Innovations in bladder cancer p.3

Synergo® II Workshop Dec. 2005- Rome Synergo® Medical Enterprises

Congress Organizer/Chairman: Prof. PF Bassi, Chairman Department of Urology, Catholic University Medical School, University Hospital “A. Gemelli”
Auditorium Centro Congressi Europa, Universita Cattlolica del Sacro Cuore, Facolta de medicina e Chirurgia “A. Gemelli”

On this page presentations 7 and 8

7.Thermochemotherapy in bladder cancer: Overview of basic science; Synergo technique – principles of operation Dr. A Lev

8.The effect of heat dose on clinical outcome A.G. van der Heijden;University Medical Centre Nijmegen The Netherlands

Thermochemotherapy in bladder cancer: Overview of basic science; Synergo technique – principles of operation Dr. A Lev

Conventional treatment regimens till this point in time still show rather high recurence rates:
TUR alone: up to 80% recurrence (20y follow up)
Thousands of review articles have concluded that the average recurrent rate of TUR alone at one year is 65%; at 2 years it is 75%
TUR + chemo prophylaxis: 25-50% (2y follow up)
Conventionally Agreed Net Benefit of +/-15% improvement
TUR + BCG: 20-65%
* Progression rate are stable: 10-20% in 5 years

European guidelines for risk assessment:

Low risk single, Ta,G1, < 3 cm diameter
High risk T1, G3, multifocal or highly recurrent, CIS
Intermediate risk all other tumors, Ta-T1, G1-G2, multifocal, > 3 cm diameter

Recurrence rates are still very high not-with-standing current improvement in TUR techniques and instillation protocols. How should we modify this fact?

Bladder instillations: some pharmaco-kinetics aspects:
Drug concentration – Wientjes et al studied the pharmacokinetics of MMC drug concentration in urine and determined that an effective MMC concentration is > 0.12 mg/ml of MMC in urine. That is, significant concentrations of Mitomycin C were found in the bladder wall, when urine Mitomycin C concentration was > 0.12 mg/ml. Wientjes et al. Penetration of MMC in human bladder. Cancer Research (1993)(53) 3314-3320.
Effective exposure time: Conclusion: 2 x 20 mg MMC = 1 x 40 mg MMC
Bladder tissue wall is equally exposed to an effective MMC drug concentration.

Questions to be addressed include the high levels at the start of the instillation
Maximum effective MMC concentration:
In-vitro experiments with:
4 human bladder cancer cell lines and
2 mouse bladder cancer cell lines
24 hours in media containing
0, 0.125, 0.25, 0.5, or 1 mg/ml of MMC
(see Wientjes et al and T.v.d. Heijden et al)
Maximum MMC effective concentration range < 0.25 mg/ml
Initial exposure of patients to higher concentrations of MMC during the first minutes of treatment, may not provide additional clinical benefit.

Maximum effective MMC concentration summary:

Dose Time above 0.12 mg/ml Effective AUC
C* 0.25 mg/ml
C* 0.12 mg/ml
40mg 40 min. 8.57 min*mg/ml
2×20 44 min. 8.71 min*mg/ml

C* -MMC Concentrations above 0.25 mg/ml calculated as 0.25 mg/ml

Instillations should keep chemotherapeutic agent’s concentration as steady as possible at effective level. Using the highest dose possible is not necessarily good

Effect of heat (alone) on tumour tissue: Known facts:
Heat may kill tumour cells
Heat alone destroys blood supply in tumour tissue.

Since 1980 there have been thousands of studies investigating the use of both hyperthermia, hyperthermia+radiation and hyperthermia+chemotherapy against cancers of all kinds.

Heat and chemotherapy The objective: delivery of the drug to the cell, enter the cell and combine to DNA
DIffusion Although diffusion is very common in biological systems, it is also a very slow process (on a macroscopic scale). There are several physical factors that affect the rate at which particles diffuse.

Size of the particle (molecular weight)
Diffusion distance – In 2 mm, without HT, about 3% of bladder MMC concentration remains
Concentration difference
Surface area
Speed of molecules
Permeability – Obviously, if a substance is not permeable through the membrane, it will not be able to diffuse through it. The more permeable a substance is, the faster diffusion through it.
For molecular weight > 200, the spontaneous permeability is close to zero.

