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THE EFFECTS & EFFECTIVENESS OF ELECTROMOTIVE DRUG ADMINISTRATION AND
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CHEMO-HYPERTHERMIA FOR TREATING NON-MUSCLE-INVASIVE BLADDER CANCER
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S Slater, P Patel, RP Viney, M Foster, E Porfiri, ND James, B Montgomery, RT Bryan.
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Stephanie Slater
The Medical School, University of Birmingham, Birmingham, UK.
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Prashant Patel
Senior Lecturer in Urology, School of Cancer Sciences, University
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of Birmingham and University Hospitals Birmingham NHS
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Foundation Trust, Birmingham, UK.
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Richard Viney
of Birmingham and University Hospitals Birmingham NHS
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Foundation Trust, Birmingham, UK.
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Michael Foster
Emilio Porfiri
Consultant Oncologist, University Hospitals Birmingham NHS
Foundation Trust, Birmingham, UK.
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Department of Urology, Heart of England NHS Foundation Trust,
Good Hope Hospital, Sutton Coldfield, UK
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Senior Lecturer in Urology, School of Cancer Sciences, University
Nicholas D James
Professor of Oncology, School of Cancer Sciences, University of
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Birmingham and University Hospitals Birmingham NHS
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Foundation Trust, Birmingham, UK.
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Bruce Montgomery Consultant Urologist, Frimley Park Hospital NHS Foundation
Trust, Frimley, UK.
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Richard T Bryan
Senior Research Fellow, School of Cancer Sciences, University of
Birmingham, Birmingham, UK.
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22
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Keywords:
Bladder cancer, urothelial cancer, electromotive drug
administration, chemo-hyperthermia.
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25
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Correspondence to: Mr RT Bryan, School of Cancer Sciences, University of
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Birmingham, Edgbaston, Birmingham B15 2TT, UK.
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r.t.bryan@bham.ac.uk
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07785 396958
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31
Word count:
2050 (manuscript) + 249 (abstract).
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ABSTRACT
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Introduction
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Preliminary studies show that device-assisted intravesical therapies appear more
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effective than passive diffusion intravesical therapy for the treatment of non-muscle-
37
invasive bladder cancer (NMIBC) in specific settings, and phase III studies are now
38
being conducted. Consequently, we have undertaken a non-systematic review with the
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objective of describing the scientific basis and mechanisms of action of electromotive
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drug administration (EMDA) and chemo-hyperthermia (CHT).
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Methods
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A PubMed literature search, search of the ClinicalTrials.gov database and Cochrane
43
library was performed to source evidence for this non-systematic review. Randomised
44
controlled trials, systematic reviews and meta-analyses were evaluated. Publications
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regarding the scientific basis and mechanisms of action of EMDA and CHT were
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identified, as well as clinical studies to date.
47
Findings
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EMDA takes advantage of three phenomena: iontophoresis, electro-osmosis and
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electroporation. EMDA has been found to reduce recurrence rates in NMIBC patients,
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and has been proposed as an addition or alternative to BCG therapy in the treatment
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of high-risk NMIBC. CHT improves the efficacy of MMC by three mechanisms: tumour
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cell cytotoxicity, altered tumour blood flow, and localised immune responses. Fewer
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studies have been conducted with CHT than EMDA, but they have demonstrated utility
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for increasing disease-free survival, especially in patients who have previously failed
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BCG therapy.
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Conclusions
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It is anticipated that EMDA and CHT will play important roles in the management of
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NMIBC in the future. Techniques of delivery need be standardised, and there is a need
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for more RCTs to evaluate the benefits of the treatments alongside quality of life and
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cost-effectiveness.
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INTRODUCTION
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In the Western world, bladder cancer is the fourth most common cancer in men and
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ninth most common in women 1, with a rising global incidence 2, 3. In the UK the
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disease accounts for approximately 10,000 new cases and 5,000 deaths per year 1, 4.
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Over 90% of bladder cancers are transitional cell carcinomas of urothelial origin
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(urothelial carcinomas or UCs), and at presentation over 75-85% will be non-muscle-
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invasive tumours (NMIBC, stages Ta/T1/CIS), with the remainder being muscle-invasive
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(stages T2-4) 4-6.
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50-55% of bladder cancer patients present with Ta tumours, where recurrence is the
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main clinical issue, occurring in up to 80% of cases 4, 6; for the 20-25% of patients
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presenting with T1 tumours, progression is the main clinical concern, occurring in up to
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45% of cases 4, 6. Progression to (or presentation with) muscle-invasive disease (stages
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T2-4) represents a critical step, necessitating more radical and aggressive therapies,
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and carries a 5-year survival rate of only 27-50% 4, 6-8.
