Microwave-Induced Hyperthermia in combination with Chemotherapy: A retrospective analysis from Harlaching Hospital (2009-2015) Germany

We wish to congratulate Dr. Miriam Heibeler - with Head of department Prof. Dr. Oliver Reich at Klinikums Harlaching Lehrkrankenhaus der Ludwig-Maximilians-Universität München for her comprehensive thesis work on Synergo® published in 2020. We are extremely proud to share data from her study (translated from German). Full text: https://edoc.ub.uni-muenchen.de/25860/1/Hiebeler_Miriam.pdf

The following is a summary translated from Dr. Hiebeler study and with her permission.

The intended information is for professionals only.

Microwave-Induced Hyperthermia in combination 

with Chemotherapy: 

A retrospective analysis from Harlaching Hospital (2009-2015) 

Munich, Germany

Dr. Miriam Hiebeler

A total of 44 non-muscle invasive bladder cancer patients were treated with Synergo® in München Harlaching Hospital Munich between 2009-2015. 41% of the patients were treated according to the prophylactic (adjuvant) protocol and 59% treated according to Synergo® ablative (neo-adjuvant) protocol.

Synergo prophylactic (adjuvant):

18/44 (41%) intermediate and high-risk patients, of which 50% had history of recurring disease with an average of 2.3 incidences prior to Synergo therapy.

Results: At the end of Synergo® treatment cycle, all patients but 2 (11%), who were lost to follow-up, were tumor-free. 

14 of the 16 patients were tumor-free after completion of the Synergo therapy. This corresponds to 87.5% of the patients. The 2 patients who had a recurrence (mean time 2.3 years) both had pTaG1 tumor prior to Synergo which presented itself also when recurrence was recorded. 

The follow-up period for this cohort lasted an average of 3.2 years. 

No cystectomy had to be performed during that period. 

Synergo ablative (neo-adjuvant):

26/44 (59%) of the patients were treated. 90% were classified as high-risk (according to the EAU guidelines), with TaG3, T1G2, T1G3 and/or CIS. 73% of the patients thad history of recurring disease. 

An analysis of two groups who received Synergo ablative was performed. One group (62%) treated according to the protocol and the other (38%) was given Synergo as a therapy attempt although patients had contraindications prior to treatment (e.g. history of other tumours or urothelial carcinoma of the upper urinary tract). 

The Kaplan-Meier curve of all patients treated according to the ablative protocol shows 83% disease-free at one year and 70% at disease-free 5 years.

Below are the two ablative cohorts analysed separately:

Results of ablative Synergo:

16 patients were treated according to the Synergo recommended protocol. 15/16 of the patients were classified high-risk (according to EAU), one patient was classified as intermediate-risk. 73% of the patients had a history of disease and several were highly recurrent (3 or more episodes in the previous two years). 6 patients were “first episode” who had been diagnosed with T1 or high-grade carcinoma. Five of the latter had concomitant carcinoma in situ (CIS).

Of the 16 patients treated, 15 (93.8%) patients showed a complete response rate (tumor-free urinary bladder biopsies at the end of the ablation series). The average time to complete response was 1.9 months.

In one patient, the ablation therapy had no effect and a progression from TaG3 to pT2aG2 was recorded. This patient was cystectomised. Patients with complete response continued treatment and follow-up. The mean follow-up time was 24.2 months.

13/15 (86.7%) of the patients remained disease free for an average of 26 months and showed no further tumor formation during this period. Two patients (13.3%) had tumor recurrence. They were ultimately cystectomised after a follow-up period of 24.2 months.

In total, four of the 16 patients had to have their bladder removed. Two patients suffered tumor recurrence, one patient showed tumor progression and a cystectomy was performed on another patient with a reduced bladder capacity of less than 90 ml. The resected bladder, however, was completely tumor-free. One patient was partially resected because of a suspected tumor recurrence. The resected material was tumor-free. In the subsequent examinations, no new tumor was detected in the rest of the urinary bladder.

Results of ablative Synergo in patients with known exclusion criteria for Synergo 10/26):

One patient stopped therapy prematurely due to severe allergic skin reactions. His therapy results were not taken into account.

7/9 (77.8%) showed no tumor recurrence or progression after a follow-up period of an average of 33.4 months.

Two patients (22.2%) experienced recurrence in the form of muscle-invasive carcinoma. One developed pT2G3 carcinoma from TaG3 stage, the other developed invasive pT3aG3 carcinoma from T1G3 tumor. This patient (11.1%) underwent a cystectomy ten months after start of Synergo therapy.

A total of three patients (33.3%) died as a result of bladder carcinoma. In two patients the urinary bladder was tumor-free at the time of death; they died from extensive metastasis. The average time to death was 14.3 Months.

Side effects to therapy:

Side effects noted in a total of 63% of the prophylactic treated patients and in 69% of the ablative treated patients.

The most common were pain in the form of bladder cramps during treatments, dysuria, nocturia and allergy. Severe complications in the form of urethral strictures occurred in 27.8% of the patients, although there was no stricture impeding a cystoscope to pass. The most noted side effect observed in almost all patients during cystoscopy was posterior thermal wall reaction (average grade 2 in both groups). The posterior thermal wall reaction is symptom-free and disappears after a few months. Below are the detailed tables of side effects recorded in both prophylactic and ablative Synergo treatments.

Medical Disclaimer

While clinical studies support the safety and effectiveness of the Synergo® RF thermo-chemotherapy system when used in the treatment of non-muscle invasive bladder cancer, results may vary. There are no guarantees of outcome. Before you decide on treatment options, discuss them with your doctor. Understanding the risks of each treatment can help you make the best decision for your individual situation. Synergo treatment may not be appropriate for every individual; it may not be applicable to your condition. Always ask your doctor about all treatment options, as well as their risks and benefits. Only your doctor can determine whether Synergo is appropriate for your situation. 

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. 

"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.