Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: 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 Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022 Keita Uchino, Shingo Tamura, Shoji Kimura, Keisuke Shigeta, Takahiro Kimura, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3882691/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Mar, 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) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC). G-CSF Urothelial Cancer Neutropenia dose dense MVAC Meta-analysis Figures Figure 1 Figure 2 Introduction The first-line treatment for urothelial carcinoma is a combination of gemcitabine and platinum (cisplatin and carboplatin)-based anticancer agents (GC and GCarbo therapy) or a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC therapy). MVAC therapy is associated with a high incidence of myelosuppressive toxicity (febrile neutropenia [FN] incidence: 26%); therefore, GC is commonly used in clinical practice. Second-line therapies, including immune checkpoint inhibitors, such as pembrolizumab and avelumab, and third-line therapies, including enfortumab vedotin, do not have a high incidence of FN. The only regimen listed in “Guidelines for the Appropriate Use of G-CSF 2013 ver. 5” is MVAC, which has an incidence of FN > 20%; however, the regimen used in clinical practice is GC therapy. Therefore, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is unlikely to be used. Dose-dense MVAC therapy to increase therapeutic intensity was shown to be effective in improving the progression-free and five-year survival compared to standard MVAC therapy, but the use of primary G-CSF prophylaxis was recommended in clinical trials that evaluated dose-dense MVAC. Rather than determining the appropriateness of primary prophylactic administration of G-CSF based on the incidence of FN, in this guideline, we conducted a systematic review to evaluate the usefulness of primary prophylactic administration of G-CSF for urothelial carcinoma. Material and Methods To assess this clinical question (CQ) and construct G-CSF guidelines, a systematic review was performed following the “Medical information network distribution service (Minds) Handbook for Clinical Practice Guideline Development 2014” [ 1 ] and “Minds Clinical Practice Guideline Development Guide 2017” [ 2 ]. A comprehensive literature search of the electronic databases (PubMed, Cochrane Library, and Ichu-shi) was performed on January 10, 2020, to identify studies published between January 1990 and December 2019 that investigated the impact of prophylaxis on clinical outcomes. From all extracted articles, an initial screening was performed using the titles and abstracts, and the screened articles were evaluated for their full text to exclude inappropriate ones. Two reviewers independently conducted this search, and disagreements were resolved by a third party. The following search terms were used: transitional cell carcinoma, urothelic/urologic neoplasms, ureteral neoplasms, drug therapy, granulocyte colony-stimulating factor, filgrastim, lenograstim, neutrogin, nartograstim, nartograstim, neu-up, pegfilgrastim, G-Lasta, biweekly, schedule, maintenance, dense, Drug Administration Schedule, Dose-Response Relationship, administration, and dosage. In this CQ, urothelial carcinoma patients receiving cancer chemotherapy were targeted, and cancer chemotherapy with enhanced intensity of therapy based on primary prophylaxis with G-CSF and with a conventional dosage and administration without enhanced therapeutic intensity were compared, with six items ultimately evaluated: the overall survival (OS), cancer-specific survival (CSS), incidence of FN, infection-related mortality, quality of life (QOL), and pain. The Review Manager software program (RevMan; The Cochrane Collaboration, London, UK), version 5.41, was used for the statistical analyses. After a qualitative analysis using the Excel software program (Microsoft Windows; Redmond, WA, USA), studies were eligible for inclusion in the meta-analysis if the study design was a randomized control trial (RCT) that compared the use of G-CSF for primary prophylaxis against a non-administration control group. The risk ratio (RR) for each endpoint was calculated, and the effect size was expressed as the 95% confidence interval (CI) for each study. These values were calculated using fixed- or random-effects models, depending on the level of heterogeneity. The calculated RRs for individual studies and overall meta-analyses were represented using a forest plot. Heterogeneity was assessed using the I 2 test and the chi-square-based