u0026thinsp;=\u0026thinsp;1.18, 95% CI\u0026thinsp;=\u0026thinsp;1.03\u0026ndash;1.34, P\u0026thinsp;=\u0026thinsp;0.01, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The quality/certainty of evidence for this outcome was strong because multiple RCTs were available without any inconsistency or any publication bias.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between infection-related mortality and the type of G-CSF\u003c/h2\u003e \u003cp\u003eAmong 288 patients from three RCTs [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] available to compare infection-related mortality between single-dose PEG G-CSF and multiple-dose non-PEG G-CSF, there was only one event in the PEG G-CSF group, and meta-analysis was not performed. Qualitative synthesis revealed no apparent difference. The quality/certainty of evidence for this outcome was weak because of the absence of events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between the duration of neutropenia (less than 500/\u0026micro;L) and the type of G-CSF\u003c/h2\u003e \u003cp\u003eData from a total of 18,165 patients, including 16,223 patients [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] who received a single dose of PEG G-CSF from 13 RCTs and patients from four non-RCTs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], were used to evaluate the outcome. The duration of neutropenia (less than 500/\u0026micro;L) ranged from 1.3 to 10.4 days in the PEG G-CSF group and from 1.9 to 9.8 days in the non-PEG G-CSF group, highlighting the large heterogeneity in each group. In addition, selection bias was identified, and meta-analysis was considered meaningless. Qualitative synthesis indicated no apparent difference between the two arms. The quality/certainty of evidence for this outcome was weak.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between quality of life and the type of G-CSF\u003c/h2\u003e \u003cp\u003eNo articles were selected in the literature screening, and this outcome could not be assessed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between pain and the type of G-CSF\u003c/h2\u003e \u003cp\u003eMeta-analysis was performed using 11 RCTs [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and 4 non-RCTs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] comparing the incidence of pain between single-dose PEG G-CSF and multiple-dose non-PEG G-CSF. There was a numerical increase in pain in the non-PEG G-CSF group, but no significant difference was observed (RR\u0026thinsp;=\u0026thinsp;0.86, 95% CI\u0026thinsp;=\u0026thinsp;0.73\u0026ndash;1.01, P\u0026thinsp;=\u0026thinsp;0.06, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The quality/certainty of evidence for this outcome was strong because the meta-analysis included many RCTs with little heterogeneity in the results of each trial.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eG-CSF is an essential drug for patients receiving chemotherapy for various cancers. Primary prophylaxis of FN using G-CSF has been recommended in particular situations. In the present systematic review, we found a significantly lower incidence of FN for a single dose of PEG G-CSF than for multiple doses of non-PEG G-CSF. The quality/certainty of evidence for this outcome was strong, and single-dose PEG G-CSF was demonstrated to have an apparent benefit. The difference in other outcomes associated with benefit, such as OS, infection-related mortality, the duration of neutropenia (less than 500/\u0026micro;L), and quality of life, were not apparent, but the quality/certainty of evidence for these outcomes was weak. The evaluation of pain, which was the only outcome assessing harm, revealed no difference between the groups with strong quality/certainty of evidence. Consequently, we concluded that a single dose of PEG G-CSF has more benefit than harm compared with multiple doses of non-PEG-GCSF.\u003c/p\u003e \u003cp\u003eOn the basis of \u0026ldquo;Minds Handbook for Clinical Practice Guideline Development 2014\u0026rdquo; [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and \u0026ldquo;Minds Clinical Practice Guideline Development Guide 2017,\u0026rdquo; we had to assess both the balance between harm and benefit and patients\u0026rsquo; preference and financial burden. We thought that most patients prefer the single dose of PEG G-CSF to the multiple doses of non-PEG G-CSF because the former had distinct advantages such as decreasing the incidence of FN and pain without any increase of adverse events. Moreover, as an apparent benefit of PEG G-CSF, patients only have to visit hospital on 1 day, whereas several days are required to receive non-PEG G-CSF, which could also explain patients\u0026rsquo; preference for PEG G-CSF. There were no data regarding the financial burden, and we could not judge which treatment was better.