A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations

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Despite growing research, a comprehensive synthesis of the evidence on the efficacy and safety of HDIVC in advanced solid tumors remains limited. Materials and Methods This review will follow the six steps of the Arksey and O’Malley framework, as adapted by Levac et al, namely: identifying the research question, identifying relevant studies, study selection eligibility, charting the data, collating, summarizing and reporting the results, and consultation. PubMed, Scopus, ScienceDirect, and Google Scholar databases will be used for the search of articles from 2000 – 2025. Grey literature will also be conducted. The Preferred Reporting Items for Systematic Reviews and the Meta-Analysis for Scoping Reviews (PRISMA-ScR) will be used as a guide for this scoping review protocol. A two-stage screening process will be used to determine the eligibility of articles with two independent reviewers. Discrepancies will be handled by consensus or by consulting an expert in cancer care. The selection of studies for the review is anticipated to be completed within 12 weeks, from 01 October to 31 December 2025. The extracted data will be analyzed and presented in a report. Conclusion This scoping review will consolidate evidence on HDIVC for advanced solid tumors, identifying efficacy outcomes, safety profiles, and patient experiences in African populations that will inform clinical practice and guide policy making. Ethics and Dissemination Ethical approval is not required for this scoping review. However, the results of this search will be disseminated through academic presentations and publications in peer-reviewed journals. 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F1000Research 2025, 14 :965 ( https://doi.org/10.12688/f1000research.169079.1 ) 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 ▬ ✚ Study Protocol A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] Olufunmilayo Olukemi Akapo https://orcid.org/0000-0003-1267-1576 1 , Olubunmi Margaret Ogbodu https://orcid.org/0000-0002-2488-2963 2 Olufunmilayo Olukemi Akapo https://orcid.org/0000-0003-1267-1576 1 , Olubunmi Margaret Ogbodu https://orcid.org/0000-0002-2488-2963 2 PUBLISHED 22 Sep 2025 Author details Author details 1 Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, Eastern Cape, 5100, South Africa 2 Department of Anesthesiology & Critical Care, Walter Sisulu University Faculty of Health Sciences, Mthatha, Eastern Cape, 5100, South Africa Olufunmilayo Olukemi Akapo Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Olubunmi Margaret Ogbodu Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Oncology gateway. Abstract Background High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential antioxidative and cytotoxic effects. Despite growing research, a comprehensive synthesis of the evidence on the efficacy and safety of HDIVC in advanced solid tumors remains limited. Materials and Methods This review will follow the six steps of the Arksey and O’Malley framework, as adapted by Levac et al, namely: identifying the research question, identifying relevant studies, study selection eligibility, charting the data, collating, summarizing and reporting the results, and consultation. PubMed, Scopus, ScienceDirect, and Google Scholar databases will be used for the search of articles from 2000 – 2025. Grey literature will also be conducted. The Preferred Reporting Items for Systematic Reviews and the Meta-Analysis for Scoping Reviews (PRISMA-ScR) will be used as a guide for this scoping review protocol. A two-stage screening process will be used to determine the eligibility of articles with two independent reviewers. Discrepancies will be handled by consensus or by consulting an expert in cancer care. The selection of studies for the review is anticipated to be completed within 12 weeks, from 01 October to 31 December 2025. The extracted data will be analyzed and presented in a report. Conclusion This scoping review will consolidate evidence on HDIVC for advanced solid tumors, identifying efficacy outcomes, safety profiles, and patient experiences in African populations that will inform clinical practice and guide policy making. Ethics and Dissemination Ethical approval is not required for this scoping review. However, the results of this search will be disseminated through academic presentations and publications in peer-reviewed journals. READ ALL READ LESS Keywords High-dose intravenous vitamin C (HDIVC), oncology, safety and efficacy, cancer-related morbidity and mortality Corresponding Author(s) Olufunmilayo Olukemi Akapo ( [email protected] ) Close Corresponding author: Olufunmilayo Olukemi Akapo Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Olukemi Akapo O and Ogbodu OM. 