A history note: 1995 post R&D

25 years ago!

Synergo at the very outset. The year is 1995. A group of urologists and scientists at HSR publishes its first article and presents a new device based on a microwave source delivering local bladder hyperthermia together with intravesical chemotherapy.



44 patients treated. Overall response rate in 90.8%: 70.4% complete and 20.4% partial.

Positive, repetitive results have led to the development of the “Synergo®”.

Synergo® RITE technology was specifically developed and designed to deliver local microwave hyperthermia (radiofrequency) in combination with chemo to treat Non Muscle invasive Bladder Cancer. All administered via Synergo transurethral RF applicator.

Starting as early as 1992 and continuously to date clinical trials have been conducted to study the benefits of combined treatment of Synergo® over chemotherapy and immunotherapy alone for people who suffer from NMIBC and other tumors in the bladder. The treatment has become a common practice in leading centres both as a prophylactic treatment (after TUR) and ablative treatment (for tumour eradication).

Photo below: pre-Synergo: transurethral microwave bladder with chemo instillation. A lamp was used to hold the embedded antenna within the silicone catheter.

Photo: 25 years ago! Synergo at the very outset. A designed device. Arm replaces the lamp. 

Radiofrequency impairs viability of bladder cancer cells and has an additive effect when combined with chemotherapeutics in vitro

Presented by I.S.G. Brummelhuis et al. ESUR, Porto

A study comparing the effects of two techniques combined with chemotherapy on cell viability of bladder cancer cells in vitro.

 

MMC and epirubicin showed the greatest impact on the cell viability of all cell lines. RF-induced HT inhibited cell viability of T24, J82 and RT4 cancer cell lines. In combination with MMC and epirubicin this effect was additive. The majority of the effects of RF-induced HT were not attributable to the effect of HT, implying that the effect of RF adds independently to the effects of HT and chemotherapy. The cell viability of benign hbSMC was not affected by RF. 

European Urology Supplements 18(8):e3152-e3153 · October 2019

 

"Tough times never last, but tough people do."—Robert H. Schuller

Together, we are facing a truly unprecedented situation. The global coronavirus pandemic is affecting all of our families, our businesses, our communities, and our way of life.
We are truly inspired by the selfless healthcare workers around the world who are on the front lines working tirelessly to care for people in need.

We wish you and your families stay safe & healthy, gradual and phased return, as we continue to work together as a collective community to support business continuity and each other.

Sincerely, 

Medical Enterprises Team

Updates from the European Association of Urology Guidelines 2017

Bladder Cancer - Updates from the European Association of Urology Guidelines:

Background:

The Synergo® treatment has become a common practice in leading centers both as a prophylactic treatment (after TUR) and ablative treatment (for tumour eradication). The prophylactic induction phase includes 6 weekly sessions followed by 6 in a maintenance phase, once every 6 weeks. The clinical outcomes of this adjuvant protocol were recently included in the European Association of Urology Guidelines. A multinational randomised controlled trial comparing the efficacy and safety of Synergo® vs. BCG, presents better results in the Synergo® group (Disease free patients: 81.8% vs. 64.8% respectively in 2-yr follow-up). 

With the new recommendations, Synergo®’s level of evidence makes it the only non-experimental device for the treatment of NMIBC.

The following is taken from the EAU 2017 guidelines:

EAU Guidelines. Edn. presented at the EAU Annual Congress London 2017. ISBN 978-90-79754-91-5.

 

7.3.3.Treatment of BCG failure and recurrences after BCG

Treatment recommendations are provided in Sections 7.5 and 7.7. They reflect the categories mentioned in Table 7.2 and tumour characteristics at the time of recurrence.

Patients with BCG failure are unlikely to respond to further BCG therapy; RC is therefore the preferred option. Various studies suggest that repeat BCG therapy is appropriate for non-high-grade and even for some high-grade recurrent tumours [232,233] (LE: 3). Additionally, there are now several bladder preservation strategies available that can be categorised as intravesical immunotherapy [234], intravesical chemotherapy, device-assisted therapy (see Section 7.2.1.3.2), and combination therapy (see Section 7.2.3) [235]. Changing from BCG to these options can yield responses in selected cases with BCG treatment failure [232,234-242] (LE: 3).

