What is RITE (Radiofrequency-Induced Thermo-chemotherapy Effect) for bladder cancer?

Hyperthermia is being used in many medical fields.

Synergo® uses a unique combination of local microwave energy hyperthermia (heating) with simultaneous instillation of cooled chemotherapeutic drug. The target of hyperthermia is to reach effective temperature inside the tissue to enable higher drug penetration and accelerate drug-DNA reactions.

Tissue heating should be adjusted per patient and dynamically maintained during treatment while the tissue temperature is constantly measured and closely followed.

Conduction is governed by the Boltzmann equation: Heat conduction is proportional to a constant K which cannot be changed: (for example: Kfat=0.2, Kmuscle=0.38, Ksilver=420)

Since the bladder wall acts as a good thermal insulator, heat penetration from heated liquid is not efficient (conduction/convection heating). On the other hand, during microwave heating the energy is absorbed directly deep in the tissue to enable efficient homogeneous heating, real-time measurement and follow-up on the tissue temperature and dynamic adjustment of the transmitted energy for each per patient over time (e.g. when blood flow in tissue is increased due to heating).

Warm liquid does not allow any simple adjustments in order to tailor heating per patient over time (e.g. different patients have different blood circulation, different tissues, dynamic changes that occur over time such as vasodilation etc.)

Moving from hot liquid to microwave radiation in the Synergo® systems was based on previous experience, as well as on articles already published by other researchers.

Richmond A. Owusu et. al describes the effect and mechanism of hyperthermia together with intravescical chemotherapy in his recently published paper (Owusu et al. 2013)."HT has cytotoxic effects on tumour cells via several mechanisms including improved anti-tumour immunity and by direct cytotoxic effects. Heat plays a role in causing cytotoxicity to tumours (additive effect), enhancing drug toxicity to tumours (synergistic effect), and thermosensitization by noncytotoxic drugs....”

Studies, showing the effect of the Synergo® RITE were performed in the 90's by Paroni et.al. (Paroni et al. 1997; Paroni et al. 2001). The findings indicated the clinical effectiveness benefits of RF hyperthermia associated with chemotherapy. The marked effect on bladder wall permeability resulted in enhanced MMC penetration through the urothelium and the tissue layers. It also showed that the dose administered in the Synergo treatment with hyperthermia, consisting of two 30-minute dwell periods of 20 mg MMC each, actually represented a total dose of not less than 40 mg for the 60 minutes treatment. The same study also showed that the MMC solution is not affected by the RITE method.

The re-fueling of the bladder with a fresh instillation of 20 mg MMC solution (following 30 minutes of treatment) after the bladder is drained of residual urine – eliminates the dilution of the drug with urine and thereby maintains a more optimal and homogeneous drug dose throughout the entire treatment duration. This technique also minimizes the inter-patient variability of parameters such as concentration in residual urine and bladder MMC concentration.

Another study made on animals, showed that indeed bladder walls are heated while adjacent organs are not (Rath-Wolfson et al. 2003). It also showed the evenly distributed heating and that the thermometers of the Synergo® reflect faithfully and accurately the temperature of the tissue and not of the liquid in the bladder vault.

In a 2004 study van der Heijden at al. assessed the effect of hyperthermia on mitomycin C-induced cytotoxicity in bladder cancer cell lines (van der Heijden et al. 2004) showing a decrease in cell proliferation after treatment with increasing concentrations MMC. The apparent synergy of chemotherapeutics and hyperthermia was further addressed by the same group demonstrating a similar phenomenon for epirubicin, EO9, mitomycin C and, to a lesser extent, gemcitabine (van der Heijden et al. 2005).

