Comparing two chemotherapeutic regimens VDC/IE (or VAC/IE) v/s VIDE for patients suffering with Ewing sarcoma: A systematic review on survivorship and regime difference across borders

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It is usually treated with a combination of treatment options, including but not limited to chemotherapy, surgery, and radiation therapy. In this systematic review, we focus on comparing two different chemotherapeutic regimens i.e., VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) and VIDE (vincristine, ifosfamide, doxorubicin, and etoposide), for patients with Ewing Sarcoma, with Overall survival as the primary outcome and event-free survival as the secondary outcome. Methods MEDLINE, Embase (via Ovid), and Web of Science were searched methodically to identify studies which satisfied our inclusion and exclusion criteria. After obtaining the studies, deduplication was performed (manually and automatically). Once duplicates were removed, the studies were scanned against the inclusion and exclusion criteria predefined in the registered Prospero protocol. The process of screening was carried out in two phases: in the first stage, the Titles and Abstracts were scanned, and those which were included were scanned in the second stage of full-eligibility screening. The studies obtained were assessed for Risk of Bias using the JBI’s checklist. Results Post Risk of Bias Assessment, three studies were deemed suitable for inclusion. Through analysis of the data and text of these studies, we conclude that the VDC/IE regime yields better survival outcomes when compared to the VIDE regime, and hence should tentatively be used as standard of care for treating Ewing Sarcoma. 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F1000Research 2025, 14 :393 ( https://doi.org/10.12688/f1000research.151734.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Comparing two chemotherapeutic regimens VDC/IE (or VAC/IE) v/s VIDE for patients suffering with Ewing sarcoma: A systematic review on survivorship and regime difference across borders [version 1; peer review: awaiting peer review] Kritika Grover https://orcid.org/0000-0002-8905-6304 1,2 , Suleyman Noordeen https://orcid.org/0009-0007-6531-0439 2 , Mariam Bihnam 2 Kritika Grover https://orcid.org/0000-0002-8905-6304 1,2 , Suleyman Noordeen https://orcid.org/0009-0007-6531-0439 2 , Mariam Bihnam 2 PUBLISHED 04 Apr 2025 Author details Author details 1 Department of Clinical Neuroscience, University of Cambridge, Cambridge, England, UK 2 School of Clinical Medicine, University of Cambridge, Cambridge, England, UK Kritika Grover Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Suleyman Noordeen Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Supervision, Writing – Review & Editing Mariam Bihnam Roles: Formal Analysis, Investigation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS AWAITING PEER REVIEW Abstract Background Ewing sarcoma is the second most common primary bone cancer in adolescents and young adults, with a poor prognosis. It is usually treated with a combination of treatment options, including but not limited to chemotherapy, surgery, and radiation therapy. In this systematic review, we focus on comparing two different chemotherapeutic regimens i.e., VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) and VIDE (vincristine, ifosfamide, doxorubicin, and etoposide), for patients with Ewing Sarcoma, with Overall survival as the primary outcome and event-free survival as the secondary outcome. Methods MEDLINE, Embase (via Ovid), and Web of Science were searched methodically to identify studies which satisfied our inclusion and exclusion criteria. After obtaining the studies, deduplication was performed (manually and automatically). Once duplicates were removed, the studies were scanned against the inclusion and exclusion criteria predefined in the registered Prospero protocol. The process of screening was carried out in two phases: in the first stage, the Titles and Abstracts were scanned, and those which were included were scanned in the second stage of full-eligibility screening. The studies obtained were assessed for Risk of Bias using the JBI’s checklist. Results Post Risk of Bias Assessment, three studies were deemed suitable for inclusion. Through analysis of the data and text of these studies, we conclude that the VDC/IE regime yields better survival outcomes when compared to the VIDE regime, and hence should tentatively be used as standard of care for treating Ewing Sarcoma. READ ALL READ LESS Keywords Ewing Sarcoma, Chemotherapy, Survival, VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) , VIDE (vincristine, ifosfamide, doxorubicin, and etoposide), Survival Corresponding Author(s) Kritika Grover ( [email protected] ) Close Corresponding author: Kritika Grover Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Grover K et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Grover K, Noordeen S and Bihnam M. Comparing two chemotherapeutic regimens VDC/IE (or VAC/IE) v/s VIDE for patients suffering with Ewing sarcoma: A systematic review on survivorship and regime difference across borders [version 1; peer review: awaiting peer review] . F1000Research 2025, 14 :393 ( https://doi.org/10.12688/f1000research.151734.1 ) First published: 04 Apr 2025, 14 :393 ( https://doi.org/10.12688/f1000research.151734.1 ) Latest published: 04 Apr 2025, 14 :393 ( https://doi.org/10.12688/f1000research.151734.1 ) Background Epidemiology Ewing sarcoma is the second most prevalent primary bone cancer in adolescents and young adults, with a median age of 15 years, accounting for less than 5% of all soft tissue sarcomas. 