5 So, I must add docetaxel to the drugs used in thermotherapy. Docetaxel in a microtubule inhibitor that hinders cancer cell replication. The drug was rst reported in intravesical therapy in 2006 by McKiernan et al in a phase 1 study. There was no systemic absorption, so the classical side effects of docetaxel did not occur. Protein size greater than 300 Daltons cannot penetrate the bladder wall and docetaxel weighs in at 862 Daltons. Once again, as with the other chemotherapeutic drugs there were local side effects mostly of the grade 1 variety. In terms of handling the drug there again are hazards. It is a ammable liquid and vapourises. It is suspected of causing genetic defects. The drug may damage fertility, or the unborn child and it may cause harm to breastfed babies. Docetaxel will cause eye irritation. It needs to be handled with protective clothing and washing of hands afterwards is essential. When is heat added to the equation, is the safety of each of the drugs mentioned altered? The rst trial of MMC HIVEC was conducted by Colombo et al. in 1995. The complete response rate was 70% and after a mean follow-up of 24 months, 16% recurred. Multiple studies have since followed. No one has been reporting any serious consequences of heating up these drugs in terms of patient safety from the drug itself. In a meta-analysis of twelve trials involving 888 patients published in 2020 by Liu et al, the forest plot for all the recorded adverse events slightly favoured thermal therapy over the control. The drugs looked at in the various studies analysed included mitomycin C, gemcitabine and pirarubicin. Systemic side effects were minimal, and this makes sense. In my previous article covering the basic science of thermal therapy, it has been shown that there is very little systemic absorption of these drugs placed into the bladder during above body thermal conditions. The machinery for heating up the intravesical solutions also need to be considered in the realm of patient safety. My articles have been written for the urologist and not large oncology units, so I am not going to consider the hugely expensive external radio frequency units like the Pyrexar which cost many hundred of thousands of dollars and require a specialist physicist to run them. The Synergo system which falls under the classication of a RITE system (Radiofrequency-induced thermochemotherapy effect) is also expensive and will probably only be affordable in large private or academic units. This device uses a catheter with a radio frequency transmitter built in it to heat the uid bathing the bladder. It was on this device however where most of the original intravesical research was performed using mitomycin C. Devices, like the Combat, that heated the uid outside and circulated it through the bladder continuously came later. These devices fall under the classication of CHT (conductive thermochemical therapy). These machines are a lot more affordable, and the outcomes from these devices are now appearing more often in the literature. Comparison between the radio frequency catheter systems and recirculating heated systems have shown similar clinical results. I discussed their delivery methods and the positives and negatives of each system in the last article. NICE published an article in 2021 on various aspects of the Synergo system including its safety. The report was based on 19 separate studies. The item that was highlighted, was pain that built up over the course of treatment. In most patients however, the pain could be tolerated and managed by the nursing personnel. Implanted metal in the pelvis was associated with pain during the procedure. The posterior bladder wall tended to be burnt by the catheter, but the burn was supercial and would heal without incident or medical therapy. Patients with pacemakers needed to be monitored by a cardiologist during the treatment period. With the Combat and other systems such as Unithermia, the side effects are mostly some enhancements of the effects seen with cool intravesical chemotherapy, most notably with bladder pain, or bladder spasm, haematuria, and dysuria. It has been noticed that men tend to have more pain than women during the treatment, regardless of the device used. There have not been any head-to-head to head comparisons with RITE devices and CHT devices but in a pooled analysis by Zhou et al in 2022 there was a slight bias in favour of CHT over RITE, but no fair direct comparison could be made. In this analysis of 15 studies consisting of 1190 patients, thermal therapy adverse events were slightly worse than normothermia patients. On the forest plots the RITE arms showed a greater difference in adverse events to the normothermia arm compared with a smaller noticeable difference between CHT and normothermia arms. When one looks at the physical devices, they have multiple safety mechanisms built in to monitor overheating, pump failure or over pressurisation etc. So once switched on they do not have to be monitored on a continuous basis for fault monitoring. Lastly, I would like to give some general hints for practitioners wishing to employ HIVEC in their clinical practice. These points would include the following: • Handlers and patients receiving these drugs should not be pregnant or planning to be pregnant. • After the procedure sexual activity should involve the use of a condom for the rst fortyeight hours in male patients and a female UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
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