Evaluation of Immediate Treatment Response

The immediate response to any type of percutaneous ablation procedure is generally assessed with contrast-enhanced US (CEUS), enhanced spiral CT, or T2-weighted MRI—the gold standards for this purpose (Chen et al, 2007; Cioni et al, 2001). The presence at the ablation site of a well-defined, nonenhancing area as large or larger than the treated tumor itself is regarded as reliable evidence of a complete response, or complete radiologic necrosis. The timing of the imaging study is important. CEUS examinations performed too soon after ablation are characterized by numerous artifacts caused by gases produced during ablation or the diffusion of chemical substances within tissues surrounding tumor. Under these circumstances, it is impossible to distinguish the origin of the hyperechoic signals. If CEUS, CT, and MRI are performed in the days following the ablative procedures, it is impossible to determine whether the peripheral enhancement observed is due to residual tumor tissue or the hyperemic/inflammatory response of the liver parenchyma. This enhancement is a result of inflammatory tissue response, and it resolves within a month of tumor ablation. Therefore the persistence of an enhancing rim after this point must be considered evidence of residual tumor viability. For these reasons, the contrast-enhanced imaging studies should be scheduled at least 4 weeks after the procedure. If the results of this study are ambiguous, US-guided FNB can resolve the problem (Rossi et al, 1998).

Evaluation of Long-Term Results

Abdominal US/CEUS studies and tumor marker assays are performed every 4 to 6 months, or even more frequently if needed. Local recurrence is diagnosed when enhancement reappears within the ablation zone or within 2 cm, 1 cm according to some authors, from its margins, or when there is histologic evidence of tumor viability in this area (Berber et al, 2005). If the ablation zone remains unenhanced but fails to shrink during follow-up, or when levels of tumor markers are elevated in the absence of other intrahepatic or extrahepatic lesions, focused US-guided biopsy of the ablation zone is indicated. Nonlocal recurrence comprises extrahepatic metastases and all new intrahepatic regrowth located more than 2 cm from the ablation zone.

Physical Principles

Direct injection of ethanol into a tumor results in its distribution in the tissue by diffusion and convection. Diffusion is favored by the existence of a concentration gradient between the injection point and the surrounding tissues, by the low molecular weight of the ethanol, by the increase in local pressure determined by the injection, and by the hypervascularity of the tumor (Ho et al, 2007). Ethanol spreads through the tumor tissue, exerting cytotoxic effects that include cytoplasmic dehydration and denaturation of cellular proteins. The endothelial cell necrosis and platelet aggregation it causes occlude tumor vessels and produce ischemic damage in the neoplastic tissue (Shiina et al, 1991; Ebara et al, 1995). The final result is coagulative necrosis within the tissue around the site of injection.

Technique

PEI is usually performed on an outpatient basis. Patients are treated after an overnight fast. Prophylactic antibiotics are not usually administered, and in most cases, general anesthesia is unnecessary, but in some centers, anxious patients are moderately sedated.

The procedure is performed under real-time US monitoring. The ethanol is usually injected with a 20- to 22-gauge endhole needle (Chiba or Chiba-like) or a conical-tip needle with multiple sideholes (Livraghi et al, 1995). The tip is positioned at the desired point in the HCC nodule with the aid of real-time US guidance, and the predetermined amount of ethanol is infused slowly into the tumor. After few seconds, the HCC nodule becomes completely hyperechoic. Light aspiration is applied during withdrawal to prevent excess ethanol from leaking into the peritoneum through the insertion tract. If all goes well, the patient is kept under observation for about 2 hours.

The volume of ethanol required to ablate a tumor nodule depends on the size of the tumor, but the final decision on the total dose is based on the results of imaging studies performed at the end of each session (Livraghi et al, 1995; Shiina et al, 1991).

An alternative to this multiple-session approach is one-shot PEI. As the term implies, the total amount of ethanol required for the ablation, based on the calculations reported above, is injected during a single session (Giorgio et al, 1996; Livraghi et al, 1993). This technique has been proposed for HCCs with diameters exceeding 3 cm. It is more painful than conventional PEI and is therefore performed under general anesthesia. In one study, the amounts of ethanol administered with this technique ranged from 20 to 165 mL (mean, 62 mL).

