Though initially introduced in the 19th century, cryoablation entered mainstream clinical medicine in the mid-1960s.1 Because of technical limitations, however (i.e., large-bore probes to accommodate the large gas flow required and to facilitate adequate heat exchange), its applications were limited in the operative setting. In the last few years, as technology spawned the introduction of thinner cryoprobes (down to 14-gauge), image-guided, percutaneous cryoablations have carved out an ever-expanding niche. Currently, cryoablation is extensively used in the treatment of prostate cancer and renal cancer (either during open surgery or laparoscopically). Image-guided percutaneous cryoablation is mostly used for the treatment of small renal cancers and for the palliation of painful bone lesions. To a lesser extent, it is also used for the treatment of primary and secondary liver and chest neoplasms.
The technical goal of cryoablation is to reduce the temperature of the target tissue as well as an appropriate surrounding margin (equivalent to the surgical margin) to below lethal levels, without damaging vital nearby organs. For mammalian tissue, lethal temperature is below approximately −20° to −25°C (or −4° to −13°F). Cytotoxicity is mediated via various mechanisms, including ischemia, denaturing of protein structures, and the breakdown of cellular and intracellular membranes due to the formation of ice crystals. Some authors believe that the extracellular scaffolding structure is relatively preserved during cryoablation. This theoretically allows for the cellular repopulation of the tissue, which may explain why cryoablation is more forgiving, compared with radiofrequency ablation (RFA), in cases of nontarget ablation.
♦ The Physics of Cryoablation
The objective of cryoablation (kryo = “cold” in Greek; and ablatus = “to carry away” in Latin) is to reduce the temperature of the target tissue to below the lethal −20°C. This requires a continuous removal of energy from the entire target tissue. There are three ways that thermal energy may be transferred from one volume to another: (1) by conduction, the transfer of energy (or heat) from an object to a another at a lower temperature by virtue of physical conduct (direct molecular kinetic energy exchanges); (2) by convection, the transfer of energy (or heat) from an object to another at a lower temperature, with one of the objects being a flowing fluid (thus providing a continuously refreshed heat sink or heat source); and (3) by radiation, which removes radiant energy from all bodies above absolute zero temperature. No significant radiation losses are observed in our case; therefore, we can concentrate on conduction and convection (Fig. 2.1).
Conduction is a steady-state transfer because (in our case) it depends only on the temperature difference, which is relatively stable (i.e., tissue temperature [37°C] versus probe temperature [approximately −140°C]). On the other hand, convection depends on the flow rate of the blood through or adjacent to the volume of interest. Therefore, large-diameter arteries or very vascular tissues, to a lesser degree, will limit the extent of cryoablation. The reverse of this phenomenon (cooling of tissue by nearby flowing blood) has been termed “heat sink” in the case of thermal ablations (such as RFA or microwave ablation).
One advantage of cryoablation over RFA and microwave ablation is that the tissue energy transfer characteristics do not appreciably change with temperature. In contrast, in the case of RFA, tissue desiccates at high temperature and no further transfer of energy is possible. Irrespective of the tissue temperature, further temperature reduction is always theoretically possible with cryoablation.
The removal of energy (cooling) from the tissue surrounding the cryoprobe is effected by the Joule-Thomson law.2 During gas expansion two opposing mechanisms take effect. First, as intermolecular distances increase with cooling, the potential energy stored between molecules increases. Because total energy must be conserved, this translates into lower molecular kinetic energy and therefore lower temperature. Second, as intermolecular distance increases, however, fewer molecular collisions result in a relative decrease in potential energy stored between molecules. Again, because total energy must be conserved, this results in greater molecular kinetic energy and therefore greater temperature. Which of the two competing mechanisms dominates depends on the so-called inversion temperature of the gas, which is an intrinsic property. For argon, nitrogen, or oxygen, the inversion temperature factor is greater than room (or ambient) temperature and the first mechanism dominates. For helium and hydrogen, the inversion temperature is less than room temperature. Therefore, expansion of compressed argon, nitrogen, or oxygen causes cooling, whereas expansion of helium or hydrogen causes warming.
The gas is supplied by a gas tank to the probe via a pressure regulator (Fig. 2.2). Gas expansion occurs within the dual chambered cryoprobe (Fig. 2.3). The gas, once it expands, cools, absorbs thermal energy from the surrounding tissues, and is siphoned back through the tubing and eventually released into the atmosphere. The diameter of the “ice ball” depends on the rate of energy transfer, which in turn depends on the flow rate of the cooling gas through the probe. The length of the ice ball mostly depends on the uninsulated length of the probe (Fig. 2.4).
