{ "abstract": "Introduction: Radical cystectomy (RC) is the standard treatment for high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to adequate BCG therapy; however, many patients are ineligible or decline surgery. Current Food and Drug Administration-approved bladder-preserving therapies—including immune checkpoint inhibitors, viral gene therapy, and cytokine-based regimens—are under investigation but show limited efficacy, safety concerns, high costs and are mainly restricted to carcinoma in situ. Both intravesical mitomycin-C (MMC) and gemcitabine (GEM) as monotherapy have proven effective salvage monotherapies for BCG-unresponsive HR NMIBC and their sequential use (MMC/GEM) may offer mechanistic synergy. Prospective evidence supporting the clinical effectiveness and feasibility of sequential MMC/GEM as an effective salvage therapy for BCG-unresponsive HR NMIBC patients remains limited and insufficiently substantiated.\n\nMethods and analysis: We designed the IMGeS study, a prospective, open-label, multicentre, single-arm phase II trial to assess the efficacy and safety of sequential intravesical MMC/GEM in patients with histologically confirmed BCG-unresponsive HR NMIBC per American Urological Association criteria who are unsuitable for or decline RC. Key exclusions include muscle-invasive or metastatic disease, upper tract urothelial carcinoma, prior intravesical MMC or GEM within 2 years (except a single immediate postoperative dose) and other predominant histological subtypes. Eligible, consenting patients undergo a 6-week induction phase of intravesical sequential MMC (40 mg/20 mL) followed by GEM (2000 mg/50 mL), starting 1–4 weeks after transurethral resection of bladder tumour. Each drug is retained in the bladder for 1–2 hours. Patients without recurrence at the 3-month evaluation then receive monthly maintenance therapy for up to 12 months. The primary endpoint is 1-year high-risk recurrence-free survival (HR RFS). Key secondary endpoints include additional time-to-event measures such as progression-free, cystectomy-free, cancer-specific and overall survival, as well as safety, tolerability and patient-reported outcomes. Exploratory endpoints encompass predictive multi-omics biomarker analyses of tumour tissue, urine and blood samples collected during the study. Assuming a historical 1-year RFS rate of 20% with valrubicin and an anticipated 1-year HR RFS rate of 35% for intravesical sequential MMC/GEM, 73 patients are needed to achieve 90% power using a one-sample log-rank test at a two-sided 5% significance level. Accounting for a maximum dropout rate of 10%, a total of 82 patients will be enrolled across eight centres in South Korea.\n\nEthics and dissemination: This study protocol was approved by the National Cancer Center Institutional Review Board (NCC2024-0026) and the ethics committees of all participating centres. Written informed consent will be obtained from all participants or their legal guardians. The findings will be disseminated through publication in peer-reviewed journals and presentation at academic conferences.\n\nTrial registration number: NCT06388720\n\nProtocol version: V.2.1 (14 July 2025).", "abstract_shown": true, "affiliations": [ "Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)", "Department of Urology, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Korea (the Republic of)", "Department of Urology, Pusan National University Hospital, College of Medicine, Pusan National University, Busan, Korea (the Republic of)", "Department of Urology, National Cancer Center, Goyang, Korea (the Republic of)", "Biostatistics Collaboration Team, Research Institute, National Cancer Center, Goyang, Korea (the Republic of)", "Department of Urology, Korea University Hospital, Seoul, Korea (the Republic of)", "Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea (the Republic of)", "Department of Urology, Chonnam National University Medical School, Hwasun, Korea (the Republic of)", "Department of Urology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea (the Republic of)" ], "article_type": "research article", "arxiv": null, "author_total": 13, "authors": [ { "affs": [ 0 ], "name": "Hye Won Lee", "orcid": "0000-0002-0303-4658" }, { "affs": [ 1 ], "name": "Yong Hyun Park", "orcid": "0000-0003-4860-6127" }, { "affs": [ 2 ], "name": "Kyung Hwan Kim" }, { "affs": [ 3 ], "name": "Eui Hyun Jung", "orcid": "0009-0001-6704-0221" }, { "affs": [ 3 ], "name": "Geehyun Song" }, { "affs": [ 3 ], "name": "Hyung Ho Lee" }, { "affs": [ 4 ], "name": "Dong Eun Lee" }, { "affs": [ 5 ], "name": "Seok Ho Kang", "orcid": "0000-0002-1524-5233" }, { "affs": [ 0 ], "name": "Byung Chang Jeong" }, { "affs": [ 6 ], "name": "Won Sik Ham", "orcid": "0000-0003-2246-8838" }, { "affs": [ 7 ], "name": "Seung Il Jung", "orcid": "0000-0003-4864-8175" }, { "affs": [ 8 ], "name": "Jong Jin Oh" }, { "affs": [ 3 ], "name": "Ho Kyung Seo", "orcid": "0000-0003-2601-1093" } ], "bibtex": "https://research.draconitic.com/paper/9t64n11txtm8m.bib", "cited_by": 0, "doi": "10.1136/bmjopen-2026-117239", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13723802/", "id": "9t64n11txtm8m", "issns": [ "2044-6055", "2044-6055" ], "landing_url": "https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2026-117239", "language": "en", "licence": "CC-BY-NC-4.0", "licence_label": "CC BY-NC 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "1506" ], [ "heading", "1717" ], [ "heading", "Oncology" ], [ "heading", "Protocol" ] ], "openalex": null, "pdf_url": null, "pmcid": "PMC13723802", "pmid": "42957299", "published": "2026-10-29", "publisher": "BMJ", "ris": "https://research.draconitic.com/paper/9t64n11txtm8m.ris", "sources": [ { "first_seen": "2026-10-30T12:19:44Z", "native_id": "10.1136/bmjopen-2026-117239", "source": "crossref", "url": "https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2026-117239" }, { "first_seen": "2026-11-04T12:22:22Z", "native_id": "PMC13723802", "source": "pmc", "url": "https://doi.org/10.1136/bmjopen-2026-117239" } ], "subjects": [ { "field": "medicine", "origin": "heading:Oncology", "subfield": "oncology" } ], "title": "Sequential intravesical mitomycin-C and gemcitabine therapy for BCG-unresponsive high-risk non-muscle-invasive bladder cancer: protocol for a prospective, open-label, single-arm, multicentre phase II (IMGeS) study", "title_text": "Sequential intravesical mitomycin-C and gemcitabine therapy for BCG-unresponsive high-risk non-muscle-invasive bladder cancer: protocol for a prospective, open-label, single-arm, multicentre phase II (IMGeS) study", "type": "peer-reviewed", "updated_at": "2026-11-05T12:20:33Z", "url": "https://research.draconitic.com/paper/9t64n11txtm8m", "venue": "BMJ Open", "versions": [] }