Physical Principles and Technique

After ethanol, the most widely used agent for chemical ablation is acetic acid. In vitro studies have shown that it dissolves lipids and extracts collagen from various kinds of tissues (Ho et al, 2007). Compared with ethanol, acetic acid offers certain advantages, including more effective destruction of tumor septa and capsules. In addition, the same degree of cell kill can be obtained with a smaller infusion volume (Ohnishi, 1998).

The technique of PAI is quite similar to that of PEI. The infusion consists of a 50% solution of acetic acid and sterile water injected with the same technique and needles used for ethanol. Observations in animal models and clinical explants indicate that the volume of acetic acid needed to ablate a tumor nodule is roughly one third of the volume calculated with the formula used for ethanol: ablation of a nodule measuring 3 cm in diameter would require 34 mL of ethanol but only 11.3 mL of acetic acid (Giorgio et al, 2000).

Physical Principles

Radiofrequency (RF) energy generates heat in the tissue that is in direct contact with the noninsulated tip of the needle electrode (McGahan et al, 1990; Rossi et al, 1990). The heat is the result of ionic and molecular friction, and it spreads into the surrounding tissues by a process of conduction. The highest temperatures are created in the tissue immediately adjacent to the electrode tip, and the heat rapidly decreases as the distance from the tip increases. Permanent tissue destruction occurs at temperatures of 45° C or higher (Cosman et al, 1983; Organ, 1976). Temperatures ranging from 46° C to 60° C produce irreversible cellular damage only after relatively long periods of exposure. In contrast, temperatures between 60° C and 100° C cause almost instantaneous protein coagulation with irreversible damage to mitochondria and cytosolic cell enzymes. When temperatures exceed 100° C, tissue fluids undergo boiling, vaporization, and ultimately carbonization. The final size of the thermal lesion, an area of coagulative necrosis that is gradually replaced by fibrotic tissue, depends on the total amount of heat deposited in the tissue, the thermal and electrical conductivity of the tissue, and the amount of heat lost through convection; specifically, it depends on heat lost through local blood flow, which acts as a heat sink. Tissue impedance limits the amount of heat that can be introduced into a tissue. It is inversely related to tissue hydration, which in turn reflects the ion content of the tissue (Djavan et al, 1997). During RFA the ions are quickly destroyed, and the tissue undergoes desiccation and charring, and the resultant increases in impedance ultimately prevent further delivery of RF energy.

Conventional RF electrodes used in the monopolar mode produce thermal lesions with a maximum diameter of about 1.8 cm (Rossi et al, 1996). Consequently, the ablation of a relatively small HCC nodule requires the creation of multiple, overlapping lesions. This used to mean multiple needle insertions and multiple treatment sessions; however, second-generation RF electrodes produced thermal lesions with diameters as large as 3 cm, and the volume of tissue that could be ablated with a single pulse of energy increased exponentially. These advances were achieved by increasing the active surface area of the electrode with a set of retractable hooks or prongs (expandable-tip electrodes; Rossi et al, 1998) or by cooling the electrode tip by means of an internal water-circulation system (cooled-tip electrodes) (Goldberg et al, 1998b). The expandable electrodes allow the delivery of larger amounts of RF energy, because rapid charring is less likely when the volume of tissue to be dehydrated is large. Cooled-tip electrodes achieve the same result by preventing temperatures rising above 100° C in tissues adjacent to the active surface of the electrode. The heat dissipation prevents charring and keeps impedance low, thereby allowing the delivery of larger amounts of RF energy. Larger thermal lesions, those 4 cm or larger, have also been produced with multiple cooled electrodes combined in a cluster (Head & Dodd, 2004), cooled catheter electrodes, and expandable spiral electrodes (Rossi et al, 2006).

