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Cryosurgery is a novel technique for treatment of cancer which has been approved by the United States~ Food & Drug Administration (FDA) in 1998 and China~s SFDA in 1999. Fuda Cancer Hospital-Guangzhou has used the technique since 2000. To date, Fuda has the greatest amount of experience in this minimally invasive operation; often Fuda trains doctors from around the world on the cryosurgery technique. Recently, Fuda's number of cryosurgery cases has nearly topped 5,000 cases with a variety of malignant tumors (more than 34 different kinds of cancers). In this field, Fuda Cancer Hospital leads the world in experience and research.
Cryosurgery is an important ablation technique for tumors. It destroys tumors by cycles of freezing and thawing. Cryosurgery's destructive effects on tumors are due to two major mechanisms, one immediate, the other delayed. The immediate mechanism is the damaging effect of freezing and thawing the cells. The delayed mechanism is the progressive failure of microcirculation; ultimately, vascular stasis becomes operative as an important cause of tumor tissue destruction.
Once the temperature falls below -40oC, ice crystals may form within the cells. Once it occurs, cell death is almost certain.
During cryosurgery, progressive failure of microcirculation occurs due to a cascade of events: endothelial layer destruction causing vessel walls to become porous, interstitial edema, platelet aggregation, microthrombii, and ultimately vascular congestion and obliteration.
It was theorized that during cryosurgery, the immune system of the host became sensitized to the tumor being destroyed by the cryosurgery. Any primary tumor tissue undamaged by the cryosurgery and the metastases were destroyed by the immune system after cryosurgery. This response was termed the "cryo-immunological response".
Procedure of cryosurgery
Cryosurgery is performed through intraoperative, endoscopic or percutaneous routes depending upon the location and size of tumor.
Cryoablation is performed by using argon-helium system. Two to three cycles of the freezing/thawing are performed. The freezing continues until the "ice-ball" formed at the tip if the cryoprobe is large enough to cover tumor. A 5-10 mm margin of normal tissue is included in the freezing process. For larger tumors, multiple cryoprobes were used. In some cases, it may become necessary to perform at least 2-3 sessions of the cryoablation procedure. This is possible because the procedur0e is minimally invasive, and often does not require cutting. The probes are simply inserted through the skin and guided by real-time ultrasound.
Cryosurgery is a localized medical procedure. It can be used as the sole means of cancer treatment or it can be combined with other conventional treatment techniques such as surgical operation, chemotherapy, radiotherapy.
Combining cryosurgery with excision can be advantageous since freezing the tumor before excision minimizes the risk of spreading the cancerous cells during excision
In addition to sparing healthy tissue, cryosurgery is advantageous because it is not dose-limited can be repeated as necessary in order to destroy all cancerous tissue
In situations where the tumor is not removed after freezing, especially percutaneous cryosurgery, operative blood loss is small and post-surgical discomfort is minimized
Cryoprobes are relatively small (generally in the range of 24 mm in diameter) and therefore they may be used in minimally in-vasive surgical procedures
There are no major side effects which are commonly found in chemotherapy or radiotherapy
Cryosurgery is adaptable for treatment of tumor close to large vessel which cannot be removed by operation
Cryosurgery can treat small as well as large tumors, and solitary as well as multiple tumors
Cryosurgery per se aims at a local effect, namely, destruction in situ of neoplasms resistant to conventional treatments, but it also elicits an immunologic reaction (cryoimmunologic reaction) against cancer for eradication of residual or metastatic tumors
There is evidence that the recurrence rate of cancer after cryosurgery is lower than that of operation
Nearly all parenchymal cancers are prime candidates for cryoablation.
These malignancies include:
* Liver cancer
* Lung cancer(non-small cell lung cancer)
* Kidney cancer
* Ovarian cancer
* Pharyngeal cancer
* Testicular cancer
* Uterine tumors
* Vaginal cancer
* Pancreatic cancer
* Breast cancer
* Sarcoma and other benign or malignant lesions of bone
* Prostate cancer
* Skin cancer and melanoma
* Head and neck cancer
* Tumor of soft tissues
In addition, cryosurgery can be an effective treatment for the following:
* Retinoblastoma (a childhood cancer that affects the retina of the eye).
