The use of hyperthermia in the treatment of bladder cancer

We are delighted to edit this special issue of the International Journal of Hyperthermia dedicated to the use of heat in the treatment of bladder cancer. A growing amount of important work is being done on this topic and the time is ripe to synthesise what is currently known. The authors featured in this issue are pioneers in the use of hyperthermia to treat bladder cancer and hail from a wide variety of geographical locations. An assortment of disciplines is represented, from physicians and surgeons to physicists, engineers and biologists. The cast is therefore varied and the collective experience deep. Some of the contributions in this issue are more clinical in nature, and predominantly targeted to physicians treating patients with bladder cancer. Other contributions are more fundamental in character and will appeal to the scientist at large.

Bladder cancer has two major distinct clinical phenotypes, non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), and each is characterised by a different prognosis, treatment paradigm, and set of outcomes. While hyperthermia can be used successfully to treat both of these phenotypes, it is used in each case with slightly different goals. In NMIBC, which accounts for approximately 75% of bladder cancer, the main clinical problem is recurrence of tumours within the bladder after standard transurethral surgery has been performed to remove them. This is akin to weeds coming back in your garden after a long weekend spent pulling them out; it is frustrating and demoralising, though generally it will not kill you. In NMIBC, hyperthermia has two principal goals: 1) to make intravesical therapy (your weed killer) work better, and 2) to make the local bladder immune system (your soil) more resistant to new tumour (weed) formation. As we will see in the following papers, hyperthermia is effective at accomplishing these goals.

In MIBC, the main clinical problem is the spread of tumour cells to distant sites beyond the bladder. Metastasis of bladder cancer is devastating, and usually, despite a plethora of toxic and morbid treatments, results in death. Therefore, the goal of hyperthermia in MIBC is to help prevent the distant spread of cancer by making local (radiation) and systemic (chemotherapy) treatment more effective. Additionally, hyperthermia may synergise with modern immunotherapies given for metastatic disease states, such as immune checkpoint modulators, though this remains to be proven in humans.

With this landscape of disease in mind, we have solicited experts to summarise their personal experiences as well as the collective literature with respect to hyperthermia and bladder cancer. Liem et al. [1] have provided a general overview of the literature regarding hyperthermia and NMIBC, and have generated some general treatment recommendations useful for readers.

van Valenberg et al. [2] present the experience with intravesical catheter-delivered and radiofrequency-induced hyperthermia, exemplified by the Synergo^® SB-TS 101 device. Of all the methods used to heat the bladder for NMIBC, this device has the largest patient experience, and the authors describe in excellent detail current treatment protocols, clinical indications, and results. Additionally, the authors highlight important clinical trials that are currently ongoing that will address some key unknowns.

Recirculating convection hyperthermia is discussed by Sousa-Escandon et al. [3] where heat is delivered by the Combat BRS^® device, the latest bladder heating system to have entered the market. The authors describe their experience with the device, their current treatment protocol, and toxicity outcomes. Interestingly, they present results of treatment prior to standard transurethral resection and raise the possibility that combination bladder hyperthermia and intravesical chemotherapy may be sufficient to eradicate tumours in many patients. This has the potential to be a paradigm shifting treatment strategy if these results are confirmed.

Longo et al. [4] discuss deep regional hyperthermia as achieved by external radiofrequency emitters. In their manuscript they review over 30 years of data generated on a multitude of heating platforms including the BSD/Pyrexar^® devices, the AMC device, and the Thermotron^® device. Clinical results, target temperatures, and toxicity are presented. These devices are not exclusively used for NMIBC, and Longo et al. present the results for these devices when used to treat MIBC as well.

The use of hyperthermia in combination with bladder radiotherapy, predominantly for MIBC, is considered by Datta et al. [5] and Snider et al. [6] albeit with slightly different focuses. Snider et al. summarise the evidence with respect to the combination of hyperthermia and radiotherapy, both with and without radiosensitising chemotherapy. Datta et al. describe a similar experience but focused on an elderly and highly co-morbid patient population. They demonstrate that the technique is safe and appears effective. Both papers raise the question as to whether hyperthermia should more commonly be combined with bladder-sparing chemoradiation.

Appropriate heating techniques and reliable dose control are crucial for the successful application of hyperthermia. Two papers focus on the technical aspects of bladder hyperthermia, the heating techniques and temperature monitoring. Stauffer and van Rhoon [7] give an overview of the devices currently used for the application of hyperthermia in bladder cancer. The advantages and disadvantages of each technique are discussed and summarised in clear tables. MIBC and NMIBC pose different requirements on heating technology. This paper guides clinicians in selecting the appropriate technique for the tumour stage under treatment.

Schooneveldt et al. [8] discuss the methods used to control the temperature distribution in the target region. Traditionally thermometry is performed during treatment with a limited number of minimally invasive thermometry probes inserted in the bladder. Alternative methods including non-invasive thermometry and temperature reconstruction by treatment planning are discussed. The authors conclude that invasive thermometry is more accurate but gives limited information about the spatial temperature distribution. They therefore suggest that a combination of invasive and non-invasive thermometry and simulation techniques gives the most accurate results.

Effectively exploiting the cytotoxic effects of hyperthermia requires a thorough knowledge of the underlying mechanisms. The relevant biological mechanisms of hyperthermia in combination with chemotherapy and radiotherapy are discussed in three papers. Van der Heijden and Dewhirst [9] give a review of the effects of hyperthermia on uptake and cytotoxicity of chemotherapy, focusing on the most used agents used in combination with hyperthermia in bladder cancer treatment: cisplatin, mitomycin C (MMC), gemcitabine, doxorubicin and epirubicin. Hyperthermia increases both drug uptake and cytotoxicity, in particular for cisplatin and MMC. However, the conclusion is that the mechanisms responsible for the success of this combination therapy are only partially understood. The authors also suggest investigating whether hyperthermia enhances the effectiveness of intravesical bacillus Calmette–Guérin in the treatment of bladder cancer.

Van den Tempel et al. [10] give an overview of the latest insights in the biological effects of hyperthermia and how these can be exploited in oncology. The physiological changes incurred by hyperthermia have an impact on tumour oxygenation and the tumour micro-environment. Hyperthermia also activates a heat shock response, which is relevant for both treatment scheduling and for cancer immunology. The immune response to hyperthermia is discussed, as well as the chemo- and radiosensitising effects of hyperthermia on drug uptake and DNA repair. The future perspectives section provides a rationale for combining hyperthermia with proton therapy.

Lastly, Multhoff et al. [11] present the biological and clinical rationale for using hyperthermia in the treatment of bladder cancer. Then special attention is given to the impact of hyperthermia on adaptive and innate immunity. Detection of hyperthermia-induced Hsp70 is proposed as an innovative method suitable for both biological tumour detection and monitoring of treatment outcome.