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The four mechanisms of NMIBC recurrence are described as incomplete tumour
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resection, tumour cell reimplantation, the growth of microscopic tumours present (but
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undetected) at initial TURBT, and “genuine” new tumour formation 9, 10. As highlighted
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by Brausi 11, optimising all of our existing capabilities to abrogate each of these
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mechanisms could further improve our therapeutic impact on NMIBC, and new
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technologies should be seriously and critically evaluated, not only for efficacy but for
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cost-effectiveness 12. In this regard, device-assisted intravesical chemotherapy
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regimens appear to show improved efficacy versus passive diffusion regimens: studies
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comparing EMDA and CHT to conventional treatment have yielded promising results,
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showing potential to improve intravesical therapy for NMIBC patients 13. In this review
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we outline the scientific basis and mechanisms of action of EMDA and CHT, present a
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brief summary of their clinical utility, and highlight important areas for future studies.
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METHODS
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A PubMed literature search, search of the ClinicalTrials.gov database and Cochrane
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library was performed to source evidence for this non-systematic review. Search terms
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used included; ‘EMDA’, ‘hyperthermia’, bladder cancer’. Randomised controlled trials,
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systematic reviews and meta-analyses were evaluated primarily. 34 papers were
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selected for this review.
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FINDINGS
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EMDA
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EMDA utilises an electric current to enhance transepithelial drug penetration 14. EMDA
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is administered via a battery-powered generator delivering an electric current of 0-30
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mA/0-55 V DC, which is passed between 2 electrodes 15: an Active electrode is placed
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into the bladder as part of a transurethral catheter, and Dispersive ground electrode
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pads are placed on the skin of the lower abdomen.
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EMDA takes advantage of three phenomena: iontophoresis, electro-osmosis and
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electroporation. Iontophoresis involves propelling a substance into tissues by passing
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an electrical current through a solution containing the active charged ingredient 16.
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Electro-osmosis transports non-ionised polar molecules (eg. MMC) against their
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columbic gradients when there is convective flow of water in association with ions 16.
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Electroporation is the increase in electrical conductivity and permeability of cell plasma
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membranes due to the application of an electrical field 16.
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MMC is a polar and non-ionised molecule in the range of pHs which may be present in
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the bladder (4.5-8.5) 17. It is delivered in a solution of Na+/Cl-/MMC, and when a
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current with a positive polarity is applied to this solution the sodium ions move via
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iontophoresis, and MMC molecules are carried with them via electro-osmosis,
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increasing the rate and depth of delivery 17.
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In vitro studies demonstrate that the penetration of MMC into non-cancerous bladder
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wall with EMDA is significantly greater than that achieved by passive diffusion (PD)
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alone 16, 17: measurements made in the urothelium, lamina propria and muscularis
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layers and concentrations are significantly greater for EMDA at all levels than for PD
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(EMDA increases MMC delivery by 4-7 fold) 17. In these studies penetration of the drug
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into the muscularis propria was insufficient to inhibit a significant proportion of the
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proliferating cells in this layer 18, but since cancerous tissue is more permeable to
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water and solute than normal urothelium the drug concentration in bladder tumours
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may be sufficient to achieve inhibition of proliferating cells in the muscularis propria 19.
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In terms of efficacy, the results of published EMDA clinical trials are summarised in
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Table 1. The majority of these studies have evaluated EMDA MMC as first-line
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intravesical therapy following TURBT (adjuvant therapy), and there remains a paucity
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of evidence supporting the use of EMDA MMC following failure of BCG therapy 20. In
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terms of tolerability, to date the use of EMDA MMC in clinical practice has never
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resulted in haematological toxicity, severe allergic reactions, life-threatening adverse
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events or any treatment-related deaths 21.
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Chemo-Hyperthermia
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The effect of hyperthermia on cancer cells has been investigated since the 1950s, and
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the use of CHT to manage bladder cancer has recently been the subject of a systematic
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review 22. The review indicated potential for CHT in becoming a part of standard
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therapy for high-risk NMIBC patients with recurrent tumours whom are unsuitable for
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radical cystectomy or whom have contraindications for BCG therapy 22. The Synergo
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SB-TS 101 system is currently the most commonly used system of CHT delivery 23,
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utilising an RF generator to deliver radio-frequency (heat energy) at 915MHz. The
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Combat BRS system is now also in the marketplace, utilising a heat exchanger instead
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of a radio-frequency system. There is a theoretical independent advantage of radio-
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frequency energy for tumour cell killing, additional to hyperthermia, but a heat
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exchange fluid recirculation system is likely to reduce hot and cold spots and burning
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of the bladder wall 24. However, until the Combat BRS system becomes more widely
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used, direct comparisons cannot be made.