* Early-stage skin cancers (both basal cell and squamous cell carcinomas)
* Precancerous skin growths known as actinic keratosis.
* Pre-cancerous conditions of the cervix known as cervical intraepithelial neoplasia (abnormal cell changes in the cervix that can develop into cervical cancer).
THE MECHANISMS OF CROSURGERY
The effect of cooling
The effect of freezing
Thawing and warming
Thermal parameters specific to cryosurgery
Local monitoring of cryosurger
Imaging monitored cryosurgery
Cryosurgery, referred to as cryoablation, is a surgical technique in which freezing is used to destroy undesirable tissues. Developed first in the middle of the 19th century it has recently incorporated new imaging technologies and is becoming a fast growing minimally invasive surgical technique, especially in field of cancer treatment.
The history of cryosurgery is relatively short and is closely intertwined with developments in low temperature physics, engineering, and instrumentation that were made during the last century. A review of the history of the field will show that cryosurgery appears to advance in jumps triggered by immediately preceding technological advances.
Around 1845, Michael Faraday achieved a temperature of 163K by mixing solid carbon dioxide and alcohol under vacuum.
During the same period, James Arnott of Brighton, England, who is recognized as the first physician to use freezing for treatment of cancer, began applying these low temperatures in medicine, used a solution of crushed ice and sodium chloride to freeze advanced cancers in the breast and the uterine cavity .
In 1892, Dewar of Great Britain designed the first vacuum flask, which facilitated storage and handling of liquefied gases.
At the end of the 19- century, solid carbon dioxide, liquid air, and other gases were readily commercially available.
In 1899, Campbell White of New York, reported the use of liquid air for the treatment of diverse skin diseases.
Since then, several methods were developed for the application of liquid air to undesirable tissue. The liquid air was used for treatment of various diseases of the skin, such as warts, varicose leg ulcers, carbuncles, herpes zoster, epitheliomas, and erysipelas.
Solid CO2 was first used for therapeutics in 1907 by William Pusey, and soon became the most popular method of tissue freezing during the first half of the century. "Cryotherapy" became an established therapeutically technique in dermatology and gynecology.
Liquid oxygen became commercially available in the 1920~s with the development of new and large air separation facilities and was used in treatment of skin diseases in 1929.
The development of chloro-fluorocarbon refrigerants led to the first closed cycle refrigeration cryosurgery system in 1942.
Starting from the early 1940~s, Kapitsa in the Soviet Union and Collins in the United States began developing commercial techniques for large-scale liquefaction of hydrogen and helium, with liquid nitrogen as an abundant and low cost by-product.
In 1950 liquid nitrogen was introduced by Allington and was applied in treatment of verrucae, keratoses, and various non-neoplastic lesions.
A notable exception is the pioneering work of TempleFay who in about 1939 treated patients with advanced carcinoma, glioblastoma, and Hodgkin~s disease with local freezing.
The year 1959 produced several scientific results that led to the emergence of "modern" cryosurgery. Several scientists reported devices for freezing of brain tissue in 1959.
"Modern" cryosurgery began through the collaborative work of a physician, Irving Cooper, and an engineer, Arnold Lee. They built a cryosurgical probe capable of freezing brain tissue, with good control over the site where the cryogenic lesion was produced.
Many new applications of cryosurgery were introduced between the years 1961 and 1970.
Cahan and his collaborators applied cryosurgery to the uterus.
Rand and his colleagues expanded the use of cryosurgery in neurology.
Gonder and Soanes and their colleagues were the first to apply cryosurgery to the prostate.
Marcove and Miller applied cryosurgery to orthopedics. Torre and Zacarian and their colleagues made advances in skin cryosurgery.
In the decade between 1960 and 1970, Gage investigated freezing in a broad range of tissues.
Since the end of the 1970~s the cryosurgical probes developed allow for precise application of cryosurgical treatment deep in the body, and cryosurgery has been as the first minimally invasive surgical technique.
In 1980~s argon-helium system developed and was introduced in cancer treatment. The new cryosurgical probes could be applied at a precise location, their effect on the tissue treated by freezing was more precise. This unique ability made cryosurgery very promising and resulted in the expansion of the method and clinical experience.
