Information on Product and Application for

ERBE CRYO 6In collaboration withDr. Schder and Dr. Pistorius, Univ. HomburgERBE

1. Cryosurgery

Cryosurgery is an addition to existing surgical methods for the treatment of hepatic metastases.

Cryosurgery is the term used to describe tissue destruction (devitalization) using extreme cold. During this process intracellular ice is formed leading to cell necrosis.

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1. Cryosurgery

In modern cryosurgery 4 coolants are employed:

Nitrous oxide (N2O)min. temperature - 80 CLiquid nitrogen (LN2)min. temperature - 196 CCarbon dioxide (CO2)min. temperature - 60 CArgonmin. temperature - 135 C

N2O and CO2 units are not suitable for the cryosurgical treatmentof malignant tumors.ERBE

1. Cryosurgery

The following parameters are of particular importance for successful cryosurgery:

extreme cooling of the tumor cells (at least - 50C)a freezing temperature of at least - 100C / min.in order to freeze large metastases or tumors simultaneously, several cryoprobes can be inserted concurrently.

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1. CryosurgeryCompared to the beginnings of cryosurgery approx. 25 years ago the following has changed:

Improved knowledge of cryobiology(ice cell necrosis, freezing times, freezing speed and freezing cycles)Improved cryounits(rapid freezing speed, constant power output, simultaneous insertion of several probes possible)Improved cryoprobes(thin, high-powered)Improved application methods(intra-op.-ultrasound, positioning sets)ERBE

1. CryosurgeryImprovements in cryo-technology together with the intra-operative use of ultrasound have made the reliable destruction of hepatic metastases accompanied by only minimal complications possible.

The advantages of cryosurgery in the treatment of hepatic metastases are:

Treatment option for irresectable metastases of the liverCombined OP (resection and cryosurgery)Freezing of the edges of the resected area (to increase the safety margin)Treatment method with minimal complicationsLimited range of application means that healthy liver parenchyma is not affectedERBE

1. CryosurgeryERBE

Germany U.K.NetherlandsJapanItalyFrance SpainU.S.A.Male40,9Female52,2Male51,7Female51,3Male43,4Female44,6Male47,4Female36,9Male64,8Female58,5Male51,0Female41,5Male34,4Female30,2Male57,9Female40,0Colorectal CancerWorldwide incidence**Incidence are per 100.000 population.International Opportunities in Cancer Management - SRI InternationalERBE

2. Liver metastases through colon carcinoma

In the Federal Republic of Germany there are an average of approx. 48.050 new cases of colon carcinoma per year.

Of these patients, approx. 7.200 develop synchronous and approx. 7.200 develop metachronous liver metastases per year

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2. Liver metastases through colon carcinomaCancer of the colon and the rectum Germany 1991

Men Women totalNew cases 21.460 26.590 48.050

Synchron. liver metastases (estimated) approx. 15 % 7.200

Metachron. liver metastases (estimated) approx. 15 % 7.200

New cases of liver metastasesper year 14.400ERBE

2. Liver metastases through colon carcinoma

Hematogenous metastasis develops primarily in the liver and secondarily in the lungs.

All in all, of the 14.000 new cases of liver metastases, approx. 10% = 1.400 can be treated with cryotherapy.

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2. Liver metastases through colonic carcinoma Summary

14.000 new cases of liver metastasis per year

5 - 10 % resectable = 700 - 1.400

25 - 35 % irresectable despite only few metastases

5 - 10 % treatable by cryotherapy = 700 - 1.400ERBE

Distribution of liver metastases according to type(Study carried out at the Univ. Homburg/Saar n = 162 Pt.)ERBE

2. Liver metastases through colonic carcinoma

Prognostic factors for the resection of colorectal liver metastases:

Number of metastases (3 - 10)Tumor-free marginLymph-node status of the primary tumorInterval of time between primary operation and the occurrence of metastases

The combination of cryotherapy and resection offers patients with an unfavorable distribution of metastases a therapeutic option.ERBE

3. Equipment/Instruments

For successful cryosurgical therapy of liver metastases and liver tumors the following preconditions are of particular importance:

A good high-resolution U/S - unit (preferably with a good radiologist)A high-powered cryounit with a connection for multiple probesA temperature measurement gauge to monitor tissue temperatures using temperature-measuring needlessterile dilatator sets for the introduction and positioning of cryoprobesERBE

3. Equipment/Instruments

10450-00020450-001ERBE

3. Equipment/InstrumentsTwo newly developed cryo contact applicators are available for the ERBE Cryo 6:

Paddle applicator, 50mm , Art.-No.: 20450-070Flat applicator, 50mm , Art.-No.: 20450-071

These cryo contact applicators are particularly suitable after the resection of liver tumors.Either the flat or the paddle applicator can be utilized depending on the localization of the resected area.Use of these special cryo contact applicators increases the size of the safety margin after resection.ERBE

3. Equipment/Instruments

Formation of ball of ice using flat applicatorERBE20450-07120450-070

3. Equipment/Instruments

20450-006 20450-00820450-003ERBE

3. Equipment/Instruments

20450-007 20450-002ERBE

3. Equipment/Instruments

Important requirements for the exact staging of tumors :

A good U/S - unit with high resolutionU/S - transducer:- for open liver procedures 5 MHz or possibly 7.5 MHz- percutaneously 3.5 MHz

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3. Equipment/InstrumentsIntra-operative sonography

Intra-operative sonography offers the followingadvantages:

exact identification of metastasesprecise positioning of the cryoprobesMonitoring of ice formation

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4. Operative technique

The same conditions which apply to resection also apply to indications for cryosurgery, i.e. extra-hepatic metastases (exception: the lungs) must be precluded, basically a remedial approach.