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: Olukemi Akapo O and Ogbodu OM. A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.12688/f1000research.169079.1 ) First published: 22 Sep 2025, 14 :965 ( https://doi.org/10.12688/f1000research.169079.1 ) Latest published: 22 Dec 2025, 14 :965 ( https://doi.org/10.12688/f1000research.169079.2 )  There is a newer version of this article available. Suppress this message for one day. Introduction Solid tumors represent approximately 90% of human malignancies and continuously contribute strongly to global cancer-related morbidity and mortality ( Sung et al., 2021 ; Xiaoyu et al., 2024 ; Santucci et al., 2020 ). Significant progress has been made with targeted therapies, immune checkpoint inhibitors, and combination treatment strategies, but the clinical management of advanced solid tumors continues to pose a formidable challenge ( Li et al., 2023 ). These cancers exhibit biological heterogeneity and varied tumor microenvironments (TME), and recurring resistance to conventional therapy including chemotherapy, radiation, and surgery ( Garcia et al., 2024 ; Ge et al., 2022 ; Taeb et al., 2022 ). The tumor microenvironment strongly impacts tumor progression, immune evasion, metastasis, and therapeutic resistance, with factors such as hypoxia, acidity, and immune suppression presenting significant barriers to the success of therapy ( Wang et al., 2023 ; Ghosh et al., 2024 ; Zhou et al., 2024 ). There has been renewed interest in adjunctive therapies that may enhance the therapeutic index of standard treatments. Traditionally known for its antioxidant activity, vitamin C has garnered interest for its potential pro-oxidant effects when administered at pharmacologic concentrations achievable via high-dose intravenous infusion ( Giansanti et al., 2021 ; Böttger et al., 2021 ; Pawlowska et al., 2019 ). High-dose intravenous vitamin C (HDIVC) has demonstrated the ability to modulate the tumor microenvironment by potentially reversing epithelial-to-mesenchymal transition, suppressing hypoxia-driven and oncogenic signaling pathways, and promoting anti-tumor immune responses ( Böttger et al., 2021 ; Suraweera et al., 2018 ; Hoffer et al., 2015 ). HDIVC is proposed to selectively generate oxidative stress in tumor cells, inducing cytotoxicity while minimizing harm to normal tissues. ( Gibson et al., 2020 ; Paller et al., 2024 ). Preliminary clinical studies indicate that HDIVC is safe and effectively attains the pharmacologic plasma levels necessary to elicit anti-tumor effects. ( Böttger et al., 2021 , Zhao et al., 2025 ). Furthermore, preclinical studies have highlighted the potent antitumor effects of HDIVC, including the induction of apoptosis, suppression of tumor cell proliferation, and disruption of metastatic mechanisms. ( Fan et al., 2023 ; Carr & Cook, 2018 ; Böttger et al., 2021 ). HDIVC has also demonstrated potential synergistic effects when combined with conventional chemotherapy and radiotherapy, enhancing tumoricidal efficacy while concurrently reducing the toxicities associated with standard treatments. ( Böttger et al., 2021 ; Carr & Cook, 2018 ; Didier et al., 2023 ). Nonetheless, although phase I and II trials increasingly support the safety and potential efficacy of high-dose intravenous vitamin C (HDIVC), conclusive evidence from phase III trials is still lacking, and reported outcomes related to tumor response, survival, and patient-reported measures remain inconsistent ( Shah et al., 2022 ; Wang et al., 2022 ). Rationale for scoping review Existing studies are largely concentrated in North America, Europe, and parts of Asia, with limited relevance to the sociocultural, genetic, and healthcare infrastructure realities of African patients. Africa’s public health sector will benefit from adjunctive treatments like HDIVC, which offer potential benefits in mitigating treatment-related side effects, enhancing quality of life, and providing consistent, comprehensive oncology care. Synthesizing the current global and emerging local evidence will identify gaps in knowledge, underscore the need for context-specific evidence to inform tailored therapeutic interventions, and support the development of African-centered clinical guidelines. Methodology Study design This scoping review will adopt the Joanna Briggs Institute (JBI) methodological framework for scoping reviews and adhere to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist for reporting ( Hadie, 2024 ). These frameworks provide transparency, rigor, and reproducibility in scoping reviews by clearly articulating the processes for identifying, selecting, and synthesizing literature. This review also aligns with the enhanced methodology proposed by Arksey and O’Malley ( Arksey & O’Malley, 2005 ) and later refined by Levac et al ( Levac et al., 2010 ; Ouzzani et al., 2016 ), ensuring systematic rigor through six key steps ( Figure 1 ): 1. Identifying the research question 2. Identifying relevant studies 3. Study selection 4. Charting the data 5. Collating, summarizing, and reporting results 6. Consultation Figure 1. Six stages of conducting a scoping review. Stage 1: Identifying the research question The research question was developed using the technique suggested by Arksey and O’Malley ( Arksey & O’Malley, 2005 ) and further refined by Levac et al. ( Levac et al., 2010 ), which builds on Arksey and O’Malley’s framework, with guidance from subsequent enhancements. The proposed scoping review methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR, Figure 2 ) guidelines and checklist to allow us to make use of literature across study designs and in both peer-reviewed and grey literature. The process will involve five key stages and an optional sixth stage that we have included in our process. Figure 2. PRISMA for Scoping Reviews (PRISMA-ScR) flowchart for study selection – A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations. Source: Tricco et al. (2018) . The process will include: (1) Identifying the research question –clearly defining the purpose, concepts, and target population to maintain a balance between breadth and focus; (2) Identifying relevant studies – developing an