In 1990~s to now, cryosurgery is being evaluated in the treatment of a number of cancers, including prostate cancer, liver cancer,non-small cell lung cancer, breast cancer, colon cancer, kidney cancer, brain and spinal tumors, and certain types of precancerous conditions. Results of cryosurgical treatment are encouraging.
The mechanisms of cryosurgery
To control the outcome of cryosurgery it is important to understand the mechanisms of damage.
In cryosurgery tissue is frozen with a cryosurgical probes that is brought in good thermal contact with the undesirable tissue. Within several minutes after cooling begins, the temperature of the tissue in contact with the probe reaches the phase transition temperature and the tissue begins to freeze. As more heat is extracted the temperature of the probe continues to drop and the freezing interface begins to propagate outward from the probe into the tissue. A variable temperature distribution in both the frozen and unfrozen regions of the tissue ensues.
In typical cryosurgical protocols, after freezing was completed the cooling system keeps the tissue frozen for a desired period of time, followed by heating and thawing. The cells near the cryosurgical probe surface will be cooled with a higher cooling rate and to lower temperatures than those farther away from the probe. The cells at different locations in the frozen lesion will be at different temperature for various periods of times, as a function of their distance from the probe surface, the cooling material employed, the shape of the cryosurgical probes, the number of the cryosurgical probes used, the type of tissue frozen.
Cell damage during cooling and freezing occurs at several length scales: nanoscale (Armstrong) - molecular, mesoscale (micron) - cellular and macroscale (millimeter) - whole tissue. The damage during cryosurgery is of two types, acute - immediately during cryosurgery and long term.
The effect of cooling
Most types of mammalian cells and tissues can withstand low, non-freezing temperatures for short periods of time. The phenomena related to cooling occur primarily at the nanoscale, with typical consequences at the mesoscale.
Cells are entities with a highly specific intracellular chemical content, separated from the non-specific extracellular solution by the cell membrane. The cell membrane acts as a selective barrier between the intracellular and the extracellular milieu. The membrane selectively controls the transport of chemical species into and out of the cell. Therefore the membrane must be mostly impermeable except at particular sites where it can control the mass transfer. The by-layer lipid structure of the cell membrane makes it impermeable. The mass transfer through the cell membrane is controlled through membrane proteins that span the membrane.
Mammalian cells have become optimized to function at the temperature in which the organism lives.
One aspect of cooling the cell to temperatures lower than their normal physiological temperature is the lipid phase transition process.
Normally the membrane proteins control the intracellular composition by selectively introducing and removing ionic species from the cell interior. However life processes are temperature dependent chemical reactions. Lowering the temperature also reduces the efficiency of the membrane proteins and their ability to control the intracellular content. Therefore, during cooling, the intracellular composition and in particular the intracellular ionic content begins to change as undesirable ions diffuse into the cells and are not removed.
Additional mechanisms of damage relate to the cytoskeleton. The cytoskeleton structure depends on chemical bonds between membrane proteins and the cell scaffold. Lowering the temperature weakens these bonds and makes them particularly vulnerable to mechanical damage.
A third mechanism of damage relates to the denaturation of proteins as a function of both temperature and change in the intracellular ionic content. Most cells and tissues can withstand brief cooling to above freezing temperatures, in the time scale typical of a cryosurgical procedure and under the cooling circumstances typical of cryosurgery.
Major exceptions are cells that are highly sensitive to their ionic content, such as platelets. Cooling platelets to temperatures lower than their lipid phase transition temperature allows calcium influx, which appears to trigger platelet activation. This could lead to a cascade of events that would end in platelet aggregation and the eventual obstruction of blood vessels in the cooled region around the frozen lesions. Other cells whose function is strongly dependent on their ionic content are muscle cells, in particular in the heart and around arteries. These may be also damaged in the cooled region beyond the frozen lesion.
The effect of freezing
The thermal processes during freezing for preservation (cryopreservation) are different from the thermal processes during cryosurgery.
In cryopreservation cells and tissues are frozen in vitro, they are usually frozen with uniform conditions to very low cryogenic temperatures, are kept in a frozen state for long periods of time and most important are frozen in the presence of chemical additives that improve survival.
In contrast, in cryosurgery the tissue is frozen in vivo, it experiences a large variation in cooling and warming conditions and in a frozen state it experiences a wide range of temperature, from the phase transition temperature on the outer edge of the frozen lesion to cryogenic temperatures near the probe.