Heat and chemotherapy – rationale:
Activation energy – the minimum energy that is necessary before a chemical reaction can occur
The activation energy provides the energy needed to break (at least partially) some bonds before others can be formed. For a bimolecular reaction mechanism, not only must the two species collide but they must also possess the activation energy for the reaction before the collision will be successful.
In summary – Having the target tissue heated will cause Chemotherapy molecules to arrive fasterand higher quantities to target cells and chemically act faster

Heating vs. RF Why does RF work better than liquid heating?
Temperature dramatically drops across the bladder
With the RF catheter used in the Synergo® method, temperature gradient across outer bladder tissues is maintained; Special thermocouples constantly measure temperature of the bladder walls

SAR- Specific Absorption Rate
This value will tell us if we have enough energy to heat the tissue. In a point where SAR is higher then 100W/Kg, the heating ability of our device enables hyperthermia.

Summay of hyperthermia + chemotherapy
Drug will arrive in higher quantities, faster and at more stable concentration.
Drug will act faster by factor of X10-100
Temperature in bladder is homogenous and measurements are therefore reliable.
Temperature outside bladder is safe
Conclusion: the application can be administered safely with high potential efficacy.


The effect of heat dose on clinical outcome A.G. van der Heijden;University Medical Centre Nijmegen The Netherlands

Untreated high risk TCC:
Within 3 years 30% invasive progression
In case of CIS even 50% progression
More than 70% recurrence

Treatment purpose of TCC:
Eradication neoplasia
Prevent recurrence
Prevent muscle invasive progression
Prevent metastatic disease

Treatment TCC according to risk

Low Single chemo instillation
Intermediate cycle/course of chemo instillation; thermo-chemotherapy
High BCG (maintenance); thermo-chemotherapy

Thermo-chemo vs. chemo
Drug uptake improved
Intracellular distribution improved
Reaction chemotherapy with DNA is increased
DNA repair is inhibited

Objectives heat dose analysis
Follow up recurrences plotted as a function of treatment parameters
Empirical relationship between treatment parameters and the time to recurrence
Optimizing treatment parameters in microwave thermo-chemotherapy treatments

Materials and Methods
1994-2005: several hundred patients underwent prophylactic or ablative thermo-chemotherapy
A list of criteria was made to select those which could be used to obtain meaningful results

Criterion Inclusion Exclusion
Type of patient For efficacy only Not for efficacy
Type of treatment Prophyactic Ablative
N Treatments Six weekly Less then six weekly
Follow up >one FU cystoscopy No FU cystoscopy

T0 determined as first chemotherapy treatment
Video cystoscopy performed every three months
Outcome data is last cystoscopy
In case positive cystoscopy ? time to recurrence
In case of negative cystoscopy ? no recurrence
Maximum follow up time 30 months

Data Collection: Each patient two data sets:
Treatment parameters for all treatments extracted from the Synergo system
Follow up data collected from patient files including cystoscopy results
Cross-checking records for consistency

Average bladder temperature is measured throughout treatment
Threshold temperature put at 40, 41, 42 and 43ºC
Analysis ‘time over threshold’ (thermal dose)
Thermal dose represented as (XXXTDYY); 250TD42 represents 250 min over 42ºC

picture 12

Results After filtering for eligibility 124 patients included
N treatments ranged from 6 to 16 (mean 10.6)
Tumour characteristics intermediate and high risk

Patients by country:

Country N patients Male Female
Israel 62 50 – 12
Netherlands 14 13 – 1
Austria 6 5 – 1
France 2 1 – 1
Italy 40 31 – 9
Total 124 100 – 24

Calculations: Heat dose effect
Treatment broken down in 2 temperature ranges: below 42ºC and above 42ºC
Function showing relationship between mix of these two ranges versus clean ratio

Treating above 42ºC is 44% more effective than working below 42 ºC
Calculation can be applied by all temperature ranges

Circulation speed was not included in analysis
It was varied very little between patients
Not a time cumulative effect
Drug-epithelium contact time variable (urine production)
RF power not included in analysis

Treating above 42ºC is significantly more effective than below 42ºC
Effectivity thermo-chemotherapy increases significantly by temperature increase
Temperature intensity more important than duration