iterative, comprehensive search strategy in collaboration with an information specialist, covering both peer-reviewed and grey literature; using predefined keywords and Boolean operators (3) Study selection – applying well-defined inclusion and exclusion criteria with independent screening of titles and abstracts and full articles by two reviewers, including pilot testing to ensure consistency; (4) Charting the data – using a standardized and iteratively refined extraction form to capture key study characteristics and contextual information; (5) Collating, summarizing, and reporting results – analyzing and presenting findings through descriptive numerical summaries, thematic synthesis, and interpretation of implications for research, policy, and practice; and (6) Consultation with stakeholders – engaging relevant experts and knowledge users to validate findings, identify gaps, and guide dissemination and inform implications for research and practice. Research Sub-questions: • What types of solid tumors have been studied concerning HDIVC? • What adverse effects and safety concerns are documented with HDVIC? • What are the reported clinical efficacy outcomes or quality-of-life measures with the use of HDIVC? This study will use the Population, Intervention, Comparison, Outcomes, and Timeline (PICOT) format to align the study selection with the research question. This study’s applied PICOT framework is shown in Table 1 . The timeline for this study will span 12 weeks from 01 October 2025 to 31 December 2025, and eligible studies will be from 2000 to 2025. The use of high-dose intravenous vitamin C as a potential adjunct in oncology started to receive renewed scientific attention in the early 2000s following the pioneering pharmacokinetic studies conducted by NIH researchers that showed intravenous but not oral vitamin C could achieve pharmacologic plasma concentrations with potential cytotoxic effects on tumor cells. Prior to 2000, most studies were anecdotal or lacked a thorough clinical approach. Over the past 20 years, there has been an increasing push to improve the infrastructure for clinical research in low- and middle-income countries (LMICs) and Africa ( Böttger et al., 2021 ). Table 1. PICOT framework for study selection. Criteria P- Population Adult patients aged 18-60 years on HDVIC for over 6 months, following diagnosis of tumors I- Intervention High Dose Intravenous Vitamin C (HDVIC) C- Comparison No comparison group O- Outcome Primary - types of tumors studied concerning HDVIC Secondary outcomes - Adverse effects and safety concerns documented with HDVIC - reported clinical efficacy outcomes or quality-of-life measures with the use of HDVIC. T- Timeline 2000 – 2025 Stage 2: Identifying relevant studies We will comprehensively search electronic databases (PubMed, ScienceDirect, Scopus, and Google Scholar) and grey literature sources for studies published between 2000 and 2025. An initial exploratory search strategy based on the PICOT framework will be developed on PubMed to determine some relevant terms to the research question. However, there is no comparator for this study hence PIOT framework will be used. A second search strategy will be developed using the most relevant Medical Subject Headings (MeSH) terms, while some keywords will be searched in the title, abstract, and subject headings of the other electronic databases. Additional grey literature will be searched through cancer research institutes’ organizational reports, and manual searching of reference lists from included studies, including consulting websites such as the World Health Organization (WHO) and the United Nations (UN). The initial search strategy in the electronic databases is stated in Table 2 . Table 2. Initial search strings using electronic databases. Electronic database Search strings PubMed "Antineoplastic agents" [Mesh] OR "high dose intravenous vitamin c*" [tw] OR "intravenous vitamin c*" [tw] OR "cancer metastasis*" [tw] OR "efficacy*"[tw] OR "adverse effects*" [tw] OR "clinical outcomes*" [tw] OR " quality of life impacts*"[tw] AND "safety*" [tw] AND "Africa*"[tw] OR "African males*"[tw] OR "Adult African population*"[tw] AND (2000/1/1:2025/7/23[pdat])). ScienceDirect vitamin C " AND cancer therapy" OR "safety" AND "clinical outcomes" "high strength vitamin C" OR "clinical outcomes" OR "cancer therapy" AND "Africa" Scopus high dose intravenous vitamin C" AND tumors" OR "clinical outcomes" AND vitamin C " AND cancer therapy" OR "safety" AND "efficacy" vitamin C " AND cancer therapy" OR "safety" AND "clinical outcomes" Google Scholar "high strength intravenous vitamin C" OR “high dose vitamin C” OR "clinical outcomes" OR "cancer therapy" AND "African adult population" Stage 3: Study selection of eligible studies To ensure a rigorous selection process, we will employ the PIOT framework (Population Intervention Outcome Time) as a guide for title and abstract screening, with the two reviewers working independently. It is anticipated that the selection of studies for the review will be completed within 12 weeks, and this process will adhere to the guidelines provided by the PRISMA-ScR checklist. Once all identified records have been extracted from all databases, duplicates will be eliminated using the EndNote X9 (Clarivate) software. Rayyan, a reviewing platform, will be used to execute the entire selection process to facilitate collaboration between the reviewers to maintain transparency and streamline the reviewing process. Any discrepancies between the