Q-test. A p-value < 0.05 in the Z test was considered to be significant. A funnel plot was used to graphically investigate the potential publication bias. Results Selected literature A total of 83 articles, including 56 from PubMed and 27 from Ichu-shi Japanese Medical Journal, were screened for this systematic review (Fig. 1). A qualitative systematic review was conducted of seven articles selected after two rounds of screening. In addition, a meta-analysis was conducted because infection-related mortality was evaluated in two RCTs. The CSS and QOL could not be evaluated in any of the extracted articles. Results of a systematic review for each outcome OS (benefit): One randomized controlled study (RCT) [ 3 , 4 ] and three cohort studies [ 5 – 7 ] evaluated the OS. Of these, three cohort studies had no comparators, but an RCT of dose-dense MVAC with G-CSF support that compared conventional dosage and administration demonstrated an OS benefit (hazard ratio 0.76 [95% CI 0.58–0.99]) [ 4 ]. Incidence of FN (benefit): The incidence of febrile neutropenia was evaluated in 1 RCT with a relative risk of 0.38 (95% CI 0.209–0.687) [ 3 ]. Infection-related mortality (benefit): Two RCTs [ 4 , 8 ] and two cohort studies [ 5 , 9 ] evaluated the infection-related mortality. A meta-analysis of the 2 RCTs was performed (Fig. 2a), showing a relative risk of death due to infection of 0.97 (95% CI: 0.27–3.54), indicating no significant reduction in mortality due to infection. The small number of references covered made this difficult to decide, but no obvious publication bias was found (Fig. 2b). Pain (adverse effects): Only one cohort study [ 9 ] evaluated pain. This study reported a pain incidence rate of 78%; however, it was difficult to evaluate because this study was not a comparative study. Discussion and Summary of Systematic Review Benefits One RCT regarding dose-dense MVAC therapy showed a reduction in the incidence of FN, and a report evaluating long-term follow-up showed a benefit in the OS. However, no studies have been conducted on other regimens. Adverse effects Only one cohort study on pain was reported, making an evaluation difficult. Patient values and preferences No studies related to values or preferences were extracted. Cost and resources There were no studies that examined costs/resources. Conclusion A systematic review was conducted of seven articles in the CQ. Regarding the OS, the most important outcome, 1 RCT on dose-dense MVAC therapy and 3 other cohort studies were selected. The RCT showed a hazard ratio of 0.76 and 95% CI of 0.58–0.99. Evidence regarding the incidence of FN, the third-most important outcome, was strong. Based on an evaluation of 1 RCT, the RR was 0.38, and the 95% CI was 0.209–0.687, indicating a reduction in the incidence of FN. Mortality due to infection was evaluated in 2 RCTs (RR: 0.97, 95% CI: 0.27–3.54), showing no marked reduction in mortality due to infection. In terms of adverse effects, the association between pain and G-CSF use was limited because it was reported in cohort studies. The majority of the studies selected for this CQ were based on studies of patients with unresectable urothelial carcinoma, which was considered a suitable population for this CQ. Although the authors discussed the use of intensified cancer chemotherapy with G-CSF primary prophylaxis, the literature only attempted to increase the intensity of MVAC therapy with G-CSF support, with no other regimens studied. Therefore, the relevant regimen was defined as dose-dense MVAC therapy. Deliberation and Voting at the Consensus Meeting Twenty-three members (physicians, 21; nurses, 1; pharmacists, 1) participated in the recommendation decision meetings. Based on preliminary reports from committee members, it was determined that there was no influence of any economic or academic conflict of interest on the recommendation decision. As described above, a draft recommendation was presented based on the systematic review report. After discussion and voting on the recommendation decision, all 23 members agreed with the draft and reached a consensus. In summary, the results of the systematic review showed a prolongation of the OS, the most important outcome, but since the basis for the decision was only a single RCT and a limited number of regimens, we made a "weak recommendation to perform" annotation of the relevant regimen. After the publication of this guideline, the results of a phase III trial (VESPER trial) comparing dose-dense MVAC and GC as perioperative chemotherapies for muscle-invading bladder cancer were published [ 10 ]. The results of that trial are included in