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4. Operative technique

a. Positioning of the cryoprobes with the help of a U/S - unit and dilatator sets:

ERBE CRYO 6 offers the possibility of utilizing up to 6 cryoprobes concurrently.Prior to the positioning of cryoprobes in the metastases, the size of the metastases must be ascertained using U/S, in order to determine the number of cryoprobes required. The following system should be applied:

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4. Operative technique

Metastases with a up to:

1.5 cm1 cryoprobe 2.5 cm2 cryoprobes 3.5 cm3 cryoprobes 5 cm4 cryoprobes 6 cm5 cryoprobes >7 cm6 cryoprobesERBE

4. Operative technique

To begin with, the needle together with a guiding channel is precisely positioned in the metastasis under U/S - monitoring.The needle is then removed from the channel.A guide-wire is then introduced through the channel using the Seldinger technique. The guide-wire is provided with a J - hook at one end, which can be clearly visualized under U/S - control. The J - hook must be positioned exactly at the distal end of the channel. The channel is then removed. A synthetic cone with the dilatator is introduced into the hepatic metastasis with the help of the guide-wire.

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4. Operative technique

Cone and dilatator must be inserted up to the hook at the end of the guide-wire.The guide-wire and the cone are then removed from the dilatator.Once the cryoprobe has been completely inserted into the dilatator up to the very end, the dilatator is then partially retracted in order to ensure that the freezing zone of the cryoprobe lies outside of the dilatator and is correctly positioned.Note! Dilatator sets should only be used once!ERBE

4. Operative technique

One dilatator set per cryoprobe is required.If the patient presents with several metastases, then the same dilatator set can be reused several times.After positioning the cryoprobes, the freezing cycle is activated. Note! The cryoprobes are only firmly positioned in the liver when the necessary freezing temperature has been reached. During freezing the cryoprobes should be held still in order to avoid creating tension between the probes (danger of cracking).ERBE

4. Operative technique

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4. Operative technique

If the metastases are larger than 5 cm , then the cryoprobes must be withdrawn after the first cryo-cycle in order to freeze the entire metastasis during a second cryo-cycle.After one freezing cycle (15 min at -195C) and a period on hold (5 - 10 min at -150C) the freezing process is halted for every cryoprobe. If the ice extends up to the surface, then the heating system is only activated after reaching a temperature of approx. -20 C to -30 C, because of the danger of cracking.

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4. Operative techniqueOnce the cryoprobe has achieved a temperature above zero, then the surgeon can carefully begin to detach the probe form the ball of ice.If the ice has formed within the liver, then the heating system can be activated immediately.After the cryoprobe has been detached from the ball of ice, the heating system can be deactivated.

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4. Operative technique

b. Utilization of thermo-measuring needles

ERBE CRYO 6 offers the possibility of utilizing up to 6 thermo-measuring needles concurrently.With the help of the thermo-measuring needles, it is possible to measure the temperature in various tissue areas or in the vicinity of a particular vasculature or organ.In order to ascertain whether the required freezing temperature of - 50C has been achieved at the periphery of the metastasis, a thermo-measuring needle should be positioned within the area in question with the help of U/S monitoring.

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4. Operative technique

If the cryoprobe has been properly positioned, the temperature after 15 min. should be - 50 C.Thermo-measuring needles are available in various different sizes, optimized for open and percutaneous operations.

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5. Temperature distribution in liver tissue

In order to completely achieve the required temperature of - 50 C in metastases and tumors of different shapes and sizes, it will be necessary in most cases to utilize more than one cryoprobe.

When only one cryoprobe is used, the isotherm of - 50 C will have a diameter of 22 mm after a freezing time of 15 min. The entire ball of ice will be approx. 45 mm . This means that the outer margin of the iceball of 1 cm will not be sufficient for cell necrosis. It will be therefore necessary to freeze an area of at least 1 cm over and above the actual tumor margin. This can easily be monitored sonographically.

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5. Temperature distribution in liver tissue

When treating tumors larger than 20 mm , more than one cryoprobe must be utilized (s. Fig. 11).

Fig. 12 clearly shows that with the synergistic use of three concurrent cryoprobes it is possible to achieve an extremely high isotherm of - 50 C.

Fig. 11

Fig. 12

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5. Temperature distribution in liver tissue

If the tumor is not circular in shape, as shown in Fig. 13, then an additional cryoprobe must be inserted.