two reviewers during the screening and selection stages will be resolved through discussion with an expert in cancer care to reach an agreement. Eligibility criteria Titles and abstracts will be screened for eligibility by two independent reviewers based on the inclusion criteria: Inclusion criteria: • Published peer-reviewed studies and review articles that evaluated high-dose intravenous vitamin C (HDIVC) in patients with advanced solid tumors in African countries • Conference proceedings and grey literature. • Study designs: Randomized Clinical Trials, observational studies, cohort studies, case series, qualitative studies, and mixed-methods studies. • Outcomes addressing efficacy (e.g., tumor response, survival), safety (e.g., adverse events), and patient-reported experiences (e.g., quality of life). • Published studies in English from 2000-2025 Exclusion criteria: • Studies on oral vitamin C. • Studies from non-African countries • Preclinical (animal or in vitro) studies. • Studies exclusively involving hematologic malignancies. • Studies on advanced-stage disease. Stage 4: Data charting process A standardized data extraction form will be developed and piloted to ensure clarity and consistency. The form will capture key details shown in Table 3 . Table 3. Data charting form. 1 Author(s) 2 Year of publication 3 Title of study 4 Aim of the study 5 Study design 6 Study setting/country 7 Study population 8 Age group 9 Intervention characteristics – (HDVIC dosing, schedule) 10 Study outcomes (efficacy, safety, quality of life) 11 Key Findings 12 Recommendations from the study Stage 5: Data collation, summarization, and reporting The key findings across studies will be synthesized. The NVivo software will be used for qualitative synthesis of data. Qualitative data will be summarized narratively in themes. Descriptive statistics will be used for quantitative outcomes, where applicable, and presented in tables and figures. A PRISMA-ScR flow diagram would be used to illustrate the selection process. Quality assessment of included studies Quality assessment is not a primary focus in the scoping review. The study designs of included studies, such as qualitative, quantitative, and mixed methods, will be described to improve the quality of scoping reviews by enhancing transparency and uniformity in reporting. This assessment will help contextualize the strength of the evidence and identify methodological gaps. There will be no risk of bias assessment for this scoping review. Stage 6: Consultation Stakeholders, including researchers, policymakers, and alternative medicine practitioners, will be consulted to validate and interpret the findings of this scoping review. Though these stakeholders have not directly contributed to the design of this review, they will be consulted and involved in interpreting our findings for practical and evidence-based decision-making. Discussion This scoping review will provide an evidence map of the role of HDIVC in treating advanced solid tumors in adult African populations with results for practice, policy, and future integrative oncology guidelines and research. Given a rising incidence of cancer in Africa, a synthesis of current global and emerging local evidence will identify gaps in knowledge and inform tailored therapeutic interventions, particularly in resource-constrained settings in Africa. Strengths and limitations The review will follow a well-established scoping review methodology using the Arksey and O’Malley framework, refined by the Levac et al framework. The selection of articles will cover studies published in the last two decades (2000 –2025), synthesizing old and current evidence from the literature. The inclusion of grey literature strengthens our review by reducing publication bias and enhancing the comprehensiveness of our findings. However, studies un-indexed in languages other than English, in the consulted databases, and in grey literature will be omitted from the review. Supporting information PRISMA-ScR flowchart PRISMA-P Checklist Patient consent for publication Not applicable. Data availability statement The current study did not produce or analyze any datasets, as no primary data will be collected, and all sources will be from publicly available literature. Upon research completion, all pertinent data will be made public. There will be a scoping review, and the outcomes will be presented. All data generated or analyzed during this scoping review will be included in the published article and its supplementary materials. No primary data will be collected, and all sources will be from publicly available literature through the systematic search process. Detailed search strategies, data charting forms, and extracted datasets will be provided as supplementary files to ensure transparency and reproducibility. https://figshare.com/s/2b7848500cf6c97ee346 Data type Data availability statement Data citation Data deposited into generalist repository Figshare: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations. https://figshare.com/s/2b7848500cf6c97ee346 Data is available under the terms of the Creative Commons Attribution 4.0 International license (CCO licence) Not Applicable. This is a scoping review protocol. Acknowledgment The authors acknowledge and thank the library personnel at Walter Sisulu University for helping to optimize the search plan. References Arksey H, O’Malley L: Scoping studies: towards a methodological framework. Int. J. Soc. Res. Methodol. 2005; 8 (1): 19–32. 