Collaborative Review – Bladder CancerThe Role of a Combined Regimen With Intravesical Chemotherapy and Hyperthermia in the Management of Non-muscle-invasive Bladder Cancer: A Systematic Review
Introduction
Management of non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor generally consists of surveillance and intravesical therapy. Unfortunately, current intravesical therapies are associated with undesirable toxicities and suboptimal efficacy. Particularly challenging is the treatment of patients who have not responded to first-line intravesical bacillus Calmette-Guérin (BCG) or that have high-risk features [1]. For such patients, radical cystectomy remains a commonly recommended treatment alternative [1], [2].
One of the developing treatments for high-risk NMIBC is the combination of intravesical chemotherapy and hyperthermia (HT), called chemohyperthermia (C-HT). The most common form of C-HT uses the Synergo HT system, in which local HT is administered via direct microwave irradiation of the urothelium by means of a 915-MHz intravesical microwave applicator. The target intravesical temperature is set between 41 °C and 44 °C and is measured by five thermocouples integrated in a 20-F treatment catheter. To avoid injury, the urethra is continuously cooled (Fig. 1) [3]. Due to extensive global experience with its use and a significant amount of preclinical data demonstrating improved antineoplastic efficacy when heated, mitomycin C (MMC) is the most common intravesical chemotherapy agent used in conjunction with HT.
There are several potential reasons for improved MMC efficacy when combined with heat. One explanation is that heat increases the penetration of MMC into the urothelium due to increased cellular membrane permeability and/or modified blood perfusion. HT is also directly cytotoxic and is known to alter intracellular metabolism, to damage DNA, to impair cellular proliferation, and to increase tumor cell apoptosis [4], [5]. Lastly, HT has been shown to increase the cytotoxicity of MMC, making the drug itself more effective [4], [5].
This collaborative review provides a critical overview of current literature concerning the role of HT for the treatment of NMIBC.
Section snippets
Evidence acquisition
Although the term thermochemotherapy has been used to describe the combination of HT and intravesical chemotherapy, in this review we preferentially use the terms HT and C-HT to describe supraphysiologic HT given in the 40–45 °C range. Unless otherwise stated, C-HT in this manuscript refers to the combination of HT and MMC.
A search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken in January 2011. Candidate manuscripts were limited to the
Search results
The search strategy generated 68 hits, of which 38 were excluded because the abstract or the manuscript did not meet inclusion criteria [3], [5], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. Of the remaining 30 eligible publications, full review determined that 11 were reviews. Another four articles were excluded because they were about preclinical work. Consequently, 15 original
Conclusions
Our systematic review indicates that C-HT reduces the risk of NMIBC recurrence by 59% when compared with MMC alone. Overall bladder preservation after C-HT is 87.6%. However, due to a limited number of randomized trials and different study designs, definitive conclusions cannot be drawn with respect to time to recurrence and time to progression. AEs are more common after C-HT than with MMC alone, but this difference is not statistically significant. In the future, C-HT may become standard
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