the revised manuscript. Description in relevant medical practice guidelines In the ASCO guidelines (2015) and ESMO guidelines (2010), G-CSF primary prophylaxis is recommended when using regimens with an FN incidence of ≥ 20%; in the ASCO guidelines (2006, 2015), their regimen examples include the use of paclitaxel and CBDCA for bladder cancer. The ESMO guidelines (2010) list MVAC and TC (Paclitaxel, CDDP) as regimens for bladder cancer in their regimen examples. The NCCC guidelines (Hematopoietic Growth Factors; Version 1.2022) list dose-dense MVAC for bladder cancer as an example regimen for primary prevention. Declarations Acknowledgments The authors thank Dr. Toshimi Takano and Ms. Natsuki Fukuda for their valuable comments and suggestions. Funding The present study did not receive any funding. Author contributions All authors contributed to the conception and design of the study. The first draft of the manuscript was written by K.U. , and all authors commented on the previous version of the manuscript. All authors have read and approved the final manuscript. References Morizane T, Yoshida M, Kojimahara N, et al (2014) Minds Handbook for Clinical Practice Guideline Development 2014. Japan Council for Quality Health Care, Tokyo. https://minds.jcqhc.or.jp/s/developer_manual (in Japanese) Kojimahara N, Nakayama T, Morizane T, et al (2017) Minds Manual for Guideline Development 2017. Japan Council for Quality Health Care, Tokyo. https://minds.jcqhc.or.jp/s/developer_manual (in Japanese) Sternberg CN, de Mulder PH, Schornagel JH, et al. (2001) Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 19(10):2638-46. Sternberg CN, de Mulder PH, Schornagel JH, et al. (2006) Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 42(1):50-4. Plimack ER, Hoffman-Censits JH, Viterbo R, et al. (2014) Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 32(18):1895-901. Dodd PM, McCaffrey JA, Mazumdar M, et al. (2000) Evaluation of drug delivery and survival impact of dose-intense relative to conventional-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy in urothelial cancer. Cancer Invest. 18(7):626-34. Inoue T, Obara T, SaitoM et al. (2007) Possible survival benefit of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin combination therapy (HD-MVAC) over conventional MVAC in metastatic urothelial carcinoma patients. Hinyokika Kiyo. 53(9):613-8. Kuroda M, Kotake T, Akaza H, et al. (1998) Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group. Jpn J Clin Oncol. 28(8):497-501. Seidman AD, Scher HI, Gabrilove JL, et al. (1993) Dose-intensification of MVAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial cancer. J Clin Oncol. 11(3):408-14. Pfister C, Gravis G, Fléchon A, et al. (2022) Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 40(18):2013-2022. Cite Share Download PDF Status: Published Journal Publication published 22 Mar, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Accept 12 Feb, 2024 Reviewers agreed at journal 23 Jan, 2024 Reviewers invited by journal 23 Jan, 2024 Editor assigned by journal 23 Jan, 2024 First submitted to journal 19 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. 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. 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-3882691","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":269015334,"identity":"00722db6-0493-45a6-8fdb-50fafab7538e","order_by":0,"name":"Keita Uchino","email":"","orcid":"","institution":"NTT Medical Center Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Keita","middleName":"","lastName":"Uchino","suffix":""},{"id":269015335,"identity":"9843fe79-f785-4ae6-8591-e0079c0b879c","order_by":1,"name":"Shingo Tamura","email":"","orcid":"","institution":"National Hospital Organization Kyushu Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Tamura","suffix":""},{"id":269015336,"identity":"a5958c21-4ba0-4fa1-8a00-e1469aa7946c","order_by":2,"name":"Shoji Kimura","email":"","orcid":"","institution":"Jikei University School of Medicine Kashiwa Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shoji","middleName":"","lastName":"Kimura","suffix":""},{"id":269015337,"identity":"6d4b7772-95a9-4f3a-95ad-c2668ff45c37","order_by":3,"name":"Keisuke Shigeta","email":"","orcid":"","institution":"Keio University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Keisuke","middleName":"","lastName":"Shigeta","suffix":""},{"id":269015338,"identity":"d37ec834-8b62-4694-9354-2a8ba1c8fe97","order_by":4,"name":"Takahiro Kimura","email":"","orcid":"","institution":"Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Kimura","suffix":""},{"id":269015339,"identity":"497baa4a-370b-4206-a187-be522d2b14a8","order_by":5,"name":"Yukinori