More relevant to understanding the mechanism of damage during cryosurgery are experimental results of cancer cells frozen with specified cooling rates to different subzero temperatures. For cooling rates of 1 and 5oC/min there is a gradual, almost linear increase in cell death to temperatures of about -40oC. For higher cooling rates of about 25 oC/min there appears a sudden step like increase in cell death at a temperature of about -10oC. At the beginning of the freezing process cells accumulate on the change of phase interface, which has the appearance of a vertical line. The increased solute concentration on the change of phase interface has the effect of colligatively lowering the temperature of the change of phase interface. Because thermal diffusion is much faster than mass diffusion the increased concentration and related change in phase transformation temperature leads to a phenomenon known as "constitutional supercooling" and the so-called Mullins-Sekerka interface instability. It causes the planar freezing interface to become unstable and take the finger like shape. In this configuration the concentration of the solution at the tip of the finger like ice crystal structure is very close to the bulk solution concentration and the rejected solutes become accumulated between the fingers like ice crystal structures. The cells in the freezing solution are unfrozen and find themselves in the high concentration solute channels, between the ice crystals. This is the hallmark of the process of freezing in biological materials. Although referred to as freezing of tissue or cells, in fact during most of the freezing processes the freezing begins in the extracellular milieu and the interior of the cell is unfrozen.
The blunt tip probe, shown above left, produces a spherical iceball in the prostae, shown above right.
The flat probe, shown above left, produces a hemispherical iceball in the prostate, shown above right
There is a sequence of events that cells experience in the hypertonic solutions, between ice crystals .At lower temperatures, as the extracellular concentration increases cells shrink. This shrinkage is caused by the fact that the unfrozen cells are super-cooled relative to the extracellular solution, which is in thermodynamic equilibrium with the ice. To equilibrate the difference in chemical potential between the extracellular and intracellular solutions, water will leave the cell through the cell membrane that is readily permeable to water. This causes an increase in the intracellular solute concentration, with a decrease in temperature. Increased hypertonic extracellular solutions damage the cells. The mechanisms are not entirely clear and they could relate to chemical damage or osmolality induced changes in the cell structure. This is consistent with the hypertonic extracellular solution mechanism of damage, as the hypertonic extracellular concentration also increases gradually with a decrease in temperature.
There are several additional phenomena worth mentioning in relation to the hypertonic mode of damage. While cell death increases with extracellular concentration time affects survival only during the first few minutes of exposure after which a plateau is reached and the percentage of death cells remains constant. This is because while the mesoscale processes that occur during exposure of cells to hypertonic solutions, cell shrinkage as water leaves through the cell membrane, have been observed and are understood, the nanoscale processes are not. However, in cryosurgery these mechanisms of damage are more important than in cryopreservation because many cells in the frozen region will remain throughout the procedure in the region dominated by hyperosmotic phenomena where the solution is partially frozen and the cells are not.
There are, however, additional mechanism of damage in the region of temperatures and cooling rates associated with hypertonic solution damage. Experiments have shown that the percentage of death cells after freezing is larger than the percentage of death cells after exposure to a similar extracellular hypertonic solution. This suggests that mechanical interaction between ice and cells may contribute to cell death. This is a reasonable assumption, since ice rejects cells in the space between ice crystals. This may generate a mechanical force on the cells, whose cellular cytoskeleton is weakened by cold, and destroy them. Another possible mode of damage is the contact and interaction between ice and the lipid bilayer, which by itself may be damaging.
For a cooling rate of 25 oC/min, at a temperature of about - 10 C there is a sudden decrease in cell destruction. Experiments have shown that this sudden increase in cell destruction corresponds to sudden formation of intracellular ice. Intracellular ice forms because the water transport through the cell membrane is a rate dependent process. When cells are cooled too rapidly to equilibrate in concentration with the extracellular solution, the intracellular solution becomes increasingly thermodynamically supercooled and unstable. The probability for intracellular ice formation increases with supercooling. The nucleation sites for intracellular ice formation are intracellular, or extracellular or on the membrane. Whatever the cause of intracellular ice may be, it appears that it is almost always lethal to the cell. It is possible that intracellular ice per se is lethal or the processes that led to the formation of the intracellular ice, such as damage to the cell membrane, are lethal. As with the hyperosmotic solution mechanism of damage, with intracellular damage the mesoscale phenomena are known while the nanoscale are not. In cryosurgery the mechanism of rapid cooling and intracellular ice formation occurs usually in the frozen lesion near the cryosurgical probe. It is thought that near the cryosurgical probe the cells are completely destroyed.