\u003c/p\u003e \u003cp\u003e Based on this systematic review, Clinical Practice Guidelines for the Use of G-CSF 2022 strongly recommend single-dose PEG G-CSF over multiple-dose non-PEG G-CSF when G-CSF is required for patients receiving chemotherapy because of the significant decrease of the incidence of FN and patients\u0026rsquo; preferences. However, this review had several limitations. One limitation was the lack of evidence, especially for evaluating OS and quality of life, which are among the most important outcomes for patients with cancer. Another limitation was that the current systematic review included various cancer types. The situations are possibly different between patients receiving chemotherapy with severe myelosuppression such as auto-PBCST and regular chemotherapy for solid tumors. The final limitation was that the type and duration of non-PEG G-CSF were not standardized.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eFor the primary prophylaxis of FN with G-CSF, a single dose of PEG G-CSF is strongly recommended over multiple doses of non-PEG G-CSF. This systematic review of the literature demonstrated that a single dose of PEG G-CSF better prevents FN than multiple doses of non-PEG G-CSF. We should consider single-dose PEG G-CSF as the first choice if G-CSF is necessary for the primary prophylaxis of FN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to Mr. Naohiko Yamaguchi for his contribution to the initial literature search. We would also like to thank Ms. Natsuki Fukuda for their valuable comments and suggestions. We additionally thank Joe Barber Jr., PhD, from Edanz (www.edanz.com/ac) for editing a draft of this manuscript..\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study did not receive any funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTetsuhiro Yoshinami\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKazuki Nozawa\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Center for Cancer Genomics and Advanced Therapeutics, Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTakamichi Yokoe\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Surgery, Keio University School of Medicine, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYukinori Ozaki\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHiroshi Nishio\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKenji Tsuchihashi\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEiki Ichihara\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCenter for Clinical Oncology, Okayama University Hospital, Okayama, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYuji Miura\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Medical Oncology, Toranomon Hospital, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMakoto Endo\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Orthopaedic Surgery, Kyushu University, Fukuoka, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShingo Yano\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDivision of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDai Maruyama\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Hematology Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNobuyuki Susumu\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Obstetrics and Gynecology, International University of Health and Welfare Narita Hospital, Chiba, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMunetaka Takekuma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeparment of Gynecology, Shizuoka Cancer Center, Shizuoka, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTakashi Motohashi\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Obstetrics and Gynecology, Tokyo Women\u0026apos;s Medical University Hospital, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMamoru Ito\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEishi Baba\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University,Fukuoka, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNobuaki Ochi\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToshio Kubo\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKeita Uchino\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Medical Oncology, NTT Medical Center Tokyo, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTakahiro Kimura\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Urology, The Jikei University School of Medicine, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYutaro Kamiyama\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShinji Nakao\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences,Kanazawa University, Ishikawa, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShinobu Tamura\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHitomi Nishimoto\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Nursing, Okayama University Hospital, Okayama, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYasuhisa Kato\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Drug Information, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, Kanagawa, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAtsushi Sato\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Medical Oncology, Hirosaki University Graduate School of Medicine, Aomori, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToshimi Takano\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor c\u003c/strong\u003e\u003cstrong\u003eontributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the conception and design of the present study. The first draft of the manuscript was written by \u003cem\u003eT.Y.