1 There are around 200 cases of Ewing sarcoma identified in children each year in the United States, which accounts for one percent of all malignancies diagnosed in children. 2 Based on the statistics provided by the Bone Cancer Research Trust (BCRT) in the United Kingdom, the number of reported instances of Ewing Sarcoma in the country are about 100 annually. 3 An analysis of data and trends derived from the National Cancer Registry Programme spanning the years 1982 to 2011 revealed that Ewing Sarcoma constituted around 15% of the total cases of bone malignancies in India. 4 Disparities in the features and outcomes were observed among patients with ES 1 belonging to various racial and ethnic groups. Specifically, when compared to white non-Hispanic patients, black patients exhibited significantly elevated rates of soft tissue tumours; it was observed that the occurrence of soft tissue tumours exhibited an intermediate prevalence among Asian and white Hispanic individuals. 5 This prevalence differs from that observed in white non-Hispanic patients. 5 Notably, white Hispanic patients demonstrated a higher proportion of larger tumours upon initial presentation than white non-Hispanic patients. 5 Pathophysiology and histopathology Ewing sarcoma is a prototypical translocation sarcoma, and it was one of the first tumours in this category to be pathologically recognized as a single entity. 6 Chromosome translocations that fuse a gene from the ETS family of transcription factors with EWS (EWSR1), located at 22q12, gives rise to Ewing sarcoma, the fusion gene EWS-FLI1 consisting of the N-terminal component of EWS and the C-terminal section of FLI1, together with the ETS DNA-binding domain, is present in approximately 90% of the cases instances. 6 It has an intricate array of conditions that require the coordination of numerous signalling pathways to manifest. 6 Without no precursor lesions, this unusual round cell creates an environment for the intricate transcriptional dysregulation controlled by EWSR1/FLI1, making illness detection and treatment difficult. 7 A periodic acid-Schiff stain can be used to detect glycogen, which is typically present in the sparse, eosinophilic, diastase-degradable cytoplasm; the cell nuclei are round, have one or more small nucleoli, and finely distributed chromatin. 8 Rosette formation observed. No matrix is generated by the EFT. 8 EFT cells show membranous expression of CD99 or MIC2 on doing immunohistochemistry analysis. 8 Diagnosis in ewing sarcoma Diagnosis is most commonly made following local symptoms such as pain, stiffness, or swelling, which are secondary to tumour growth. 1 After obtaining a patient's medical history and performing a physical examination, the doctor may order a radiograph to inspect the area. In Imaging investigations of Ewing sarcoma family of tumours (ESFT) affecting bone are characterised by a damaging neoplastic proliferation originating from the diaphysis or middle region of the bone. 9 As mentioned by Biermann et al. (2017, as cited in Durer and Shaikh 2022) the 2017 revision of the National Comprehensive Cancer Network (NCCN) guideline, imaging of main locations should include MRI either with or without CT, with or without contrast being of utmost significance. 1 In order to ascertain the possible sites of metastasis, supplementary imaging modalities, such as computed tomography (CT) of the thorax, positron emission tomography/CT (PET/CT), bone scans, and magnetic resonance imaging (MRI) of the spine and pelvis, may be utilised. 10 To ascertain the possible sites of metastasis, supplementary imaging modalities, such as computed tomography (CT) of the thorax, positron emission tomography/CT (PET/CT), bone scans, and magnetic resonance imaging (MRI) of the spine and pelvis, may be utilised. 10 Further biopsy (either a biopsy (needle or surgical) is performed to ascertain if the cells are malignant and what type of cancer it is, and gene testing is also done to confirm the diagnosis. 11 Once the diagnosis s confirmed, a treatment plan. Treatment and management Chemotherapy, surgery, and radiotherapy are currently used as part of ES treatment. 12 For all individuals with Ewing tumours, systemic combination chemotherapy is a necessary component of treatment. 13 The treatment of an Ewing tumour (Ewing sarcoma) is primarily determined by its location in the body and the extent of its propagation when it is first discovered. 14 1. For localised Ewing Sarcoma: Neoadjuvant chemotherapy is given, It is determined after nine weeks, if the tumour is shrinking and if a surgery can be done/is required. 