It is worth repeating that the lethal temperature for mammalian tissue is −20°C or colder. This does not correspond to the visible margin of the ice ball as seen under computed tomography (CT), ultrasound (US), or magnetic resonance (MR) guidance, which is at 0°C. Studies have shown that the −20°C isotherm is at least 5 mm inside the 0°C isotherm.3
♦ Ablation Systems
There are currently two U.S. Food and Drug Administration– approved cryoablation systems available in the United States, which at the time of writing of this chapter were in advanced merger discussions. Both systems, Endocare and Galil, make use of the above basic physical properties of the gases, and both utilize argon for freezing and helium for thawing. This may change in the near future as technologic advancements may allow the reintroduction of a single gas cooling-thawing system using nitrogen.
With the Endocare (Irvine, CA) system, there are four cryoprobe types available for use, differing in the shape and size of the generated ice ball (Fig. 2.5). Probe selection depends on the size and shape of the target lesion. For example, a 1-cm lesion in a difficult-to-access location is best approached with the Perc-15 probe. In general the Perc-24 is the workhorse probe for this system, as it yields the largest ablation zone. The respective isotherms for each probe are graphically shown in Fig. 2.6. Endocare also provides a percutaneously inserted temperature sensor (Fig. 2.5). This may be useful in rare instances when the temperature near a nontarget organ needs to be monitored.
The Endocare regulator is shown in Fig. 2.7. The regulator is composed of gas inlet hookups (argon and helium in); gas outlet hookups (argon, helium out); the internal regulator design; the control panel; and the screen, which can display the readings from up to eight cryoprobes and eight temperature sensors.
The Galil (Yokneam, Israel) Seednet and Presice regulators (which have the capacity to utilize and monitor up to five cryoprobes simultaneously) are shown in Fig. 2.8. The design of the cryoprobes differs slightly from that of Endocare’s in that they are a thinner (17-gauge) (Fig. 2.9). Four cryoprobes are available—the IceBulb, the IceRod, the IceSphere, and the IceSeed—which differ in the shape and size of the ice ball generated. The Galil cryoprobe isotherms are shown in Fig. 2.10 and sample ice balls are depicted in Fig. 2.11. As with Endocare, the choice of the number and type of cryoprobes depends on the size and shape of the target lesion. The operator must “sculpt” an ice ball by placing the appropriate number and type of probes at such angles with respect to each other so that the resulting ice ball covers the entire target lesion as well as a 5-mm margin, at least. For detailed temperature monitoring, Galil provides specific temperature sensors (Fig. 2.12), as the cryoprobes themselves do not have incorporated thermocouples. These sensors can be placed between the target lesion and nontarget organ to monitor the temperature near the nontarget organ, or in or near the target lesion to monitor the effectiveness of cryoablation. They are capable of providing real-time temperature measurements at multiple points, that is, at 5, 15, 25, and 35 mm from the tip.
The ablation protocols have been developed mostly based on empirical observations. Deviations from the protocols should be discouraged unless patient safety is compromised in not doing so. For example, an expanding ice ball that threatens to invade the nearby bowel may precipitate either early termination or reduction in the power of the closest probe, if more than one is used. Cell death is precipitated not only by the low temperatures but also by the effects of rapid cooling, thawing, and recooling, which result in ice crystal formation and cell membrane disruptions. Cooling for longer than the protocol recommends does not appreciably increase the size of the ice ball as the system approaches a plateau along the heat exchange curve as explained in the physics section above. Similarly, applying more than the recommended ablation cycles does not appreciably increase the cytotoxic effect of the ice ball.
Endocare Equipment Setup
Step 1: Connect gas tanks to regulator via high-pressure tubing.
Step 2: Turn on the regulator.
Step 3: Open the gas tank valves.
Step 4: Connect the cryoprobe(s) to the regulator. Connect both the gas flow tubing and the integrated thermocouple cable for each cryoprobe.
Step 5: With the cryoprobe immersed in saline, press “freeze” for 2 to 3 seconds and ensure that the probe is working and that there is no gas leak from it.
Step 6: Thaw the probes to above 10°C.
Step 7: Insert the probes and perform the ablation (see protocol below).
Step 8: Thaw to above 10°C and remove the probes.
Step 9: Record the residual gas tank pressure.
Step 10: Turn off the gas tank valves.
Step 11: Bleed the regulator (follow the on-screen instructions after pressing shutdown).
Step 12: Disconnect and discard the probes.
Step 13: Turn off the regulator.