Owusu RA, Abern MR, Inman BA. 2013. Hyperthermia as Adjunct to Intravesical Chemotherapy for Bladder Cancer. BioMed Research International 2013: 7. Paroni R, Arcelloni C, De Vecchi E, Fermo I, Mauri D, Colombo R. 1997. Plasma mitomycin C concentrations determined by HPLC coupled to solid-phase extraction. Clinical chemistry 43: 615-618. Paroni R, Salonia A, Lev A, Da Pozzo LF, Cighetti G, Montorsi F, Rigatti P, Colombo R. 2001. Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. British journal of clinical pharmacology 52: 273-278. Rath-Wolfson L, Moskovitz B, Dekel Y, Kugel V, Koren R. 2003. Combined intravesical hyperthermia and mitomycin chemotherapy: a preliminary in vivo study. International journal of experimental pathology 84: 145-152. van der Heijden AG, Jansen CF, Verhaegh G, O'Donnell M A, Schalken JA, Witjes JA. 2004. The effect of hyperthermia on mitomycin-C induced cytotoxicity in four human bladder cancer cell lines. European urology 46: 670-674. van der Heijden AG, Verhaegh G, Jansen CF, Schalken JA, Witjes JA. 2005. Effect of hyperthermia on the cytotoxicity of 4 chemotherapeutic agents currently used for the treatment of transitional cell carcinoma of the bladder: an in vitro study. The Journal of urology 173: 1375-1380.

Bladder cancer and Synergo latest updates

Bladder Cancer   Bladder cancer is the fourth most common non-dermatological cancer in men in the UK. In 2005, the estimated male and female crude incidence rates of bladder cancer were 24.6 and 9.3 per 100,000 population with 6091 and 2403 new cases, respectively, in England. In Wales the incidence is 43.0 and 17.2 per 100,000 population, that is 619 and 260 new cases, respectively. Altogether, more than 10,000 people in the UK are newly diagnosed with bladder cancer each year. Around 75–85% of these patients have non-muscle-invasive bladder cancer (NMIBC) including carcinoma in situ (CIS). NMIBC has a probability of recurrence at 5 years of up to 80% and a probability of progression of between 0.8% and 30% after initial treatment (depending on the stage and grade of disease). A combined analysis of 2596 patients from seven EORTC Trials with stage Ta T1 Bladder Cancer indicated a 70% recurrence within 3 years (Sylvester R. Eur Urol 2006) Patients with bladder cancer are differentiated into one of three groups: (1) those with low risk disease in whom the main risk is recurrent low-risk papillary disease with a small chance of dying of the disease; (2) those with intermediate and high-risk non-muscle-invasive disease and CIS in whom there is a high chance of disease progression and subsequent death from bladder cancer; and (3) those with muscle-invasive disease in whom there is imminent risk of death from bladder cancer. The goals of current treatment for patients with non-muscle-invasive bladder cancer are to prevent disease recurrence or progression to muscle-invasive disease, to avoid cystectomy and, ultimately, to enhance survival. Transurethral resection of the bladder tumour (TURBT) is the first-line treatment for patients with NMIBC. Unfortunately, the high rate of recurrence and progression after TURBT necessitates the use of adjuvant treatments. This entails instillation of a chemotherapeutic agent, usually mitomycin (MMC), or immunotherapeutic agents such as BCG, either alone or in various combinations. Intravesical BCG is the an effective treatment but patients who fail BCG treatment are often treated again with low probability to remain disease-free and are often referred to cystectomy. Some patients are unable to tolerate BCG and/or are refractory to treatment and some patients cannot receive treatment due to impaired immune system (e.g. lung/kidney transplants). Synergo technology has become a therapy option[1] in many centres throughout Europe for: ·         intermediate and high-risk patients with recurrent tumours, especially after failed BCG treatment ·         patients who are unsuitable or refuse radical cystectomy ·         patients who are unfit for operation ·         patients for whom BCG treatment is contraindicated. [1] Lammers RJ, Witjes JA, Inman BA, Leibovitch I, Laufer M, Nativ O, Colombo R: The Role of a Combined Regimen With Intravesical Chemotherapy and Hyperthermia in the Management of Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol 2011, 60:81-93 Here is some good information to read http://www.cancer.gov/cancertopics/pdq/treatment/bladder/HealthProfessional/page6