Other investigators have attempted to increase thermal lesion volumes by reducing convectional heat loss during the RF procedure (Goldberg, 1998a; Patterson et al, 1998; Rossi, 1999). HCCs are supplied almost exclusively by vessels arising from the hepatic artery (Breedis & Young, 1954); however, when RFA was performed after balloon-catheter occlusion of the hepatic artery, the thermal lesions produced were large as expected on the basis of experimental studies; when RFA was performed after embolization of the feeding arteries with gelatin sponge particles, the thermal lesions produced were larger than expected (Rossi et al, 2000). With this approach, in fact, HCC nodules more than 6 cm in diameter could be treated in a single RF session.

Low impedance during the procedure explains the unexpectedly large thermal lesions. Occlusion of the tumor’s arterial supply with gelatin sponge particles reduces impedance in at least two ways: First, it increases the hydrostatic pressure within the HCC (Rossi et al, 2007). As a result, the boiling point of tissue fluid is higher during the thermal ablation procedure, which prolongs the delivery time and allows more energy to be deposited in the tissue, before desiccation and charring occur. Second and more importantly, a gelatin sponge is a hydrogel capable of modifying the electrical and thermal conductivity of the tissue; its presence in the ablation area markedly increases the amount of RF energy that can be delivered.

It is important to recall that liver METs are more difficult to destroy with thermal energy than HCCs. For one thing, the absence of a capsule prevents the buildup of intranodular pressure that occurs in HCCs; therefore less energy can be deposited within a MET, compared with encapsulated HCCs, with a given electrode at a given power setting. More importantly, metastatic lesions are characterized by actively proliferating tissue at the periphery and a devascularized center, and these characteristics create an inhomogeneous field in terms of impedance and conductivity, both thermal and electrical. Further studies are needed to evaluate the behavior of electromagnetic energy in a field of this type.

Technique

Patients undergoing RFA are hospitalized and treated after an overnight fast. In our department, most RFA procedures are performed without general anesthesia or conscious sedation, but some investigators prefer to perform the procedure under general anesthesia or deep sedation. A grounding pad is attached to the patient’s back and connected to the RF generator to close the electrical circuit. A local anesthetic (1% lidocaine) is injected along the predefined electrode insertion line, from the skin to the peritoneum. The skin is nicked with a small lancet to facilitate insertion of the electrode, and the tip is then advanced into the HCC nodule under real-time US guidance. The RF generator is activated, and the predefined amount of energy is delivered for 8 to 12 minutes. On US, the nodule becomes hyperechoic with a posterior acoustic shadow (Rossi et al, 1996). The pull-back technique can be used to create multiple thermal lesions along the major electrode axis (Rossi et al, 2000). At the end of the procedure, the electrode is withdrawn, but the generator remains on during this phase; this way, the electrode tract itself also undergoes coagulation, which diminishes the risks of bleeding and tumor seeding.

This technique can be used for HCCs up to 3.5 cm in diameter and for CRC liver METs with diameters of 2.5 cm or less. For larger tumors, other treatment strategies have been adopted. For HCC nodules whose diameters exceed 3.5 cm, RFA has been performed with a multiple-insertion technique (Livraghi et al, 2000), an expandable triple-spiral electrode (Rossi et al, 2006), clusters of cooled electrodes (Cheng et al, 2008), and combination of RFA with other techniques (Murakami et al, 2007). As discussed above, a larger volume of necrotic tissue can also be achieved by preablation embolization of the tumor with gelatin sponge particles. Some operators perform selective transarterial chemoembolization (TACE; see Chapter 83) of larger tumors after RFA debulking. The rationale of this approach is that the amount of embolic agent will be greater in the tumor tissue if its volume was previously reduced with RFA.