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Hyperthermia affects the tumour cell directly, the vascular supply to the tumour, and
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also triggers an immune response 25:
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1. Hyperthermia induces cell killing (cytotoxicity) above 40.5C: up to 43C there
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is linear growth arrest involving reduced RNA/DNA synthesis, and cell cycle
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arrest; above 43C exponential growth arrest occurs along with impaired DNA
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repair 25.
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2. Increasing temperatures can alter blood flow and so the vascular effects of
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hyperthermia are dependent on the type and size of tumour. Increasing the
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temperature to 43C increases tumour blood flow by vasodilatation, allowing
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more MMC to be delivered; above 43C tumour blood flow is reduced, possibly
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limiting the oxygen supply to the tumour (swelling/lysis of endothelial cells,
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adherence of leukocytes to vessels, increased rigidity of red blood cells,
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increased blood viscosity) 26. Tumour vasculature is less able to dissipate heat,
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and so cancer cells are more likely to be heat damaged than non-cancerous
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cells 26.
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3. Upon heating, the tumour microenvironment becomes increasingly hypoxic
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and acidic, further increasing the sensitivity of cells to both heat and cytotoxic
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therapeutics
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plasminogen activator inhibitor 1 (PAI-1) in endothelial cells 27.
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166
26,
and angiogenesis is inhibited by the upregulation of
4. Hyperthermia mimics the increased body temperature seen in fever 28,
stimulating an immune response constituting multiple changes to enhance
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immune surveillance 29: induction of heat shock proteins can prime CD8+
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cytotoxic T cells and lead to autovaccination against the tumour 25, as well as
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increased natural killer cell infiltration, increased migration and adhesion of
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lymphocytes, increased T cell and antibody numbers, increased concentrations
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of cytokines and acute phase proteins, and a lowering of the activation
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threshold required for many immune system effector molecules. 25, 28
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In vitro studies have shown that hyperthermia also has a synergistic effect on MMC
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administration 30, potentially caused by increased MMC uptake by heated tumour cells,
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increased drug activation, and tumour cells being less able to counteract MMC’s
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cytotoxic effects. 25
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The 2011 systematic review of 22 studies by Lammers et al. indicated a 59% reduction
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in NMIBC recurrence rate when CHT is compared with MMC alone, and an improved
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bladder preservation rate (87.6%) could prove to be a significant benefit of this
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treatment regimen 22. However, definitive conclusions could not be drawn due to the
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limited number of RCTs and heterogeneity in the study designs. Subsequently,
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Moskovitz et al. have published their 10 year experience with CHT in both the adjuvant
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setting (CHT delivered after primary therapy, TURBT) and neoadjuvant settings (CHT
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delivered before primary therapy) 31, demonstrating 72% recurrence-free survival for
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the adjuvant protocol with a progression rate of 4.7%. They achieved an initial
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complete response of 79% for their neoadjuvant protocol, with 84% of these patients
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remaining free from recurrence 31. The use of CHT MMC in the setting of patients
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experiencing recurrence following induction or maintenance BCG is currently being
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assessed in the UK’s HYMN RCT (CHT MMC versus a second course of BCG or standard
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therapy), with recruitment due to be completed within the next 12months.
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The currently available CHT trial data on side effects and adverse events is limited. 22
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However, preliminary results reveal that bladder spasms and pain are the most
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common side effects, reported in around 20% of patients during active treatment,
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along with mild and transient lower urinary tract symptoms post-procedure 22. Two
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studies report a contracted bladder and severe urinary incontinence but the cause of
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these adverse events was not certain. Side effects are slightly more frequent than in
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PD MMC patients but, as suggested by Lammers et al., a structured questionnaire for
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adverse events is recommended in future research for effective evaluation 22.
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DISCUSSION
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The effective treatment of NMIBC encompasses a range of different procedures and
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interventions, and improvements to all of these areas should be considered as we
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strive to improve both outcomes and quality of life for NMIBC patients 32 - optimizing
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our existing intravesical chemotherapy regimens is just one aspect, albeit an important
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aspect. In this review, we see that both EMDA and CHT appear safe and effective in
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reducing recurrence of NMIBC, although more data are needed. Whereas the
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mechanism of EMDA is quite simple (increasing the rate and depth of MMC delivery to
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the urothelium), the effects of hyperthermia are varied and have not as yet been
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thoroughly elucidated.