14 Consolidation chemotherapy is given post primary treatment and might be accompanied by radiation therapy if cancer cells are discovered at or around the edges of surgical specimens. 14 2. For metastatic ES: The therapeutic approach for managing metastatic Ewing sarcoma remains largely consistent, albeit with an escalated treatment regimen in cases where the disease has metastasied. 14 After induction/neoadjuvant chemotherapy, if the cancer only remains in a few regions, the primary tumour may be surgically removed. 13 Another treatment option (depending upon the case) is radiation therapy at every possible site, along with induction and consolidation chemotherapy. 14 Other novel treatment options, including targeted therapy and immunotherapy (including CAR-T cell therapy for recurrent Ewing sarcoma), are under clinical trials. The utilisation of induction therapy involving vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by consolidation therapy with vincristine, actinomycin D, and either ifosfamide or cyclophosphamide (VAI or VAC), or alternatively, busulfan and melphalan (BuMel), continues to be the prevailing and widely accepted initial treatment approach for Ewing sarcoma in Europe. Conversely, in the United States, the established standard of medical care entails interval-compressed cycles of cyclophosphamide, doxorubicin, and vincristine (VDC), in conjunction with ifosfamide and etoposide (IE). 15 For the purpose of this systematic review, we focus on induction chemotherapy for Ewing Sarcoma, as it is one of the most significant components in the treatment, and it is important to either understand the reason for the two different approaches, or to bridge the gap in the absence of reasoning. Methods 1) Formulating a research question A systematic review (SR) is built on a specific and well-defined subject, and the PICO technique was used to construct the key question: Patient/Population: Adults and/or children diagnosed with Ewing Sarcoma Intervention: Usage of VDC/IE (or VAC/IE) for chemotherapy Comparison: VIDE regimen Outcome: Overall survival Secondary outcome is Event Free Survival 2) Research protocol A research protocol was registered with Prospero - crd.york.ac.uk/PROSPERO/display_record.php?RecordID=405442 3) Selection criteria Randomied control/clinical trials, case-control studies, and collective cohort studies were selected as the apt form for this systematic review, and any other type of study including secondary sources (reviews and meta-analysis), commentaries/letters to the editor, conference abstracts, and chapters from books were set for exclusion. Studies in languages other than English or animal studies were excluded as well. Studies comparing VIDE regimes. Vincristine, Ifosfamide, Doxorubicin and Etoposide drug combination) to VDC/IE (or VAC/IE) (Vincristine, Doxorubicin (Adriamycin), and Cyclophosphamide drug combination) for induction chemotherapy were selected. Studies were disregarded if one or more drugs were replaced. Only studies/trials where VDC/IE and VIDE were compared head-on were considered (as stated in the Prospero protocol). No age restriction was imposed, and studies focusing on both adults and children were included. 4) Search strategy Databases were searched for the application of unique structured search strategies for every database. Databases including Embase, Medline, and Web of Science. Informal searches of several trial registries and preprint servers were also done. The search strategy used for searching the Embase, Medline, and Web of Sciences databases can be found under extended data section . 5) Selection process Research studies were located using the search strategy and loaded into Microsoft Excel before being copied to Google sheets for further work. After importing the studies to Google sheet, the process of deduplication was carried out. The process of deduplication is important because many databases frequently contain the same study, which results in the existence of many versions of the same paper. Deduplication was split into two phases: the first phase was auto deduplication, in which duplicates with identical titles were eliminated using a Google Doc add-on (while maintaining the original copy), and the filtrate was copied to another sheet. The second phase is that of manual deduplication, which is useful but not error-free, and is why a manual process is necessary. A manual deduplication process was used to ensure that no studies were counted more than once. The title field was used to sort the studies, and duplicates were eliminated. Duplicate entries were swiftly eliminated by arranging titles alphabetically. The protocol's inclusion and exclusion criteria were then used to compare and scan the studies ( Figure 1 ). Each study was scanned by two independent reviewers; in case of disagreement, a decision was made post discussion and agreement on an explanation. Scanning against inclusion and exclusion criteria was done in two stages- a) Title and abstract screening: Studies that had no link to the review question or PICO framework were disregarded at this initial stage. b) Full-text evaluation: Papers that passed the title and abstract screening were scanned or rescreened to find papers that could satisfy every requirement. Figure 1. Flow diagram of study selection process (adapted from Page et al, 2021). 