In cryosurgery the freezing cells are in tissue, which has a different configuration from a cellular suspension. In tissue cells are in an organized structure and the volume of the extracellular space is usually smaller than that around cells in a suspension. The few experimental results show that the process of freezing of cells in tissue and in suspension is roughly similar. In tissue ice usually forms first in the extracellular space. Ice appears to usually form in the vasculature and propagate in the general direction of temperature gradients, but in and along blood vessels. In addition it was found that in the prostate ice forms in the ducts, in the breast in the connective tissue and in the kidney in the ducts. The cells in the various tissues appear to also experience cellular dehydration and intracellular ice formation. In liver freezed dehydrated hepatocytes, surrounding expanded sinusoids. A mathematical analysis of the process of freezing in the liver compared the process of freezing of hepatocytes in the liver and in a cellular suspension. The results demonstrate that in both cases hepatocytes experience a similar dehydration process and a similar probability for intracellular ice formation. Therefore cells in tissue will probably experience both qualitatively and quantitatively similar mechanisms of hypertonic solution damage and intracellular ice formation damage like cells frozen in cellular suspensions. However, it is suggested that in tissue the dehydration o f cells will most likely result in a disruption of the vasculature and of the connective tissues.
Thawing and warming
Thawing and warming can also induce cellular damage. During warming, in a frozen state, ice has a tendency to recrystalize at high subzero temperatures, to minimize the Gibbs free energy. Recrystalization will cause further disruption of the extracellular space and may disrupt the macroscopic structure of the tissue. During thawing, as ice melts the extracellular solution can be briefly and locally hypotonic causing water to enter some cells and expand them and rupture the membrane. When the thawing is rapid some cells may remain hypertonic at body temperature, which could induce metabolic disruption and additional damage.
Thermal parameters specific to cryosurgery
It is common in cryosurgery to employ double freeze thaw cycles. Comparison with a single freeze thaw cycle shows that the second freeze thaw cycle will increase damage. Double and even triple freeze thaw cycles are now commonly used in cryosurgery. The mechanisms of damage during multiple cycles are most likely related to cell membrane damage during the hypertonic variations that the cells experience upon freezing and thawing and with temperature variation.
Damage to the vascular system is probably one of the most important macroscopic mechanisms of tissue damage in cryosurgery. During cryosurgery the frozen region is obviously occluded from the blood circulation. Experiments show that after thawing there is edema on the outer margin of the previously frozen lesion immediately. Shortly thereafter the endothelial cells in the previously frozen region appear damaged, probably by the mechanism of blood vessel expansion during freezing. Within a period of several hours after thawing the endothelial cells become detached, with increased permeability of the capillary wall, platelets aggregation and blood flow stagnation. Many small blood vessels are completely occluded within a few hours after cryosurgery. The loss of blood flow will ultimately result in ischemia and tissue death. It is thought that this mechanism of tissue destruction explains why cells appear to have succumbed to cryosurgery even in those areas in which the freezing parameters would normally not cause cell death. Cryosurgery is probably the first surgical technique that has used angionesis to treat cancer.
While most of the studies on the process of cell death during freezing have employed viability tests that evaluated survival of cells immediately after freezing and hawing, it appears that some cooling and freezing conditions may produce less lethal modes of damage, which eventually result in gene regulated cell death (apoptosis). Apoptosis can be triggered by a variety of conditions present during cryosurgery, such as hyperosmolality. Apoptosis will take place after cryosurgery was finished and can produce further cell death.
In addition to the verified mechanisms of tissue damage during cryosurgery there is anecdotal evidence that cryosurgery may result in a beneficial systemic immunological response. There is no doubt that a normal immune response exists in response to the tissue injury which freezing produces. The usefulness of this immune response in treating metastatic tumors has been proved.