Ozaki","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Yukinori","middleName":"","lastName":"Ozaki","suffix":""},{"id":269015340,"identity":"ea4e9b81-27c9-4d73-8e7f-c8a2fe82c49c","order_by":6,"name":"Hiroshi Nishio","email":"","orcid":"","institution":"Keio University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Nishio","suffix":""},{"id":269015341,"identity":"1d8a431f-d4ec-4345-9c99-355309f4e27c","order_by":7,"name":"Kenji Tsuchihashi","email":"","orcid":"","institution":"Kyushu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Tsuchihashi","suffix":""},{"id":269015342,"identity":"384d2401-5115-4344-9bf8-6e80184259d8","order_by":8,"name":"Eiki Ichihara","email":"","orcid":"","institution":"Okayama University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eiki","middleName":"","lastName":"Ichihara","suffix":""},{"id":269015343,"identity":"e8530401-1ca7-4863-aa1f-ebc518ba9203","order_by":9,"name":"Makoto Endo","email":"","orcid":"","institution":"Kyushu University","correspondingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Endo","suffix":""},{"id":269015344,"identity":"e96ea3dc-33ec-4e8e-8600-d73b1508622c","order_by":10,"name":"Shingo Yano","email":"","orcid":"","institution":"The Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Yano","suffix":""},{"id":269015345,"identity":"b0ce653d-35ce-4777-b6ab-b61460fd53a3","order_by":11,"name":"Dai Maruyama","email":"","orcid":"","institution":"Cancer Institute Hospital Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Dai","middleName":"","lastName":"Maruyama","suffix":""},{"id":269015346,"identity":"b9909e49-3168-4744-ae8c-0649c322bcac","order_by":12,"name":"Tetsuhiro Yoshinami","email":"","orcid":"","institution":"Osaka University","correspondingAuthor":false,"prefix":"","firstName":"Tetsuhiro","middleName":"","lastName":"Yoshinami","suffix":""},{"id":269015347,"identity":"ff54ce9b-cf16-4b5f-beb4-32c406004f2c","order_by":13,"name":"Nobuyuki Susumu","email":"","orcid":"","institution":"International University of Health and Welfare Narita Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nobuyuki","middleName":"","lastName":"Susumu","suffix":""},{"id":269015348,"identity":"a2befb91-52cb-499d-b096-56df8dc1fdb4","order_by":14,"name":"Munetaka Takekuma","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Munetaka","middleName":"","lastName":"Takekuma","suffix":""},{"id":269015349,"identity":"c092e993-11b1-4727-856f-4e939d839e71","order_by":15,"name":"Takashi Motohashi","email":"","orcid":"","institution":"Tokyo Women's Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Motohashi","suffix":""},{"id":269015350,"identity":"e4531c50-dfc8-49ea-8142-b32176c0d340","order_by":16,"name":"Mamoru Ito","email":"","orcid":"","institution":"Kyushu University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mamoru","middleName":"","lastName":"Ito","suffix":""},{"id":269015351,"identity":"4f1753ac-b842-4b02-9cdd-0c4cc3a27c95","order_by":17,"name":"Eishi Baba","email":"","orcid":"","institution":"Kyushu University","correspondingAuthor":false,"prefix":"","firstName":"Eishi","middleName":"","lastName":"Baba","suffix":""},{"id":269015352,"identity":"d325f9fc-7be0-4687-9a70-4953005136bf","order_by":18,"name":"Nobuaki Ochi","email":"","orcid":"","institution":"Kawasaki Medical School","correspondingAuthor":false,"prefix":"","firstName":"Nobuaki","middleName":"","lastName":"Ochi","suffix":""},{"id":269015353,"identity":"99badb06-83cd-4b48-b091-fd17b845782a","order_by":19,"name":"Toshio Kubo","email":"","orcid":"","institution":"Okayama University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Kubo","suffix":""},{"id":269015354,"identity":"a9711183-ba26-45bb-a812-5a3388bc3933","order_by":20,"name":"Yutaro Kamiyama","email":"","orcid":"","institution":"The Jikei University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yutaro","middleName":"","lastName":"Kamiyama","suffix":""},{"id":269015355,"identity":"5b8ff55a-a373-477d-9b00-65ae8d906932","order_by":21,"name":"Shinji Nakao","email":"","orcid":"","institution":"Kanazawa University","correspondingAuthor":false,"prefix":"","firstName":"Shinji","middleName":"","lastName":"Nakao","suffix":""},{"id":269015356,"identity":"c306a4ce-49e8-4ad6-a84f-b5cd2686a903","order_by":22,"name":"Shinobu Tamura","email":"","orcid":"","institution":"Wakayama Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shinobu","middleName":"","lastName":"Tamura","suffix":""},{"id":269015357,"identity":"5cb18ceb-5360-4033-95b3-968b058e0360","order_by":23,"name":"Hitomi Nishimoto","email":"","orcid":"","institution":"Okayama