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PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 22 Sep 2025 ADD YOUR COMMENT Comment Author details Author details 1 Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, Eastern Cape, 5100, South Africa 2 Department of Anesthesiology & Critical Care, Walter Sisulu University Faculty of Health Sciences, Mthatha, Eastern Cape, 5100, South Africa Olufunmilayo Olukemi Akapo Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Olubunmi Margaret Ogbodu Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation, 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 (2) version 2 Revised Published: 22 Dec 2025, 14:965 https://doi.org/10.12688/f1000research.169079.2 version 1 Published: 22 Sep 2025, 14:965 https://doi.org/10.12688/f1000research.169079.1 Copyright © 2025 Olukemi Akapo O and Ogbodu OM. 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 Olukemi Akapo O and Ogbodu OM. A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.12688/f1000research.169079.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 22 Sep 2025 Views 0 Cite How to cite this report: Ali T. Reviewer Report For: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.5256/f1000research.186364.r425567 ) The direct URL for this report is: https://f1000research.com/articles/14-965/v1#referee-response-425567 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 Oct 2025 Taufeeque Ali , Urology, Northwestern University - Chicago, Chicago, Illinois, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.186364.r425567 This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the ... Continue reading READ ALL This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project. 1. Is the rationale for, and objectives of the study clearly described? Answer: Partly Explanation: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, the objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. 2. Is the study design appropriate for the research question? Answer: Partly Explanation: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output. 3. Are sufficient details of the methods provided to allow replication by others? Answer: Partly Explanation: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). 4. Are the datasets clearly presented in a useable and accessible format? Answer: Not Applicable Explanation: As this is a study protocol, no datasets have been generated or analyzed. The authors' plan to deposit all data in a public repository (Figshare) upon completion is appropriate for future transparency. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Drug Discovery, Epigenetics, Oncological Therapeutics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Ali T. Reviewer Report For: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.5256/f1000research.186364.r425567 ) The direct URL for this report is: https://f1000research.com/articles/14-965/v1#referee-response-425567 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 22 Dec 2025 Olufunmilayo Akapo , Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, 5100, South Africa 22 Dec 2025 Author Response 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer ... Continue reading 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 22 Dec 2025 Olufunmilayo Akapo , Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, 5100, South Africa 22 Dec 2025 Author Response 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer ... Continue reading 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Chen Q. Reviewer Report For: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.5256/f1000research.186364.r419301 ) The direct URL for this report is: https://f1000research.com/articles/14-965/v1#referee-response-419301 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 15 Oct 2025 Qi Chen , University of Kansas School of Medicine, Kansas City, Kansas, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.186364.r419301 This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information ... Continue reading READ ALL This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations and this information is needed. A review article filling this information gap would be very welcomed. However, there are some major comments in the methodology and in this proposal article: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. The authors themselves noted this in the Introduction. For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes References 1. Chen Q, Espey M, Krishna M, Mitchell J, et al.: Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proceedings of the National Academy of Sciences . 2005; 102 (38): 13604-13609 Publisher Full Text 2. Chen Q, Espey M, Sun A, Lee J, et al.: Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluidin vivo. Proceedings of the National Academy of Sciences . 2007; 104 (21): 8749-8754 Publisher Full Text 3. Chen Q, Espey M, Sun A, Pooput C, et al.: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proceedings of the National Academy of Sciences . 