Recently a new concept was developed that has the potential for increasing the destructive effect of freezing. It has been observed that a family of proteins known as "antifreeze proteins" has the ability to modify the structure of ice crystals. These proteins, found in a large number of cold tolerant animals and plants inhibit non-colligatively the freezing temperature of solutions. However, when the solutions eventually freeze in the presence of these antifreeze proteins, they modify the structure of ice crystals. At certain concentrations these ice crystals can become needle like and lethal to cells. In cryosurgery experiments, in which the antifreeze proteins were introduced in tissue prior to the procedure, it was found that the cells were destroyed by freezing throughout the tissue regardless of the thermal history employed during freezing. The mechanism of damage appears to be mechanical and related to the interaction between the ice crystals and the cells. It appears that the antifreeze proteins induce intracellular ice formation at high subzero temperatures, regardless of the thermal history during freezing. Obviously the use of antifreeze proteins as chemical adjuvant to cryosurgery may become important. The destruction of frozen tissue may potentially become independent of the thermal history that the cells have experienced during freezing.
The technique requires sophisticated equipment, which generally uses argon gas or liquid nitrogen as the cryogenic material. The tumors are localized by untrasound or CT. The general approach is to avoid direct puncture of the tumor and to try to have some noncancerous tissue interposed between entry point and the tumor tissue. An 18-gauge needle is placed in the centre of tumor. The needle position is confirmed in both imaging planes. A J-shaped guide wire is positioned in the tumor through the needle. A sheathed dilator (3-8mm) is introduced into the tumor over the guide wire. The dilator is removed, and the sheath is left in place. Cryogenic probes are then placed into tumor through the sheath. The sheath is then pulled back. Cryogenic material is circulated through the probes. The iceball created by this treatment is visualized and monitored by real-time untrasonography or CT, as the leading edge of the iceball echogenic. The tumors are frozen at maximum flow rate for 15 minutes, and are thawed for 5 minutes, and then refrozen for another 10 minutes. If the initial ice balls are not large enough to encompass the entire length of the tumor, then the probes are pulled back for 2-5cm, depending on the length of the tumors. The cryogenic probes are turned on maximum flow rate for an additional 15 minutes, thawed for 5 minutes, and then refrozen for 10 minutes. The entire process may be repeated for very large tumors.
For tumor <1.5 cm in diameter, a 3-mm probe is placed at the center of the tumor. For tumors larger than 3 cm, multiple combinations of 3- or 5-,or 8 mm cryogenic probes are placed around the periphery and in the center of the tumor to insure freezing of the entire tumor. The goal is to destroy the tumor plus a 1-cm margin around the tumor.
It is shown that mean iceball diameters produced by 3-mm cryoprobes in targeting tissue varies from 38 to 40 mm and is 56 mm for 8mm cryoprobes.There is no significant difference in iceball size in the different tissues.The diameter of the zone of -40oC or less, that is a critical temperature for adequate destruction of cancerous tissue, is approximately 44 mm using 8mm cryoprobes and between 27 to 31 mm using 3-mm cryoprobes in the different tissues.
Normally, two freeze-thaw cycles are employed, attempting to achieve a 5- to 10 mm ablation margin of normal tissue surrounding the targeting tissue (tumor).
To perform a cryosurgical procedure successfully, it is important to precisely monitor and evaluate the extent of freezing. Failure to do so accurately can lead to either insufficient or excessive freezing, and consequently, to recurrence of malignancies treated by cryosurgery or to destruction of healthy tissues.
Local monitoring of cryosurgery
One method to monitor the process of freezing during cryosurgery is with local measurement techniques. Cryosurgery is monitored locally, either through thermometry or through impedancemetry. Thermometry is based on direct measurements of temperature at discrete points in tissue with thermocouples or thermistors placed inside or around the undesirable tissue that is being frozen.
During the late seventies, several researchers suggested the use of local electrical impedance measurements to monitor cryosurgery .It have been shown that as tissue, which is essentially a solution of electrolytes, freezes, its ability to conduct electrical currents decreases and its impedance value increases from several kilo-Ohms in live tissue to several mega-Ohms in frozen tissue. Impedancemetry employs electrode needles placed locally inside or around the undesirable tissue that is being frozen and detects freezing-induced changes in local impedance. Local monitoring of cryosurgery, however, has several drawbacks. First, it is an invasive procedure that requires the insertion of either thermocouples or electrode needles into the tissue. Second, the information produced by local monitoring is restricted to the measured site. This means that either insufficient or excessive freezing can still occur elsewhere in the frozen lesion. Nevertheless, local measurements, and in particular thermocouple measurements are still used routinely in cryosurgery. Failure to evaluate correctly the extent of freezing can lead to either insufficient or excessive freezing, and consequently, to malignancy recurrence or to destruction of healthy tissue.