University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hitomi","middleName":"","lastName":"Nishimoto","suffix":""},{"id":269015358,"identity":"e61fdecb-18e5-4111-96ee-1d45dfc15792","order_by":24,"name":"Yasuhisa Kato","email":"","orcid":"","institution":"Shonan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yasuhisa","middleName":"","lastName":"Kato","suffix":""},{"id":269015359,"identity":"1d8f8648-eff7-482b-8493-284c27abb85c","order_by":25,"name":"Atsushi Sato","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Sato","suffix":""},{"id":269015360,"identity":"ef8b79b6-13b8-4511-934b-912bb5567638","order_by":26,"name":"Toshimi Takano","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Toshimi","middleName":"","lastName":"Takano","suffix":""},{"id":269015361,"identity":"b383a363-34ff-4dfe-8d30-549d72b2d38e","order_by":27,"name":"Yuji Miura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApElEQVRIiWNgGAWjYHCCBCBkYOAnXYtkA8l2GRwgWuWNhKcbHrbdkze+dvjhB4Yam2hitKTdSGwrNtx2O81YguFYWi5BB0K1JDBuu51gxsDYcJh4LfabZ6d/I01L4gbpHCJtkTzzIO1GwrmE5Bm3c4olEojxC9/xnLSbP8oSbPtnp2/88KHGhrAWhQM8CQheAi5lyEC+gf0AMepGwSgYBaNgJAMAXdtGKzzZsZQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-7091-628X","institution":"Toranomon Hospital: Toranomon Byoin","correspondingAuthor":true,"prefix":"","firstName":"Yuji","middleName":"","lastName":"Miura","suffix":""}],"badges":[],"createdAt":"2024-01-20 22:03:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3882691/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3882691/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-024-02491-6","type":"published","date":"2024-03-22T15:01:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50319031,"identity":"90dadd87-4eef-4b13-aacd-e61bdd13df43","added_by":"auto","created_at":"2024-01-29 16:48:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":486254,"visible":true,"origin":"","legend":"\u003cp\u003eModified PRISMA flow diagram of the literature search process. Each study was used in the meta analysis of infection related mortality. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta analyses\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3882691/v1/b8126326f363d97e5e80b524.jpg"},{"id":50319030,"identity":"e7e21623-c405-41c8-a1ce-1ccf9839cebf","added_by":"auto","created_at":"2024-01-29 16:48:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":399608,"visible":true,"origin":"","legend":"\u003cp\u003eInfection related mortality. (a) Forest plot and (b) funnel plot. CI, confidence interval; RR, risk ratio; SE, standard error.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3882691/v1/f620e73653431237047a653e.jpg"},{"id":53403841,"identity":"ca48d7db-44f9-431a-bfbd-c780b542b985","added_by":"auto","created_at":"2024-03-25 15:14:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":502919,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3882691/v1/4a9847da-64bb-4ed6-8d42-d56a5d0f5a55.pdf"}],"financialInterests":"","formattedTitle":"Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe first-line treatment for urothelial carcinoma is a combination of gemcitabine and platinum (cisplatin and carboplatin)-based anticancer agents (GC and GCarbo therapy) or a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC therapy). MVAC therapy is associated with a high incidence of myelosuppressive toxicity (febrile neutropenia [FN] incidence: 26%); therefore, GC is commonly used in clinical practice. Second-line therapies, including immune checkpoint inhibitors, such as pembrolizumab and avelumab, and third-line therapies, including enfortumab vedotin, do not have a high incidence of FN.\u003c/p\u003e \u003cp\u003e The only regimen listed in \u0026ldquo;Guidelines for the Appropriate Use of G-CSF 2013 ver. 5\u0026rdquo; is MVAC, which has an incidence of FN\u0026thinsp;\u0026gt;\u0026thinsp;20%; however, the regimen used in clinical practice is GC therapy. Therefore, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is unlikely to be used. Dose-dense MVAC therapy to increase therapeutic intensity was shown to be effective in improving the progression-free and five-year survival compared to standard MVAC therapy, but the use of primary G-CSF prophylaxis was recommended in clinical trials that evaluated dose-dense MVAC.\u003c/p\u003e \u003cp\u003e Rather than determining the appropriateness of primary prophylactic administration of G-CSF based on the incidence of FN, in this guideline, we conducted a systematic review to evaluate the usefulness of primary prophylactic administration of G-CSF for urothelial carcinoma.