\u003c/em\u003e, and all authors commented on the previous version of the manuscript. All authors read and gave their final approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTetsuhiro Yoshinami\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.\u003c/p\u003e\n\u003cp\u003eTel.: +81-6-6979-3772; Fax: +81-6-6879-3779\u003c/p\u003e\n\u003cp\u003eE-mail: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData associated with this systematic review can be accessed from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTE\u003c/em\u003e.\u003cem\u003eY\u003c/em\u003e. received honoraria from Kyowa-Kirin, Pfizer, Chugai, Eli Lilly, MSD, Astra Zeneca and Eisai. \u003cem\u003eY\u003c/em\u003e.\u003cem\u003eO\u003c/em\u003e. received honoraria from Daiichi-Sankyo, Pfizer, Chugai, Lilly and Kyowa Kirin. \u003cem\u003eK\u003c/em\u003e.\u003cem\u003eT\u003c/em\u003e. received honoraria from Ono, Chugai, Taiho and Novartis. \u003cem\u003eE\u003c/em\u003e.\u003cem\u003eI\u003c/em\u003e. received honoraria from Eli Lilly, and research funding from MSD, Ono, Janssen Pharma and Takeda. \u003cem\u003eY\u003c/em\u003e.\u003cem\u003eM\u003c/em\u003e. received honoraria from Ono, MSD, Takeda, Eisai and Bristol Myers Squibb, and research funding from MSD and Ono. \u003cem\u003eS\u003c/em\u003e.\u003cem\u003eY\u003c/em\u003e. received research funding from Otsuka. \u003cem\u003eD\u003c/em\u003e.\u003cem\u003eM\u003c/em\u003e. received honoraria from Janssen, Nippon Shinyaku, Eisai, Mundipharma, Kyowa Kirin, Chugai, Zenyaku, MSD, SymBio, Sanofi, AbbVie, Takeda, Astra Zeneca and Bristol Myers Squibb, and research funding from Biopharma, Novartis, Kyowa Kirin, Ono, Chugai, Janssen, Takeda, Otsuka, Sanofi, Astellas, Bristol Myers Squibb, AbbVie, Eisai, MSD, Taiho and Astra Zeneca. \u003cem\u003eT\u003c/em\u003e.\u003cem\u003eM\u003c/em\u003e. received honoraria from Astra Zeneca, Chugai and Myriadgenetics. \u003cem\u003eE\u003c/em\u003e.\u003cem\u003eB\u003c/em\u003e. received honoraria from Chugai, and Daiichi-Sankyo, and research funding from Taiho and Chugai. \u003cem\u003eT\u003c/em\u003e.\u003cem\u003eKU\u003c/em\u003e. received honoraria from Chugai. \u003cem\u003eT\u003c/em\u003e.\u003cem\u003eKI\u003c/em\u003e. received honoraria from Sanofi. \u003cem\u003eS\u003c/em\u003e.\u003cem\u003eN\u003c/em\u003e. received honoraria from Kyowa Kirin. \u003cem\u003eA\u003c/em\u003e.\u003cem\u003eS\u003c/em\u003e. received honoraria and scholarship donation from Chugai and Taiho. \u003cem\u003eT\u003c/em\u003e.\u003cem\u003eT\u003c/em\u003e. received honoraria from Daiichi-Sankyo, Chugai and Eli Lilly. Other authors declare that there are no conflicts of interest associated with this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFormal consent was not required for this type of study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors consented to the publication of this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCrawford J, Caserta C, Roila F, ESMO Guidelines Working Group (2010) ;. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. 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PMID: 12636878\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"PEG G-CSF, single dose, non-PEG G-CSF, multiple doses, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-3812794/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3812794/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGranulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively.\u003c/p\u003e \u003cp\u003eThe incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/\u0026micro;L), quality of life, and pain, were not apparent. Therefore, a single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.\u003c/p\u003e","manuscriptTitle":"Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: A systematic review and meta-analysis from Clinical Practice Guidelines for the Use of G-CSF 2022","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-12 17:02:05","doi":"10.21203/rs.3.rs-3812794/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-02-12T00:07:13+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-01-16T05:18:32+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-09T13:07:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-05T07:40:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2024-01-03T18:58:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5acbaaab-bdde-4ee8-b773-5abbf719b8c6","owner":[],"postedDate":"January 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T22:26:41+00:00","versionOfRecord":{"articleIdentity":"rs-3812794","link":"https://doi.org/10.1007/s10147-024-02504-4","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2024-04-23 22:26:41","publishedOnDateReadable":"April 23rd, 2024"},"versionCreatedAt":"2024-01-12 17:02:05","video":"","vorDoi":"10.1007/s10147-024-02504-4","vorDoiUrl":"https://doi.org/10.1007/s10147-024-02504-4","workflowStages":[]},"version":"v1","identity":"rs-3812794","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3812794","identity":"rs-3812794","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}