Imaging monitored cryosurgery
As with other advances in cryosurgery, the emergence of imaging-monitored cryosurgery is closely related to advances of X-ray computed tomography, magnetic resonance imaging, and ultrasound.
The first imaging technique used in clinical cryosurgery was ultrasound. Two-dimensional images of acoustic discontinuities in tissue can be produced using multiple piezoelectric elements and computer analysis of the data. Freezing interfaces can be conveniently monitored with conventional ultrasound because there is a large difference in acoustic impedance between ice and water. The frozen region appears as a hemispherical dark area with a hyperecoic rim. Ice essentially reflects all the acoustic energy and therefore the entire area behind the freezing interface is dark.
Currently ultrasound monitored cryosurgery has become a clinically accepted technique for treatment of liver and prostate cancer.
Magnetic resonance imaging (MRI) produces an image of the human body by applying an alternating magnetic field and essentially produces an image of proton density, which closely relates to tissue structure. Because the protons in ice have an entirely different relaxation time from those in water the frozen region appears signal free in conventional MRI. Almost every MRI imaging technique can be used to image freezing, including fast and ultra-fast methods such as fast low-flip-angle, echo planar and gradient recalled echo. Using a MRI compatible cryosurgical probe, T1 weighted imaging sequences can provide rapid images of the process of freezing. T2 weighted images are slower, but produce a better contrast and therefore can be used to track post-operative events, such as local edema. Using contrast agents such as gadolinium MRI can detect the region in which blood flow is occluded after the frozen lesion thaws. Because MRI produces a precise three-dimensional image of the freezing interface it can be used to calculate the temperature distribution in the frozen region, and to provide real time feedback for controlling cryosurgery. MRI is advantageous over ultrasound because it can produce a real time three-dimensional image of the frozen lesion, without acoustic shadowing. However, it is much more expensive than ultrasound and it requires special surgical tools and a special environment.
Additional imaging techniques,such as spectroscopy and optical imaging to opaque, scattering media had already been developed . There are essentially two methods for optical imaging, one uses the time of flight of a proton through the tissue and the other employs the scattering characteristics of the tissue. In both methods light is emitted on one surface of the tissue and detected on another. Tomography is than used to reconstruct the image from the optical properties of the tissue. To the eye, tissues appear to change during freezing. Therefore sufficient optical contrast should exist for monitoring the freezing process. It is demonstrated that indeed optical imaging can monitor the location of the freezing interface.
Electrical impedance tomography (EIT) is another new technique that may provide an inexpensive and flexible supplement to existing cryosurgical monitoring techniques. Injecting small sinusoidal electrical currents into the body and measuring the resulting voltages through an electrode array acquire a typical EIT image. An impedance image of the tissue is than produced from the voltage data using a reconstruction algorithm. Local impedancemetry techniques have already shown that tissue impedance changes upon freezing. Therefore EIT could be used to also image freezing.
In summary, imaging modalities have provided physicians the ability to monitor the process of freezing during cryosurgery. Imaging will most likely remain of importance to the field of cryosurgery as it develops. It is to be anticipated that new and better imaging modalities for cryosurgery will continue to develop as both the fields of cryosurgery and imaging mature.
Nearly all parenchymal cancer are considered to be given cryoablation. These malignancies include:
Lung cancer(non-small cell lung cancer)
Sarcoma and malignancies of bone
Prostate cancer, localized melanoma
Head and neck cancer
Tumor of soft tissues
In addition oC/EM>cryosurgery can be an effective treatment for the following:
Retinoblastoma (a childhood cancer that affects the retina of the eye).
Early-stage skin cancers (both basal cell and squamous cell carcinomas).
Precancerous skin growths known as actinic keratosis.
Precancerous conditions of the cervix known as cervical intraepithelial neoplasia (abnormal cell changes in the cervix that can develop into cervical cancer).
