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

Synergo presented at the SWDGU (Südwestdeutsche Gesellschaft für Urologie e.V.), Offenburg 2018

45-year-old patient suffering from a multifocal, recurrent non-muscle invasive transitional cell carcinoma of the urinary bladder since 2012.The patient had multiple transurethral resections of the bladder (max. Tumor Stage pTA, high-grade).

The patient received instillations therapy with Mitomycin (8x), 2013 followed BCG instillations, which was aborted due to BCGitis with pulmonary and hepatic infection.
In 2015, following repeated recurrences of tumors, the patient was recommended cystectomy which the patient rejected.
Synergo® treatment was performed at the patient's request. A total of 8 induction cycles (11/2015 -01/2016, 2x40 mg Mitomycin weekly) and 6 maintenance cycles (04 – 12/2016, 2x20 mg Mitomycin 6-weekly) were given.

Since 03/17 the patient receives a maintenance therapy (2x20 mg Mitomycin, once every 3 months) and has been remaining free of tumour for 2 years.
With overall good therapy compatibility, a unique Intradetrusorale Botox injection was required to treat the increasingly pronounced urge symptoms.

RF-Induced hyperthermia and chemotherapy after failure of previous instillation therapies with Mitomycin and BCG can be an effective therapy option in individual cases before offering cystectomy.

Hyperthermiegestützte Mitomycininstillation nach Versagen der herkömmlichen Instillationstherapien bei rezidivierendem, nicht muskelinvasivem Harnblasenkarzinom als Alternative zur Zystektomie 

Presentation given by Maxim Kochergin; Ulrich Witzsch; Joseph Bcheraoui; Stefan Tietz; Eduard Walter Becht from Krankenhaus Nordwest

"Knowledge of drug diffusion mechanisms into the tissue and cellular cytoplasm following bladder

instillation is a key to understand the safety profile and clinical activity of chemotherapy."

Intravesical Chemotherapy and Chemohypherthermia in Non-Muscle-Invasive Bladder
Cancer; An Overview on Drug Administration Technologies and Pharmacokinetics
Campodonico F, Di Stasi S, Lev GM, Terrone C, Bongiovanni L, Mattioli F, Pagliarulo V and Introini C
Current Drug Metabolism, 2017

https://doi.org/10.2174/1389200218666170427092421

Despite the widely adopted international guidelines’ recommendations, and recent clinical trials of device-assisted chemotherapy instillations showing markedly enhanced recurrence-free survival compared even to the standard of care, clinicians and pharmacologists are not familiar with the in-depth physical aspects, pharmacokinetics and systemic absorption of chemotherapeutic drugs following their intravesical
administration. This paper gives a comprehensive review covering various aspects of different treatments with intravesical drugs.
Device-assisted therapies have set a goal to potentiate the drug’s effect and efficacy. The Radiofrequency-Induced Thermochemotherapeutic Effect (RITE) and the Electromotive-Drug Administration (EMDA) are the two most relevant modalities used to increase the activity of intravesical chemotherapy.

This new published study examined whether RF-CHT (using Synergo system) results in higher MMC drug tissue concentrations as compared to cold MMC instillation.

Intravesical radiofrequency induced hyperthermia enhances mitomycin C accumulation in tumour tissue,
F. Johannes P. van Valenberg, Antoine G. van der Heijden, Rianne J. M. Lammers, Johannes Falke, Tom J. H. Arends, Egbert Oosterwijk & J. Alfred Witjes
International Journal of Hyperthermia

https://doi.org/10.1080/02656736.2017.1406618

Patients received either (1) cold drug instillation (Mitomycin) or (2) RF-CHT (Synergo) before a planned transurethral resection operation. After instillation, three biopsy tests were taken of both normal and tumour tissue. The results showed that the median drug concentration in tumour tissue was higher in the RF-CHT (Synergo) group (median 665.00ng/g vs. 63.75ng/g, U¼51.0, p¼0.018). Moreover, in both techniques the MMC concentration was lower in normal tissue compared to tumour tissue. They concluded that Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy.

virtual London (EAU 2017)

Enjoyed meeting all urology specialists at the last EAU conference!

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.

Recurrence Free Survival at 1, 2 and 5 years was 89.6%, 79.2 and 68.3 respectively

We were thrilled and excited to come across this newly presented Synergo® data at the last Auro National Congress. Dr. Canepa, Dr. Campodonico and team presented their long term outcomes of treatment in Genova centres, Italy.

TEN YEARS EXPERIENCE WITH INTRAVESICAL THERMO-CHEMOTHERAPY MMC 40MG FOR NON MUSCLE INVASIVE BLADDER CANCER HIGH/INTERMEDIATE RISK

G. Canepa1, F. Campodonico1, S. Tamagno1, C. Introini2, M. Puntoni3
1 E.O. Ospedali Galliera, S.C. Urologia (Genova) 2 Ospedale Evangelico Internazionale, S.C. Urologia (Genova Voltri) 3 E.O. Ospedali Galliera, Direzione Scientifica e Biostatistica (Genova)

Aim of the study: evaluate the long-term experience on a treatment combining intravesical hyperthermia with Mytomicin C (HT-MMC) delivered with the Synergo® device.

More than 1600 treatments performed since 2004

146 Intermediate and High-risk NMIBC patients

37/146 patients reported a recurrence and 14/146 patients presented a progression.

The Recurrence Free Survival at 1, 2 and 5 years was 89.6%, 79.2 and 68.3 respectively.

Progression Free Survival at 1, 2 and 5 years was 98%, 96.2 and 83.7 respectively.

The number of treatment sessions for each patients were 10.4+/- 4.7 with a median of 11 sessions (Range 4-31). The time of exposure over 42°C was 37.4+/-7.4 mins. and the mean temperature was 42.0+/-0.8°C. The safety profile showed mainly grade 1 and 2 side effects. Ten patients complained grade 3 side-effects, including 1 patient bladder spasms/pain during treatment, 3 patients dysuria and 6 patients urgency after treatment.

Presented at: XXIII Congresso Nazionale Auro May 2016