21 Risk of bias assessment Researchers have employed the evaluation of internal validity protections put in place to look at the potential trustworthiness of evidence produced within a study; such an evaluation has historically been referred to as a quality assessment since these protections defend against systematic error. 16 A risk of bias assessment is when the findings of a quality assessment are translated through the possible risk of bias using an empirical concept. 16 For this systematic review, the JBI Critical Appraisal Tools was used, the JBI checklist for randomised. The control trial and JBI checklist for cohort studies were the specific tools which were used. Two critical appraisers independently and rigorously evaluated the papers selected for inclusion. Differences in ROB assessments were reviewed in a discussion between the appraisers, following which a final outcome was generated. Results 1) included studies Post this process three studies were found to be suitable for inclusion: a) (Brennan et al., 2022) 17 b) (Umeda et al., 2020) 19 c) (Umeda et al., 2021) 20 All studies were determined to possess a sufficiently low risk of bias and were, hence, included. For the completed assessments, refer to extended data . (This table has been adapted from Page et. al 2021 which is an This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited). 2) Data extraction Data was extracted using Microsoft Excel. Fields including median age, gender distribution, Hazard Ratio and Confidence Interval were extracted from Brennan et al. (2022), 17 for both overall survival and event-free survival. Umeda et al. (2020) 19 and Umeda et al. (2021). 20 compared multiple regimens and provided an aggregate overall survival outcome, but did not provide a direct comparison between the VIDE and VDC/IE regimes. As no data for the chosen measure of the effect was available, no data extraction was done for the two studies. The authors were contacted by the team. Qualitative evidence was considered for analysis. Data analysis The median age of the patients in the Umeda group was 13.5 years and 57.9% of patients were males. There was a lack of quantitative synthesis with respect to the outcome this systematic review has targeted, narratively, there is no significant difference between overall survival when either regimen is administered. 17 In contrast, Brennan et al. (2022) found that “Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55–0·92 in favour of group 1)” with group 1 receiving the VIDE regime and group 2 receiving VDC/IE. 17 In the VIDE group, the overall survival at 3 years was 74%, but in the VDC plus IE group, it was 82% (HR 0:62, 95% CI: 0:46-0:85). 17 Discussion The Umeda group 2020 study concluded that there is no significant difference in overall survival when compared across various regimens as first-line chemotherapy, including VDC/IE and VIDE. Umeda et al. (2021) was an extension of the 2020 cohort study, in which prognostic and therapeutic variables impact the clinical outcomes of patients with metastatic Ewing sarcoma. were retrospectively analysed, but no comments were made about survival rate differences when VDC/IE and VIDE were used as induction therapy. 20 When considering the work of Brennan and her team, the study concluded that there is no evidence to suggest that the treatment effect of VIDE compared with VDC plus IE varies across different subgroups of patients and diseases. This conclusion is supported by the fact that all confidence intervals for the interaction effects included values that indicated no significant subgroup effects. The point estimate for the hazard ratio (HR) within each subgroup indicated a preference for the combination of VDC + IE, as reported by Brennan et al. (2022). 17 Conclusion made through Brennan et al. (2022) was that for all phases of newly diagnosed ewing sarcoma, dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide has been shown to have enhanced efficacy while also demonstrating reduced toxicity. 17 The average age of patients in Brennan et al. (2022) Randomised Clinical Trial was 15 years and 58% of patients were males, 17 which is similar to the age and gender characteristics of the Umeda et al. (2020), 17 The sample size of Brennan et al. (2022) 17 was significantly more (n= 640) when compared to the Umeda et al. (2020) 19 where n=57, study done by Umeda and group was a cohort study based in the Japanese setting while Brennan and group conducted a global Randomised Clinical Trial, thereby making it a better evidence for the particular outcome and intervention this systematic review focuses on; Lack of statistical data comparing VDC/IE and VIDE regimens in Umeda et al. (2020) for overall survival, makes Brennan et al. (2022) a more reliable evidence for this systematic review. 19 Strengths and limitations The group meticulously reviewed the research using a strict sc. Nevertheless, we were only able to locate three studies, and the majority of our research was based on Brennan and their team's previous work. Despite the limited number of studies available, the inclusion of a substantial number of patients in the study by Brennan et al. (2022) provides a strong foundation for our findings. Additionally, the consistency and reliability of Brennan et al. 