Treatments other than RC must be considered oncologically inferior in patients with BCG failure at the present time [150,229,230] (LE: 3).

Little is known about the optimal treatment in patients with high-risk tumours who could not complete BCG instillations because of intolerance.

Non-high-grade recurrence after BCG is not considered as BCG failure. Treatment decision should be individualised according to tumour characteristics. It could include chemotherapy or repeat BCG instillations, but the published evidence is very low.

Synergo® Technology

The Synergo® device delivers radiofrequency local radiation: a synergistic tri-modality of local, non-ionising Radiofrequency, RF, a chemotherapy instillation, and tissue hyperthermia – all in one, powerful combination, for treating intermediate and high risk Non-Muscle Invasive Bladder Cancer. A special catheter, carrying an embedded small radio-frequency (RF 915 MHz) antenna and thermocouples (special temperature measuring sensors), is introduced into the urinary bladder.

The distal end of the catheter is connected to the Synergo® computer-embedded device that enables the physician to monitor and control the system activity in real-time.

The antenna controllably radiates the bladder walls, while the thermocouples monitor the bladder wall temperature to help ensure that it is kept at a safe range. Chemotherapeutic agent is instilled through the same catheter and constantly circulated and cooled by the heat exchanger unit of the Synergo® device.

Selective effects of RF on cancer cells include phenotypical changes, the formation of micropores on their membranes, and the loss of adhesion between malignant cells – an influential parameter of tumour growth. The drug can now easily penetrate into, and in between these cells, reaching deeper hidden locations. Studies reveal that with RF, even the more resistant cancer cells, become susceptible to chemotherapy, whereas, the effects of RF are negligible on healthy cells. Tissue heating, hyperthermia, is a welcomed by-product of RF. It causes changes in blood perfusion and ruptures in blood supply to malignant cells, as well as unfolding and denaturing of proteins, causing irreparable damages to the DNA selectively in cancer cells. Temperatures of approximately 42 degrees Centigrade, 107 Fahrenheit, are monitored and maintained throughout the treatment.

Temperature elevation of the bladder walls to 42±2ºC enhances the effectiveness of chemotherapeutic agents through several mechanisms additional to those identified in-vitro, including improved tissue penetration and altered immunological response.

May 2017 was bladder cancer awareness month!
Bladder cancer is the fifth most common cancer in the Western world and the second most frequent malignancy of the urinary tract after prostate cancer.

Erlangen Urology meeting 2014

The last urology meeting in Erlangen was well organized and the Synergo® RITE was well located! Few words in German for those who came to share experience and also just to express their interest. Below is Ms. Reich and her booth neighbour dressed in traditional Bavarian costume.

Es ist uns eine Freude, unsere neuen erfahrenen klinischen Fachleute im Team von Synergo® willkommen zu heißen, die uns bei der Ausdehnung unserer Aktivitäten mit urologischen Kliniken in Deutschland und Österreich helfen werden. Unser Ziel besteht darin, urologischen Kliniken eine Verbesserung von Ausbildung, Service und Unterstützung zu bieten. Wir erweitern unsere Aktivitäten mit der Synergo® Technologie, die überall auf der Welt zunehmend routinemäßig für die Behandlung von Patienten mit Blasenkrebs im mittleren Stadium oder mit hohem Risiko eingesetzt wird.

Frau Naama Reich, unsere medizinische Kontaktperson,  

40. Gemeinsamen Tagung der Bayerischen Urologenvereinigung sowie der Österreichischen Gesellschaft für Urologie und Andrologie zu treffen. Erlangen (Germany) 2014

Synergo® RITE (durch Radiofrequenz induzierter Thermo-Chemotherapie-Effekt) gegen nicht muskel-invasiven Blasenkrebs. 

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