Cryosurgery is also used to treat some types of low-grade cancerous and noncancerous tumors of the bone. It may reduce the risk of joint damage when compared with more extensive surgery, and help lessen the need for amputation. The treatment is also used to treat AIDS-related Kaposisarcoma when the skin lesions are small and localized.
Contraindications include organs (such as liver, lung) failure, bleeding diasthesis, disseminated cancerous disease.
Fig: Cryosurgery in open surgery of the liver; the exact localization of the metastases is carried out using intraoperative sonography.
Cryoablation employs extremely, low temperature to destroy cancerous tissue. It has been shown to be as effective as surgical, resection for treatment of cancer some parenchymal organs (such as liver, lungs and kidney).
Because cryoablation is a focal treatment, it has the advantage over surgical resection of being able to destroy only the necessary amount of targeting tissue while sparing more noninvolved tissue of organ. This is of particular importance to patients with hepatocellular carcinoma, because the majority of these patients have cirrhosis and compromised liver functions. By sparing more "normal" liver, the patients will have greater liver reserve.
Because of the warming effect of flowing blood,large blood vessels, such as the aorta,superior or inferior vena cava and portal vein,are impervious to the effect of freezing.,the Hence tumors close to these venous systems can be treated with cryoablation, whereas resection of tumors close to major vascular structures is not possible.
In contrast with ethanol injection or radiofrequency ablation, which are eligible only for small tumors, cryo, , ablation is possible for treatment of larger or small tumors. Using various caliber of probes or simultaneous placement of more probes, cryoablation can treat the tumor as large as more than 10 cm in size.
The treatment can be safely repeated and may be used along with standard treatments such as surgery, chemotherapy, and radiation.
Several studies found that after presumed curative resection, many patients will re-recur, and approximately 25% of these patients will re-recur with the liver alone. This phenomenon suggests that metastatic disease is present, although undetected, within the liver of many patients at the time of resection. Study showed that partial hepatectomy has been associated with the stimulation of growth of this residual tumor. Possible mechanisms for this phenomenon have been proposed including the detrimental effects of surgical manipulation, the generalized immunosuppression provoked by resection, and partial hepatectomy. Growth factors such as FGF-basic which are produced by the liver 48 h after partial resection may be the primary stimulus for residual tumor growth stimulation. It has been proved that an increase in survival after cryoablation of hepatic tumors in animals compared to controls that had undergone resection. Unlike partial hepatectomy, cryoablation of experimental liver cancer does not accelerate residual tumor growth in the liver or result in production of the growth factor FGF-basic. The lack of residual tumor growth stimulation may provide therapeutic benefit.
Cryosurgery does have side effects, although they may be less severe than those associated with surgery or radiation therapy. The effects depend on the location of the tumor.
Cryosurgery in the liver may cause damage to the bile ducts and/or major blood vessels, which can lead to hemorrhage (heavy bleeding) or infection.
Cryosurgery in lung cancer may induce pneumothorax and pleural effusion.
Cryosurgery for prostate cancer may affect the urinary system. Although it also may cause incontinence (lack of control over urine flow) and impotence (loss of sexual function), these side effects are often temporary.
When used to treat skin cancer (including Kaposi sarcoma), cryosurgery may cause scarring and swelling; if nerves are damaged, loss of sensation may occur, and, rarely, it may cause a loss of pigmentation and loss of hair in the treated area.
When used to treat tumors of the bone, cryosurgery may lead to the destruction of nearby bone tissue and result in fractures, but these effects may not be seen for some time after the initial treatment.
Cryosurgery is an important minimally invasive surgical technique. It can be potentially applied to any procedure in which scalpels are used to remove undesirable tissues. Currently, cryosurgery is being used in many medical fields, such as oncology, dermatology, gynecology, urology, neurology, pulmonary medicine, cardiology oncology and many others. Cryosurgery is also used in veterinary medicine. Imaging monitored cryosurgery has revived the field and numerous new applications are continuously emerging. With new applications came the need for better cryosurgical probes. It is anticipated that cryosurgery will become a standard technique in the minimally invasive surgeon armamentarium. To improve cryosurgery further, there is the need to develop a better fundamental understanding of the mechanisms of tissue damage during cryosurgery, to develop improved imaging techniques for cryosurgery, new and improved cryosurgical device technology and mathematical cryosurgery optimization techniques.