Combat Medical leading the current investigation in thermotherapy device assisted therapies for NMIBC.

Combat Medical is committed over the next 5 years to creating its own clinical bibliography of fact based evidence supporting the BRS system in it’s fight against bladder cancer. By harnessing the powers of chemo-hyperthermia in an innovative and unique way we hope to prove beyond doubt that the BRS system in combination with Mitomycin C (40mg) can significantly reduce recurrence and progression rates in NMIBC bladder cancer.

Combat Medical is equally committed to improving outcomes without healthcare providers having to significantly alter their treatment model or adding additional resources, in fact we believe over time we will be able to reduce the overall treatment cost due to our streamlined approach and through the reduction in recurrence and progression rates.

We have demonstrated this potential in phase I trials and through its clinical use over the last 5 years. During this time Combat BRS has shown it is easy to use and is well tolerated by the patient with similar side effects to standard MMC instillations, but importantly with little impact in terms of time and effort for the healthcare professional in delivering Combat’s new HIVEC™ treatment.

Hyperthermia substantially increases the effectiveness of chemotherapy compared to instillation at room temperature2.

Combined effects of hyperthermia

Clinical hyperthermia is defined as the therapeutic use of temperature between 41°C to 44°C5. The introduction of thermal energy at these temperatures into cancer tumours affects the cancer cells more because of their inability to manage the heat as well as good cells6. Mitomycin C (MMC) an alkylating chemotherapy agent is stable at temperatures up to 50°C, but importantly it has shown to be 1.4 times more active at 43°C8. Hyperthermia inhibits the formation of new blood vessels (angiogenesis) by the tumour mass)9. At 43°C the cytotoxicity increases by 10 times, importantly without any increase in the toxicity to the patient8. At elevated temperatures the lipid-protein cellular membrane bilayer will become more permeable, due to the unfolding (denaturing) of the cellular membrane and cytosolic proteins, resulting in higher intracellular concentration of the chemotherapy agent. Direct effects on the DNA include; strand breaking, impaired transcription (production of messenger RNA for protein synthesis), reducing replication and cell division5. Thermotherapy has profound effects on the immune system resulting in increased activation of more natural killer cells (NKC) that target heat stressed cancer cells

as they signal heat shock proteins on the cancer cell surface à. The consequence of all these actions on the cancer cells is that they actively participate in their own demise through the natural process of apoptosis.

Chemo-hyperthermia multifactorial modes of action create a strong combination effect, ensuring cancer tumours and cells are specifically targeted. Therefore hyperthermia substantially increases the effectiveness of chemotherapy compared to instillation at room temperature2. The Combat BRS has the potential to be the first system to allow the delivery of thermotherapy within the tight parameters necessary to optimise the delivery of chemo-hyperthermia without compromising patient safety or increasing resources required.

Based on the strong body of evidence cited above to achieve the best results with the Combat BRS system in adjuvant treatment it should be used at a temperature setting of 43°C for 1 hour using 40 mg dose of Mitomycin C.

Bibliography – to see all bibliography references numbered throughout the website please click here.

Effect of hyperthermia on alkylating agents
Teicher et al (1981) demonstrated activation rates
1.3 – 1.4 times higher at 41°C, 42°C, and 43°C compared to 37°C8.

Mitomycin C remains stable at higher temperatures10
Temp. Solvent Parameter Storage Period
0 hr* 1 hr 3 hr 6 hr
37° 5 ml water Content % 100.0 94.9 92.8 91.6
5 ml of saline Content % 100.0 94.2 90.6 90.4
50° 5 ml water Content % 100.0 91.0 88.0 87.3
5 ml of saline Content % 100.0 91.3 90.2 89.7
*0 hr : immediately after reconstitution
Mitomycin C (MMC) plus hyperthermia achieves greater plasma concentration than MMC alone11, but is well below 400ng/ml associated with systemic side effects like myelosuppression12.