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eTo assess this clinical question (CQ) and construct G-CSF guidelines, a systematic review was performed following the \u0026ldquo;Medical information network distribution service (Minds) Handbook for Clinical Practice Guideline Development 2014\u0026rdquo; [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and \u0026ldquo;Minds Clinical Practice Guideline Development Guide 2017\u0026rdquo; [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A comprehensive literature search of the electronic databases (PubMed, Cochrane Library, and Ichu-shi) was performed on January 10, 2020, to identify studies published between January 1990 and December 2019 that investigated the impact of prophylaxis on clinical outcomes. From all extracted articles, an initial screening was performed using the titles and abstracts, and the screened articles were evaluated for their full text to exclude inappropriate ones. Two reviewers independently conducted this search, and disagreements were resolved by a third party. The following search terms were used: transitional cell carcinoma, urothelic/urologic neoplasms, ureteral neoplasms, drug therapy, granulocyte colony-stimulating factor, filgrastim, lenograstim, neutrogin, nartograstim, nartograstim, neu-up, pegfilgrastim, G-Lasta, biweekly, schedule, maintenance, dense, Drug Administration Schedule, Dose-Response Relationship, administration, and dosage.\u003c/p\u003e \u003cp\u003eIn this CQ, urothelial carcinoma patients receiving cancer chemotherapy were targeted, and cancer chemotherapy with enhanced intensity of therapy based on primary prophylaxis with G-CSF and with a conventional dosage and administration without enhanced therapeutic intensity were compared, with six items ultimately evaluated: the overall survival (OS), cancer-specific survival (CSS), incidence of FN, infection-related mortality, quality of life (QOL), and pain.\u003c/p\u003e \u003cp\u003e The Review Manager software program (RevMan; The Cochrane Collaboration, London, UK), version 5.41, was used for the statistical analyses. After a qualitative analysis using the Excel software program (Microsoft Windows; Redmond, WA, USA), studies were eligible for inclusion in the meta-analysis if the study design was a randomized control trial (RCT) that compared the use of G-CSF for primary prophylaxis against a non-administration control group. The risk ratio (RR) for each endpoint was calculated, and the effect size was expressed as the 95% confidence interval (CI) for each study. These values were calculated using fixed- or random-effects models, depending on the level of heterogeneity. The calculated RRs for individual studies and overall meta-analyses were represented using a forest plot. Heterogeneity was assessed using the I\u003csup\u003e2\u003c/sup\u003e test and the chi-square-based Q-test. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in the Z test was considered to be significant. A funnel plot was used to graphically investigate the potential publication bias.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eSelected literature\u003c/h2\u003e\n \u003cp\u003eA total of 83 articles, including 56 from PubMed and 27 from Ichu-shi Japanese Medical Journal, were screened for this systematic review (Fig.\u0026nbsp;1). A qualitative systematic review was conducted of seven articles selected after two rounds of screening. In addition, a meta-analysis was conducted because infection-related mortality was evaluated in two RCTs. The CSS and QOL could not be evaluated in any of the extracted articles.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eResults of a systematic review for each outcome\u003c/h2\u003e\n \u003col\u003e\n \u003cli\u003e\n \u003cp\u003eOS (benefit): One randomized controlled study (RCT) [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e] and three cohort studies [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e] evaluated the OS. Of these, three cohort studies had no comparators, but an RCT of dose-dense MVAC with G-CSF support that compared conventional dosage and administration demonstrated an OS benefit (hazard ratio 0.76 [95% CI 0.58\u0026ndash;0.99]) [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eIncidence of FN (benefit): The incidence of febrile neutropenia was evaluated in 1 RCT with a relative risk of 0.38 (95% CI 0.209\u0026ndash;0.687) [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eInfection-related mortality (benefit): Two RCTs [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e] and two cohort studies [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] evaluated the infection-related mortality. A meta-analysis of the 2 RCTs was performed (Fig.