's previous work further support the validity of our results. Conclusion We recommend utilising VDC/IE as the standard of care for Ewing sarcoma tentatively. While the research conducted by Umeda et al. found no significant differences between the two groups, the study conducted by Bennan and his group revealed a significant difference; thus, using dose-intensive VDC/IE instead of VIDE will not be detrimental, if not superior. However, we were limited by lack of widely available data and the small sample size, highlighting the need for more research before a firm standard of care could be established. Disclosure instructions During the preparation of this work, the authors used Quilt bot in order to check for plagiarism and paraphrase in a few places. After using this tool, the authors reviewed and edited the content as needed, and take full responsibility for the content of the publication. Ethics and consent Ethical approval and consent were not required. Data availability No primary data is associated with this article. Extended data Apollo: Cambridge University Library: Search strategy for comparing two chemotherapeutic regimens VDC/IE (or VAC/IE) v/s VIDE for patients suffering with Ewing sarcoma. DOI: https://doi.org/10.17863/CAM.111129.2 . 22 This project contains the following extended data: • Supplement 1.pd • ROB complete ewing final.odt Data are available under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Reporting guidelines Apollo: Cambridge University Library: PRISMA Checklist for“ Comparing two chemotherapeutic regimens VDC/IE (or VAC/IE) v/s VIDE for patients suffering with Ewing sarcoma: A Systematic review on survivorship and regime difference across borders ” Doi: https://doi.org/10.17863/CAM.113448 Data are available under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) References 1. Durer S: Ewing Sarcoma. StatPearls - NCBI Bookshelf. 2024. Reference Source 2. Niederhuber JE, Armitage JO, Doroshow JH, et al. : Abeloff’s Clinical Oncology. Elsevier eBooks; 2020. Publisher Full Text 3. Ewing sarcoma: Bone Cancer Research Trust. Reference Source 4. 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Slotkin EK, Tap WD: Towards a new era in the treatment of Ewing sarcoma. Lancet. 2022 Oct 1; 400 (10362): 1488–1489. PubMed Abstract | Publisher Full Text 16. Furuya-Kanamori L, Xu C, Hasan SS, et al. : Quality versus Risk of bias assessment in clinical research. J. Clin. Epidemiol. 2021 Jan 1; 129 (129): 172–175. Publisher Full Text 17. Brennan B, Kirton L, Marec-Bérard P, et al. : Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomized, phase 3 trial. Lancet. 2022 Oct 1; 400 (10362): 1513–1521. PubMed Abstract | Publisher Full Text 18. Barker TH, Stone JC, Sears K, et al. : The revised JBI critical appraisal tool for the assessment of risk of bias for randomized controlled trials. JBI Evidence Synthesis. 2023; 21 (3): 494–506. PubMed Abstract | Publisher Full Text 19. Umeda K, Miyamura T, Yamada K, et al. : Prognostic and therapeutic factors influencing the clinical outcome of metastatic Ewing sarcoma family of tumors: A retrospective report from the Japan Ewing Sarcoma Study Group. Pediatr. Blood Cancer. 2020 Dec 19; 68 (3): e28844. PubMed Abstract | Publisher Full Text 20. Umeda K, Miyamura T, Yamada K, et al. : Clinical outcome of patients with recurrent or refractory localized Ewing’s sarcoma family of tumors: A retrospective report from the Japan Ewing Sarcoma Study Group. Cancer Reports. 2021 Jan 16; 4 (3): e1329. PubMed Abstract | Publisher Full Text | Free Full Text 21. Page MJ, McKenzie JE, Bossuyt PM, et al. : The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Int. J. Surg. 2021 Apr 1; 88 : 105906. PubMed Abstract | Publisher Full Text 22. Grover K, Noordeen S, Bihnam M: Search strategy for comparing two chemotherapeutic regimens VDC/IE (or VAC/IE) v/s VIDE for patients suffering with Ewing sarcoma. Apollo - University of Cambridge Repository; 2024. Reference Source Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 04 Apr 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Clinical Neuroscience, University of Cambridge, Cambridge, England, UK 2 School of Clinical Medicine, University of Cambridge, Cambridge, England, UK Kritika Grover Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Suleyman Noordeen Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Supervision, Writing – Review & Editing Mariam Bihnam Roles: Formal Analysis, Investigation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 04 Apr 2025, 14:393 https://doi.org/10.12688/f1000research.151734.1 Copyright © 2025 Grover K et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Grover K, Noordeen S and Bihnam M. Comparing two chemotherapeutic regimens VDC/IE (or VAC/IE) v/s VIDE for patients suffering with Ewing sarcoma: A systematic review on survivorship and regime difference across borders [version 1; peer review: awaiting peer review] . 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