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EMDA has been more extensively studied in RCTs than CHT, and there is evidence to
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support its utility for the treatment of high-risk NIMBC as an alternative to or in
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addition to BCG, and possibly peri-operatively. Larger, adequately-powered RCTs
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should be carried out to further evaluate the addition of EMDA to current BCG therapy,
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and also studies to evaluate whether the timing of EMDA administration alters efficacy,
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either pre-TURBT (peri-operative or neoadjuvant) or post-TURBT (adjuvant). Radical
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cystectomy should be the default position following failure of intravesical BCG 20,
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although bladder-sparing options may be desirable for the very elderly or patients
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unfit for cystectomy. Although beyond the scope of this review, to date bladder
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sparing options following BCG failure only achieve recurrence-free survival of around
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50% at up to 2 years 20, and evaluation of EMDA in this setting is required.
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With regard to CHT, there are only a small number of completed RCTs and so more
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evidence is required before definitive conclusions can be drawn and before practice
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could change 22, and we eagerly await the results of the HYMN trial. In addition, CHT
224
protocols must be standardised, including variables such as duration and temperature,
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and the equipment/delivery system utilised.
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There remain a number of questions to be answered for both EMDA and CHT, and a
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co-ordinated series of carefully-conducted clinical trials are needed to address these.
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Yet both modalities are interesting and seemingly effective, and are likely to form an
229
important part of our NMIBC armamentarium in the future. Trials to directly compare
230
the clinical effectiveness and cost-effectiveness of EMDA and CHT, as well as effects on
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quality of life, may also be necessary before implementation into routine clinical
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practice. However, it is important to note that there have been no new therapeutic
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agents developed for bladder cancer in over a decade and we should continue our
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search for such agents in parallel to developing new strategies for the administration
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of existing agents 33.
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CONCLUSION
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In conclusion, the potential advantages of EMDA and CHT are important in the
239
management of NMIBC. However, the techniques and timing of delivery must be
240
standardised, and there is a need for more RCTs to evaluate not only the benefits of
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the treatments with regard to disease-specific outcomes, but also quality of life and
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cost-effectiveness. It is anticipated that these therapies will play a significant role in
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the management of NMIBC in the future, but we should not forget the urgent and
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ongoing unmet need for new therapeutic agents to treat patients with bladder cancer.
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Table 1: A summary of comparative EMDA study results to date (CR = complete response, RR = recurrence rate, PR = progression rate, DF =
disease-free, DS = disease-specific, m = months)
Study
Total N
28
Brausi
34
G1/G2 Ta/T1
108
Di Stasi 35
Multifocal
CIS, incl. 98
T1
212
Di Stasi 15
T1
Di Stasi 21
374
Arm 1
Pre-TURBT PD
MMC
Arm 2
Pre-TURBT
EMDA MMC
Post-TURBT PD
MMC
Post-TURBT
EMDA MMC
(‘maintenance’)
(‘maintenance’)
Post-TURBT BCG
Post-TURBT BCG
followed by
EMDA MMC
(induction, then
maintenance for
responders)
TURBT alone
Post-TURBT BCG
(‘maintenance’)
(induction, then
maintenance for
responders)
Post-TURBT PD
MMC
Outcome
Outcome
Outcome
Arm 1
Arm 2
Arm 3
41.6% CR
40% CR
60% RR in
responders
(7.6m)
33% RR in
responders
(6.0m)
DF interval 10.5m
DF interval 14.5m
28% CR (3m)
53% CR (3m)
56% CR (3m)
31% CR (6m)
58% CR (6m)
64% CR (6m)
Median time to
recurrence 19.5m
Median time to
recurrence 35m
Median time to
recurrence 26m
DF interval 21m
DF interval 69m
57.9% RR (88m)
41.9% RR (88m)
21.9% PR (88m)
9.3% PR (88m)
DS mortality
16.2% (88m)
DS mortality 5.6%
(88m)
64% RR (86m)
59% RR (86m)
38% RR (86m)
<0.0001
DF interval 12m
DF interval 16m
DF interval 52m
<0.0001
Arm 3
Pre-TURBT
EMDA MMC
P
0.0012
0.0012
0.004
0.01
351
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