2008; 105 (32): 11105-11109 Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Vitamin C and Cancer, translational research, EMT, cancer stem cells I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Chen Q. Reviewer Report For: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.5256/f1000research.186364.r419301 ) The direct URL for this report is: https://f1000research.com/articles/14-965/v1#referee-response-419301 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 22 Dec 2025 Olufunmilayo Akapo , Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, 5100, South Africa 22 Dec 2025 Author Response 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer ... Continue reading 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 22 Dec 2025 Olufunmilayo Akapo , Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, 5100, South Africa 22 Dec 2025 Author Response 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer ... Continue reading 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 22 Sep 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 22 Dec 25 read Version 1 22 Sep 25 read read Qi Chen , University of Kansas School of Medicine, Kansas City, USA Taufeeque Ali , Northwestern University - Chicago, Chicago, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Chen Q. This is an open access peer review report 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. 09 Jan 2026 | for Version 2 Qi Chen , University of Kansas School of Medicine, Kansas City, Kansas, USA 0 Views copyright © 2026 Chen Q. This is an open access peer review report 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. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Previous comments are addressed. I have not more comments. It is a critical improvement to include studies conducted globally with implementable settings for Africa. Competing Interests No competing interests were disclosed. Reviewer Expertise Vitamin C and Cancer, translational research, EMT, cancer stem cells I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Chen Q. Peer Review Report For: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.5256/f1000research.191107.r443808) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-965/v2#referee-response-443808 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Ali T. This is an open access peer review report 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. 29 Oct 2025 | for Version 1 Taufeeque Ali , Urology, Northwestern University - Chicago, Chicago, Illinois, USA 0 Views copyright © 2025 Ali T. This is an open access peer review report 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. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project. 1. Is the rationale for, and objectives of the study clearly described? Answer: Partly Explanation: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, the objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. 2. Is the study design appropriate for the research question? Answer: Partly Explanation: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output. 3. Are sufficient details of the methods provided to allow replication by others? Answer: Partly Explanation: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). 4. Are the datasets clearly presented in a useable and accessible format? Answer: Not Applicable Explanation: As this is a study protocol, no datasets have been generated or analyzed. The authors' plan to deposit all data in a public repository (Figshare) upon completion is appropriate for future transparency. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Drug Discovery, Epigenetics, Oncological Therapeutics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 22 Dec 2025 Olufunmilayo Akapo, Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, 5100, South Africa 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Ali T. Peer Review Report For: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.5256/f1000research.186364.r425567) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-965/v1#referee-response-425567 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Chen Q. This is an open access peer review report 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. 15 Oct 2025 | for Version 1 Qi Chen , University of Kansas School of Medicine, Kansas City, Kansas, USA 0 Views copyright © 2025 Chen Q. This is an open access peer review report 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. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations and this information is needed. A review article filling this information gap would be very welcomed. However, there are some major comments in the methodology and in this proposal article: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. The authors themselves noted this in the Introduction. For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes References 1. Chen Q, Espey M, Krishna M, Mitchell J, et al.: Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proceedings of the National Academy of Sciences . 2005; 102 (38): 13604-13609 Publisher Full Text 2. Chen Q, Espey M, Sun A, Lee J, et al.: Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluidin vivo. Proceedings of the National Academy of Sciences . 2007; 104 (21): 8749-8754 Publisher Full Text 3. Chen Q, Espey M, Sun A, Pooput C, et al.: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proceedings of the National Academy of Sciences . 2008; 105 (32): 11105-11109 Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Vitamin C and Cancer, translational research, EMT, cancer stem cells I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 22 Dec 2025 Olufunmilayo Akapo, Laboratory of Medicine and Pathology, Walter Sisulu University Faculty of Health Sciences, Mthatha, 5100, South Africa 1. Reviewer 1 Comments: This article proposing a method for conducting a scoping review on high-dose intravenous vitamin C in cancer treatment in African populations. DHIVC is recently in cancer clinical trials based on newly established scientific rationale as a pro-oxidant. The information is limited specifically in African populations, and this information is needed. A review article filling this information gap would be very welcomed. Author Response: We thank the reviewer for the feedback. 