Recirculating chemohyperthermia as a treatment for non-muscle invasive bladder cancer: Current and future perspectives

Table 1 Mechanisms of action of hyperthermia

	39-41	41-43	43-45
Direct Cytotoxic Effects	Slight growth arrest	Reversible growth arrest Mainly in phase M and S Brief RNA synthesis impaired Prolonged DNA synthesis impaired	Irreversible growth arrest Permanent protein denaturalization DNA repair impaired Activation of both ways of apoptosis
Immune effects	Initial increase of intracellular HSP followed by increase of extracellular HSP Signals to immune cells Cross-priming of CD8+ T cells Dendritic cell activation Natural Killer activation Increase cytosine release (IL-6, IL-10)	As above	Altered cytosine production Inactivation of immune cells Reduced expression of extracellular HSP
Vascular effects	Vasodilatation which means: Improved tumor blood flow Improve tissue O2 Reduce acidosis Improve drug absorption	Improved tumor blood flow: Improve tumor oxygenation Improve drug delivery	Reduced tumor blood flow due to vascular collapse Microthrombosis Endothelial cell damage Vessel permeation Increased acidosis and reduce tissue O2

Adapted from Rampersaud et al[11]. IL: Interleukin.

Table 2 Characteristic of devices for intravesical chemohyperthermia treatment

Device	Synergo™	BWT system™	Combat™
Heat Source	Intravesical 915 MHz microwave antenna (Recirculating cooling system)	External heating plates (Recirculating heating system)	External flat, low volume heat exchanger (Recirculating heating system)
Temperature and fluctuation	40 °C-44 °C ± 3 °C	45 °C	43.5 °C ± 1 °C
Priming volume	± 100 mL	± 50 mL	± 30 mL
Catheter characteristics	20 Fr. Rigid (Radiofrequency emitter + cooling system inside)	18 Fr Flexible	16 Fr Flexible
Advantages	Strong supporting evidence (neoadjuvant and adjuvant) Long term follow up Proved superior to BCG Proved effectiveness against CIS	Simple and Cheap	Lower dilution of MMC Proved effectiveness in sequential schedules Proved neoadjuvant effectiveness Medium term follow up Simple and Cheap
Disadvantages	Higher side effects Lower patient tolerance Intravesical Hot and cold spots Expensive device and disposables Continuous machine control required while working	Limited evidence Quick and Turbulent flow + higher temperature (increase hematuria and reduce patient tolerance)	Limited evidence (multicentric studies ongoing)

BCG: Bacillus Calmette-Guérin.