Fig. 13ERBE

5. Temperature distribution in liver tissue

As early as 1985, Gage established the fact that rate of necrosis is related to tissue temperature.

Rate of necrosis correlated with tissue temperature(Gage et al. 1985)Temperature C Rate of necrosis (%)

-15 to -24 72.7 -25 to -35 93.1 -36 to -50 100.0 ERBE

6. Operation time

Cryotherapy: Operation time

Average: 230 minutes (90 - 330)

Example: Ultrasound 10 Positioning of the probes 30 3 - 4 freezing cycles 60 Defrosting stage 25 -------- 125ERBE

7. Percutaneous cryosurgery of hepatic tumorsPercutaneous cryosurgery is well suited for patients with hepatic tumors which can be easily localized sono-graphically.

Tumor-staging is carried out using an U/S - transducer 3.5 MHz. The sterile dilatator set is particularly suitable for the percutaneous positioning of cryoprobes. ERBE

7. Percutaneous cryosurgery of hepatic tumors

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7. Percutaneous cryosurgery of hepatic tumors Advantages of percutaneous cryosurgery are:

no loss of blood during the operationno intra- or postoperative complicationsshort period of hospitalization of about 3 - 6 daysadditional percutaneous cryo -operations always possible

Disadvantage:

Control of therapeutic results is problematic, particularly in tumor regions adjacent to the ultrasoundERBE

8. CasesThe following OPs were carried out at the University Clinic ofHomburg from 8/1995 to 8/1998:

Patients100Resection + Cryo37Cryo 48Percutan.15Metastases total249- Cryo147- Resection 80- Freezing of resection margins using paddle applicator 3 xERBE

8. Cases

No. of metastases per patient 2 - 8Average size3.4 2.2 cmNo. of cryoprobes per patient- open3 - 5- percutan.4Average rate of survival48 months

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9. Alternative therapies for irresectable hepatic metastases and liver tumors

1. Chemotherapy2. Ethanol injection3. Laser-induced thermotherapy4. Electrotherapy5. Genetic therapy

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9. Alternative therapies for irresectable hepatic metastases and liver tumors

1. Local chemotherapy

Hepatocellular carcinomas (HCC) do not respond well to systemic chemotherapy. Nor have the benefits of a local arterial chemotherapy or chemo-embolisation been clearly demonstrated. The median rate of survival with irresectable HCC is between 4 -6 months.

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9. Alternative therapies for irresectable hepatic metastases and liver tumors2. Ethanol injection (Only for HCC)

For ethanol injection 2 - 6 ml 100% alcohol is injected using a 22 - gauge needle which is positioned in the tumor under local anesthesia under ultrasound monitoring. This creates a diffuse necrosis in and around the tumor.The injection can be administered twice a week. This form of therapy is not successful for single tumors with a diameter of more than 5 cm or for advanced cirrhosis of the liver.More than half of the patients develop a fever after receiving therapy.ERBE

9. Alternative therapies for irresectable hepatic metastases and liver tumors3. Laser-induced thermotherapy (LITT)

Laser-induced thermotherapy (LITT) is a minimally invasive method of treatment for the local destruction of solid tumors and metastases in the liver, brain, breast and in ENT - therapeutics.This technique was first carried out in 1983 using a Nd:YAG - laser.Low-powered laser light (3.3 - 8.8 watt) is applied directly into the inner area of the tumor using thin optical fibers and leads to a coagulation necrosis.

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9. Alternative therapies for irresectable hepatic metastases and liver tumors

Positioning of the fibers is carried out under CT - control. For the laser application, the patient must be removed to the MRT - measuring room. A metastasis measuring up to 2 cm can be treated with a laser applicator. One treatment session takes between 10 - 30 minutes.As it is only possible to insert one applicator, larger metastases must be treated over a period of several sessions which is extremely time-consuming.

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9. Alternative therapies for irresectable hepatic metastases and liver tumors4. Electrotherapy

During electrotherapy (HF) thin isolated electrodes are positioned in the metastases under ultrasound monitoring. Additional needles are then extended in an umbrella-like fashion into the metastasis. The ion flow which is generated locally produces heat. The temperatures of over 70C lead to coagulation necroses. Using one electrode metastases of up to 2 cm in size can be treated. One treatment session takes between 10 - 30 minutes. Only one electrode can be used during treatment.ERBE

9. Alternative therapies for irresectable hepatic metastases and liver tumors5. Genetic therapy

During genetic therapy, genetic material is inserted into the cells of the body. The basic requirement for genetic therapy is the identification of defects in the course of transcription and translation. Suitable vectors are required for the introduction of genetic material into normal or abnormal tissue.In a pilot study, 5 patients with HCC were treated by sonographically controlled percutaneous injection of p53-DNA into the tumoral nodes. 3 patients showed a tumor reduction as demonstrated by CT control. ERBE

ERBE10. Competitors Comparison Cryo-Systems

CMS LN2 SystemEndocare Argon SystemSpembly LN2 SystemERBE LN2 SystemERBE

Cryo 6 1/99 ERBE