2. Reviewer Comment: As the title suggested (Introduction also), advanced solid tumor is the concern, but in the Exclusive Criteria, “Studies on advanced-stage disease” are excluded? Author Response: We thank the reviewer for this valuable observation and agree that the phrasing within the exclusion criteria may have created confusion. We would like to clarify that the intention was not to exclude studies involving patients with advanced solid tumors, which are indeed the primary focus of this review. Rather, the exclusion was meant to filter out studies that did not clearly define or specify the tumor as a solid malignancy or where "advanced-stage" was used to describe disseminated hematologic malignancies or in vitro models simulating advanced disease, which fall outside the scope of our review 3. Reviewer Comment: The Abstract mentioned “antioxidative” as HDIVC’s anti-cancer effects, but HDIVC’s anti-cancer and cytotoxic effects are based on its pro-oxidative actions. Author Response: We appreciate the reviewer’s insightful correction regarding the mechanism of action of high-dose intravenous vitamin C (HDIVC). Indeed, the primary anticancer effect of HDIVC at pharmacologic concentrations is mediated through its pro-oxidative activity rather than antioxidative mechanisms. At high doses, ascorbate acts as a pro-drug for hydrogen peroxide generation in the extracellular space, selectively inducing oxidative stress and cytotoxicity in cancer cells while sparing normal tissues. We have now revise the abstract to more accurately reflect this mechanism. The updated sentence will reads: High-dose intravenous vitamin C (HDIVC) has gained interest as an adjunctive therapy in cancer care due to its potential pro-oxidative and cytotoxic effects(Chen et al 2005. We note that pharmacologic intravenous ascorbate acts via pro‑oxidative mechanisms, rather than classic antioxidative ones. For instance, Chen et al. (2005) demonstrated that high‑dose ascorbate functions as a pro‑drug for hydrogen peroxide generation in tissues, selectively killing cancer Subsequent work by the Levine & Chen group confirmed in vivo production of H₂O₂ in tumour interstitial fluid at pharmacologic doses (Roy et al 2025). 4.Reviewer 1 Comment: For the pro-oxidant anti-cancer effects of high dose intravenous vitamin C, please use references of original studies by Levine/Chen group (e.g. PNAS 2005, 2007 and 2008). Author Response: We agree that the seminal studies by the Levine/Chen group form the foundational scientific basis for understanding the pro‑oxidant anticancer mechanism of high‑dose intravenous vitamin C (HDIVC). These pivotal studies demonstrated that pharmacologic concentrations of ascorbate act as a pro‑drug to generate extracellular hydrogen peroxide, leading to selective cytotoxicity in cancer cells. We now incorporated the three original PNAS references into the Introduction to appropriately acknowledge this mechanistic evidence (Chen 2005, Chen 2007, Chen 2008). 5.Reviewer 1 Comment: Table 2, search strings: “African adult population” is used for PubMed and Google Scholar. Especially for Google Scholar, the string indicates “AND African adult population”, which will likely result in exclusion of studies in non-adult populations. If the review is focused on African adult population, it should be made clear. Majority of studies have been in adult cancers, but will pediatric cancer studies be included if there is any? PubMed search uses “African males”, but “African females” is not used. What is the rationale? Also, these terms are used for some of the databases, but not others. Why? Would this potentially cause imbalance in studies to be included? Author Response: A.We appreciate the reviewer for this careful scrutiny of the search string construction, which is crucial for ensuring both the transparency and inclusivity of the review. The scope of this review is specifically limited to African adult populations, as pediatric cancers often differ in biology, treatment response, and supportive care requirements. We will explicitly state this in both the Abstract and Methods sections to avoid ambiguity. Consequently, studies focused solely on pediatric populations will not be included. B. We acknowledge the concern regarding the exclusive use of "African adult population" and "African males" in the initial search strings. These terms were derived from preliminary database search to identify relevant literature, but we agree that omitting “African females” may inadvertently bias the retrieved studies. