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Intravesical device-assisted therapies for non-muscle-invasive bladder cancer

Nature Reviews Urology volume 15, pages 667–685 (2018)Cite this article

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Abstract

Non-muscle-invasive bladder cancer (NMIBC), the most prevalent type of bladder cancer, accounts for ~75% of bladder cancer diagnoses. This disease has a 50% risk of recurrence and 20% risk of progression within 5 years, despite the use of intravesical adjuvant treatments (such as BCG or mitomycin C) that are recommended by clinical guidelines. Intravesical device-assisted therapies, such as radiofrequency-induced thermochemotherapeutic effect (RITE), conductive hyperthermic chemotherapy, and electromotive drug administration (EMDA), have shown promising efficacy. These device-assisted treatments are an attractive alternative to BCG, as issues with supply have been a problem in some countries. RITE might be an effective treatment option for some patients who have experienced BCG failure and are not candidates for radical cystectomy. Data from trials using EMDA suggest that it is effective in high-risk disease but requires further validation, and results of randomized trials are eagerly awaited for conductive hyperthermic chemotherapy. Considerable heterogeneity in patient cohorts, treatment sessions, use of maintenance regimens, and single-arm study design makes it difficult to draw solid conclusions, although randomized controlled trials have been reported for RITE and EMDA.

Key points

  • Intravesical chemotherapy and BCG are the recommended adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC) to reduce the risk of disease recurrence.

  • The combination of BCG supply shortage and alternative bladder-sparing approaches in patients with BCG-refractory disease has led to the development of hyperthermia-inducing device-assisted therapies for NMIBC.

  • Radiofrequency-induced thermochemotherapeutic effect (RITE), hyperthermic conductive chemotherapy, and electromotive drug administration (EMDA) chemotherapy are the most widely used devices to augment intravesical chemotherapy.

  • Randomized controlled trials suggest that RITE and alternating BCG and EMDA mitomycin C are more efficacious than BCG alone. Data on patients with concurrent carcinoma in situ treated with RITE are currently inconclusive.

  • Adverse events from RITE, hyperthermic conductive chemotherapy, and EMDA chemotherapy are short-lived and better tolerated than BCG.

  • Other novel therapies that improve the delivery of chemotherapy by prolonging chemotherapy exposure time or targeted local therapy are promising.

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Fig. 1: The mechanism of action of how hyperthermia potentiates chemotherapy.
Fig. 2: Schematic diagram of the Synergo system.

Figure adapted with permission from Gad Lev, Medical Enterprises Europe B.V.

Fig. 3: Schematic diagram of the Combat BRS.

Figure adapted with permission from Sarah Bruce-White, Combat Medical Ltd.

Fig. 4: Schematic diagram of the electromotive drug administration system.

Figure adapted with permission from Paolo Eruzzi, Physion srl.

Fig. 5: GemRIS intravesical gemcitabine depot delivery system.

Figure adapted with permission from Chris Searcy, Taris Biomedical LLC.

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Acknowledgements

The authors thank The Urology Foundation (W.S.T.), Mason Medical Research Foundation (W.S.T.), Medical Research Council (J.D.K.), and University College London Hospitals (UCLH) Biomedical Research Centre (J.D.K.) for funding our work.

Review criteria

A comprehensive literature review was performed using Medline Pubmed and Google Scholar. The following MESH words were used: “non-muscle invasive bladder cancer”, “hyperthermia”, “chemohyperthermia”, “hyperthermia”, “radiofrequency induced thermotherapy”, “RITE”, “EMDA”, “electromotive drug administration”, “mitomycin”, “MMC”, “intravesical chemotherapy”, “device assisted”, and “novel agents”. Original research, review articles, editorials, commentaries and letters to the editor that were in English were used for this review. The reference list of articles was screened to identify additional articles.

Reviewer information

Nature Reviews Urology thanks S. Di Stasi, L. Griffiths and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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  1. Division of Surgery and Interventional Science, University College London, London, UK

    Wei Shen Tan & John D. Kelly

  2. Department of Urology, University College London Hospital, London, UK

    Wei Shen Tan & John D. Kelly

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W.S.T. researched data for and wrote the manuscript. J.D.K. contributed substantially to the writing, reviewing, and editing of the manuscript before submission.

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Correspondence to Wei Shen Tan.

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J.D.K. is chief investigator for HYMN and HIVEC-II, which are trials using hyperthermia delivery systems to treat bladder cancer, and is a consultant for Combat Medical. W.S.T. declares no competing interests.

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Tan, W.S., Kelly, J.D. Intravesical device-assisted therapies for non-muscle-invasive bladder cancer. Nat Rev Urol 15, 667–685 (2018). https://doi.org/10.1038/s41585-018-0092-z

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