The protocol is set irrespective of the location, type, and number of probes or the location, size or kind, of tumor. It consists of a 10-minute freeze, followed by an 8-minute thaw and another 10-minute freeze, of all probes simultaneously. Some authors support the notion that the thaw cycle should be active (helium circulates) and not passive (no gas circulation) because faster thawing may improve the cytotoxic effect of cryoablation. In theory this is correct; however, prior to the second freeze cycle the location of the probes must be verified as they may have moved during active thawing.
Galil Equipment Setup
Step 1: Connect the gas tanks to the appropriate inlet valve on the back of the Presice regulator. Make sure the safety clip (one for each line) is also attached.
Step 2: Open the gas tank valves.
Step 3: Power up the regulator.
Step 4: After matching the digital pressure readout, insert the GoldCard and activate the “Start Procedure” icon.
Step 5: Follow instructions ensuring the displayed information corresponds to the procedure details:
A: If the probe and the procedure are correct, activate “Continue.”
B: If the thaw setting is correct activate “OK,” otherwise move the switch on the back 180°.
Step 6: Connect the probe.
Step 7: Test the probe in sterile saline or water, as above.
Step 8: Perform the ablation.
Step 9: Thaw to above +10°C and remove probe(s).
Step 10: Record the residual gas tank pressure.
Step 11: Turn off the gas tank valves.
Step 12: Bleed the Presice regulator.
Step 13: Disconnect and discard the probe(s).
Step 14: Turn off the regulator.
As in the case of the Endocare, the protocol is conserved. Deviations from the ablation protocol are only necessary to ensure safety. If, for example, the ice ball reaches a nontarget organ and no other thermoprotective maneuver is available, then the ablation time can be shortened. In the case of the Galil, the protocol consists of a 10-minute freeze, followed by a 5-minute thaw, and finally a 10-minute refreeze.
♦ Clinical Practice
Cryoablation theoretically can be used in any part of the body; however, its specific risks and benefits must be weighed against those of other ablation modalities. Lung cryoablation is possible and occasionally necessary (Fig. 2.13); however, one has to contend with a slightly higher risk of pulmonary hemorrhage compared with doing RFA. This can be clinically significant in patients with severe chronic obstructive pulmonary disease, who represent a good portion of the patients with primary lung cancer referred for ablation. In general, cryoablation for peripheral, pleura-based lesions is safer than for central ones. In addition, cryoablation for pleura-based lesions is essentially painless, in contrast to RFA. Primary and secondary liver cancer (Fig. 2.14) can be treated with cryoablation with probably similar efficacy and safety to that of RFA, though there is vastly more published data on the latter. The efficacy of cryoablation is affected by nearby large vessels, a phenomenon whose RFA counterpart is termed “heat-sink” effect. Blood vessels larger than 3 mm in diameter are known to affect the geometry of the ice ball. In such cases, additional probes, or even balloon occlusion of a hepatic vein (if this is the culprit), may be necessary. The most commonly treated tumor with cryoablation is renal cell carcinoma (Fig. 2.15), and it is also the one with the most published efficacy and safety data. The use of cryoablation for metastatic disease is not common, and its use should be limited to three indications: (1) in cases where tumor cytore-duction has been shown to improve survival (i.e., oligometastatic colon, breast, or renal cancer); (2) for the palliation of painful metastatic foci (Figs. 2.16, 2.17, 2.18, 2.19, and 2.20); or (3) to treat a metastasis whose further growth is expected to result in significant symptoms.
- The lethal temperature is below −20°C.
- The visible ice-ball margin on CT demarcates the 0°C isotherm, which is not lethal. At least a 5-mm cryoablation margin beyond the target is thought necessary to ensure target ablation.
- An expanding gas cools if its inversion temperature is greater than the ambient temperature and warms if its inversion temperature is lower than the ambient temperature. This is termed the Joule-Thomson law or effect. This is why some gases cool (e.g., argon), whereas others warm (e.g., helium) on expansion.
- “Cryoshock” refers to cardiopulmonary collapse after a seemingly uneventful cryoablation. It is a diagnosis of exclusion, and the risk increases with increasing patient age, increasing size of ice ball, and preexisting cardiac or pulmonary disease. The risk is mitigated by staging the procedure and avoiding large-diameter ice balls.
- There is no advantage or disadvantage in using Endocare over Galil or vice versa. Therefore, the operator’s experience is the defining factor for safety and efficacy.
- It is better to err on the side of using more cryoprobes than to have to re-treat a residual tumor. Two probes placed at the margins of the target mass are far better than one probe going right through the mass’s center, even if the single probe’s ice ball theoretically covers the mass.