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population search terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. We have revised the PubMed and other database search strings to include both “African males” and “African females” to ensure gender inclusivity. We have standardized the population terms across all databases to use: "African adults" OR "African males" OR "African females" to harmonize the search strategy and reduce selection bias. Supplementary table 1 6.Reviewer 1 Comment: Stage 3, the exclusion criteria: why are studies on advanced-stage disease excluded? Author Response: We thank the reviewer for highlighting this critical point. The concern arises from an unintended ambiguity in the phrasing of our exclusion criteria. This concern has been addressed in the revised manuscript Reviewer 2 Comments 1.This is a well-structured and clearly written protocol for a scoping review that addresses a significant and under-researched topic. The focus on the African population is a major strength, as it seeks to fill a critical gap in the global literature on High-Dose Intravenous Vitamin C (HDIVC). The methodology is largely sound, following established frameworks (Arksey & O'Malley, JBI, PRISMA-ScR), which will ensure rigor and reproducibility. However, there are several critical contradictions and methodological oversights that must be addressed before the review is conducted, as they currently threaten the validity and feasibility of the entire project Author Response: We are grateful to the reviewer for the thoughtful and constructive feedback, as well as for recognizing the importance of our topic focusing on African populations as a strength, given the current underrepresentation in the literature. Revisions have been made throughout the manuscript to ensure internal consistency between research objectives, eligibility criteria, and methodological steps, thereby enhancing clarity and reducing risk of selection bias or misinterpretation during study screening. 2. Reviewer 2 Comment: The rationale is strong, clearly establishing the biological plausibility of HDIVC and the evidence gap in African populations. However, objectives are undermined by a critical contradiction: the stated focus on "advanced solid tumors" is directly negated by an exclusion criterion that rejects "studies on advanced-stage disease." Correcting this to exclude "early-stage disease" is essential for the study's validity. Author Response: We appreciate the reviewer’s positive assessment of the rationale and the recognition of the critical gap this review aims to address within African oncology research. We also thank the reviewer for pointing out the contradictory language in our exclusion criteria. The original exclusion of "studies on advanced-stage disease" was meant to apply to studies either misclassifying labeling disease stage without focusing on solid tumors, or describing advanced hematologic malignancies or non-clinical models, which fall outside the scope of this review. In response, we have revised the exclusion criteria in the revised manuscript 3.Reviewer 2 Comment: A scoping review is well-suited to map evidence. However, the strict limitation to studies conducted in Africa is a major flaw, as it will likely find no data. To be fit for purpose, the design should be expanded to also include key global studies that discuss implications or applicability for African settings, ensuring a meaningful output Author Response: We thank the reviewer for this insightful and constructive comment. We fully acknowledge the concern regarding the potential scarcity of HDIVC studies conducted exclusively within African populations. While our original intent was to foreground African data due to the pressing need for regionally relevant evidence, we recognize that an overly narrow geographic restriction may limit the comprehensiveness and practical value of the review. The study design of the selected studies in the manuscript has been expanded to include key global studies with implications or applicability for African settings, ensuring a meaningful output 4.Reviewer 2 Comment: The protocol provides a solid foundation with stated frameworks and tools. Key replicable details are missing, including: 1) a finalized, peer-reviewed search strategy for all databases, 2) the piloted data extraction form, and 3) specific methodology for the stakeholder consultation (e.g., number, type, and recruitment process). Author Response: We sincerely thank the reviewer for acknowledging the robustness of our protocol’s foundation and for pointing out these essential areas where further methodological transparency is needed. This strategy has been refined with the input of an academic librarian and subjected to internal peer review for completeness and replicability. The data extraction form will now be revised and piloted on a subset of five studies to ensure clarity, consistency, and comprehensiveness. It captures essential information such as study characteristics, tumor type, HDIVC dosing and administration, outcomes (efficacy, safety, quality of life), and relevance to African healthcare settings. Supplementary table 1 Stakeholder Consultation Methodology: Stakeholders will be recruited via purposive sampling using professional networks, institutional affiliations, and outreach through regional oncology societies. Consultation will be conducted via virtual focus group discussions and structured questionnaires to validate findings, identify contextual gaps, and refine dissemination strategies. This process is described in greater detail in the revised “Stage 6: Consultation” section of the methodology. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Chen Q. Peer Review Report For: A Scoping Review Protocol of the Efficacy and Safety of High-Dose Intravenous Vitamin C in the Treatment of Advanced Solid Tumors in African populations [version 1; peer review: 2 approved with reservations] . F1000Research 2025, 14 :965 ( https://doi.org/10.5256/f1000research.186364.r419301) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-965/v1#referee-response-419301 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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