\u0026nbsp;2a), showing a relative risk of death due to infection of 0.97 (95% CI: 0.27\u0026ndash;3.54), indicating no significant reduction in mortality due to infection. The small number of references covered made this difficult to decide, but no obvious publication bias was found (Fig.\u0026nbsp;2b).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003ePain (adverse effects): Only one cohort study [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] evaluated pain. This study reported a pain incidence rate of 78%; however, it was difficult to evaluate because this study was not a comparative study.\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n\u003c/div\u003e"},{"header":"Discussion and Summary of Systematic Review","content":"\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\n\u003ch2\u003eBenefits\u003c/h2\u003e\n\u003cp\u003eOne RCT regarding dose-dense MVAC therapy showed a reduction in the incidence of FN, and a report evaluating long-term follow-up showed a benefit in the OS. However, no studies have been conducted on other regimens.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eAdverse effects\u003c/h2\u003e\n\u003cp\u003eOnly one cohort study on pain was reported, making an evaluation difficult.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient values and preferences\u003c/h2\u003e\n\u003cp\u003eNo studies related to values or preferences were extracted.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eCost and resources\u003c/h2\u003e\n\u003cp\u003eThere were no studies that examined costs/resources.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eA systematic review was conducted of seven articles in the CQ. Regarding the OS, the most important outcome, 1 RCT on dose-dense MVAC therapy and 3 other cohort studies were selected. The RCT showed a hazard ratio of 0.76 and 95% CI of 0.58\u0026ndash;0.99. Evidence regarding the incidence of FN, the third-most important outcome, was strong. Based on an evaluation of 1 RCT, the RR was 0.38, and the 95% CI was 0.209\u0026ndash;0.687, indicating a reduction in the incidence of FN. Mortality due to infection was evaluated in 2 RCTs (RR: 0.97, 95% CI: 0.27\u0026ndash;3.54), showing no marked reduction in mortality due to infection. In terms of adverse effects, the association between pain and G-CSF use was limited because it was reported in cohort studies.\u003c/p\u003e \u003cp\u003eThe majority of the studies selected for this CQ were based on studies of patients with unresectable urothelial carcinoma, which was considered a suitable population for this CQ. Although the authors discussed the use of intensified cancer chemotherapy with G-CSF primary prophylaxis, the literature only attempted to increase the intensity of MVAC therapy with G-CSF support, with no other regimens studied. Therefore, the relevant regimen was defined as dose-dense MVAC therapy.\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDeliberation and Voting at the Consensus Meeting\u003c/h2\u003e \u003cp\u003eTwenty-three members (physicians, 21; nurses, 1; pharmacists, 1) participated in the recommendation decision meetings. Based on preliminary reports from committee members, it was determined that there was no influence of any economic or academic conflict of interest on the recommendation decision.\u003c/p\u003e \u003cp\u003eAs described above, a draft recommendation was presented based on the systematic review report. After discussion and voting on the recommendation decision, all 23 members agreed with the draft and reached a consensus. In summary, the results of the systematic review showed a prolongation of the OS, the most important outcome, but since the basis for the decision was only a single RCT and a limited number of regimens, we made a \"weak recommendation to perform\" annotation of the relevant regimen.\u003c/p\u003e \u003cp\u003eAfter the publication of this guideline, the results of a phase III trial (VESPER trial) comparing dose-dense MVAC and GC as perioperative chemotherapies for muscle-invading bladder cancer were published [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The results of that trial are included in the revised manuscript.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDescription in relevant medical practice guidelines\u003c/h2\u003e \u003cp\u003e In the ASCO guidelines (2015) and ESMO guidelines (2010), G-CSF primary prophylaxis is recommended when using regimens with an FN incidence of \u0026ge;\u0026thinsp;20%; in the ASCO guidelines (2006, 2015), their regimen examples include the use of paclitaxel and CBDCA for bladder cancer. The ESMO guidelines (2010) list MVAC and TC (Paclitaxel, CDDP) as regimens for bladder cancer in their regimen examples.\u003c/p\u003e \u003cp\u003e The NCCC guidelines (Hematopoietic Growth Factors; Version 1.2022) list dose-dense MVAC for bladder cancer as an example regimen for primary prevention.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors thank Dr. Toshimi Takano and Ms. Natsuki Fukuda for their valuable comments and suggestions.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThe present study did not receive any funding.\u003c/p\u003e\n\u003ch2\u003eAuthor contributions\u003c/h2\u003e\n\u003cp\u003eAll authors contributed to the conception and design of the study. The first draft of the manuscript was written by \u003cem\u003eK.U.\u003c/em\u003e, and all authors commented on the previous version of the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMorizane T, Yoshida M, Kojimahara N, et al (2014) Minds Handbook for Clinical Practice Guideline Development 2014. Japan Council for Quality Health Care, Tokyo. https://minds.jcqhc.or.jp/s/developer_manual (in Japanese)\u003c/li\u003e\n \u003cli\u003eKojimahara N, Nakayama T, Morizane T, et al (2017) Minds Manual for Guideline Development 2017. Japan Council for Quality Health Care, Tokyo. https://minds.jcqhc.or.jp/s/developer_manual (in Japanese)\u003c/li\u003e\n \u003cli\u003eSternberg CN, de Mulder PH, Schornagel JH, et al. (2001) Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 19(10):2638-46.\u003c/li\u003e\n \u003cli\u003eSternberg CN, de Mulder PH, Schornagel JH, et al. (2006) Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 42(1):50-4.\u003c/li\u003e\n \u003cli\u003ePlimack ER, Hoffman-Censits JH, Viterbo R, et al. (2014) Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 32(18):1895-901.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDodd PM, McCaffrey JA, Mazumdar M, et al. (2000) Evaluation of drug delivery and survival impact of dose-intense relative to conventional-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy in urothelial cancer. Cancer Invest. 18(7):626-34.\u003c/li\u003e\n \u003cli\u003eInoue T, Obara T, SaitoM et al. (2007) Possible survival benefit of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin combination therapy (HD-MVAC) over conventional MVAC in metastatic urothelial carcinoma patients. Hinyokika Kiyo. 53(9):613-8.\u003c/li\u003e\n \u003cli\u003eKuroda M, Kotake T, Akaza H, et al. (1998) Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group. Jpn J Clin Oncol. 28(8):497-501.\u003c/li\u003e\n \u003cli\u003eSeidman AD, Scher HI, Gabrilove JL, et al. (1993) Dose-intensification of MVAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial cancer. J Clin Oncol. 11(3):408-14.\u003c/li\u003e\n \u003cli\u003ePfister C, Gravis G, Fl\u0026eacute;chon A, et al. (2022) Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol. 40(18):2013-2022.\u003c/li\u003e\n\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":"G-CSF, Urothelial Cancer, Neutropenia, dose dense MVAC, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-3882691/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3882691/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGranulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a \"weak recommendation to perform\" with an annotation of the relevant regimen (dose-dense MVAC).\u003c/p\u003e","manuscriptTitle":"Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-29 16:48:33","doi":"10.21203/rs.3.rs-3882691/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2024-02-12T19:03:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-01-23T23:04:21+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-23T14:12:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-23T12:12:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2024-01-19T15:11:00+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":"33a691f1-8454-401f-8778-ffe4f58906d6","owner":[],"postedDate":"January 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-25T15:09:54+00:00","versionOfRecord":{"articleIdentity":"rs-3882691","link":"https://doi.org/10.1007/s10147-024-02491-6","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2024-03-22 15:01:06","publishedOnDateReadable":"March 22nd, 2024"},"versionCreatedAt":"2024-01-29 16:48:33","video":"","vorDoi":"10.1007/s10147-024-02491-6","vorDoiUrl":"https://doi.org/10.1007/s10147-024-02491-6","workflowStages":[]},"version":"v1","identity":"rs-3882691","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3882691","identity":"rs-3882691","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}