Complications

RFA is a safe procedure with very low rates of death and major complications. Tables 85A.2, 85A.3, and 85A.4 show the post-RFA complication rates observed in HCC or MET series reported by our group and others. Mortality rates ranged from 0% to 3.7%, whereas major complication rates were reported in 0% to 22%. Most of the adverse outcomes reported occurred in the initial clinical experiences, and fatal and nonfatal complications have become progressively less common with the increasing experience of the investigators. Indeed, in reports published during the last 5 years, mortality rates are consistently close to 0%, and major complication rates range from 0% to 10%. The complications described include abdominal hemorrhage, hepatic abscess, pleural effusion, hepatic infarction, bronchobiliary fistula, bile peritonitis, biloma, hemobilia, thrombosis of vessels in the hepatic venous system, skin burn, and perforation of the stomach, intestine, or diaphragm. Table 85A.4 shows the complications observed by our group over the last 10 years. This series includes 706 patients with 859 HCC nodules and no procedure-related deaths, which is consistent with previous reports. Less than 1% of the procedures were associated with major complications, a percentage similar of those reported after percutaneous injection therapies. The most serious adverse effect in our series involved shearing of a branch of the hepatic artery; however, all cases were promptly detected by Doppler US studies and controlled by selective embolization of the damaged vessel. Our patients receive neither general anesthesia nor sedation, and the most frequent complication is therefore mild to moderate pain during the procedure that occurs in about 30% of all patients. The pain is easily managed with intravenous analgesia and disappears entirely shortly after the procedure. Use of local, rather than general, anesthesia has several advantages, and this approach is now used by most operators. For one thing, it simplifies the procedure and reduces the cost. More importantly perhaps, it reduces the risk of extrahepatic complications such as perforations of intestinal loops, diaphragm, and gallbladder. The frequency of these events obviously depends on the operator’s skill and experience, but conscious patients can report severe pain, which almost inevitably reflects incorrect electrode placement; indeed, a conscious patient can provide important feedback that can prevent major organ damage.

Table 85A.4 Complications in Patients with Hepatocellular Carcinoma after 1921 Radiofrequency Ablation Sessions

* It is not possible to define the origin of seeding (radiofrequency ablation vs. ultrasound-guided biopsy).

A 12% seeding rate was reported by a Spanish group during their initial experience with RFA (Llovet et al, 2001). The results contrast with those of other studies, and they may be a reflection of poor technique. Seeding along the electrode tract is virtually impossible, if the electrode is activated before and during each withdrawal. If the recommendations made in the Technique section are followed, the electrode tract itself undergoes coagulation, produced by the gases that develop during the procedure or by the heat generated by the activated electrode during its withdrawal. Our group, in fact, has observed only two cases of subcutaneous tumor seeding after a total of 1921 RFA sessions, and in both cases, it is impossible to say whether the seeding was actually caused by the RFA or by previous US-guided biopsies.

When RFA is performed during or after TAE, other complications are also possible (Rossi et al, 2000). Sporadic cases have been reported of chemical cholecystitis and intimal dissection of the hepatic artery. All patients experience transient increases in serum aminotransferase levels, but baseline values are generally restored within a week. Some patients also display transient declines in liver function reflected by CTP scores, but these changes rarely last more than 2 weeks.

Local Tumor Control

Histologic examination of whole livers from transplant recipients who had previously been treated with RFA shows that more than 80% of HCCs measuring less than 3 cm are completely destroyed with a single RF electrode insertion (Mazzaferro et al, 2004). Complete response rates ranging from 95% to 98% have been documented in several studies; however, in numerous series of cirrhotic patients with small HCCs treated with RFA, the local recurrence rates range from 0% to 45%, as shown in Table 85A.5. In our series of 859 HCC nodules with maximum diameters of 3.5 cm, the overall local recurrence rate after a 10-year follow-up was 15.7%. The recurrence rate was 5.2% for nodules up to 2 cm in diameter, 12.7% for those with diameters of 2.1 to 3 cm, and 21% for those measuring 3.1 to 3.5 cm; however, in more than 70% of these cases, complete and persistent ablation of the recurrent disease was achieved with a single additional “clean-up” RFA session. This brought the overall local control rate close to 94%, obtained with one treatment in 82% of the cases and with two treatments in 12%.

As shown in Tables 85A.5 and 85A.6, similar complete response rates have been reported for RFA of CRC liver METs, but the recurrence rates in these cases are higher, ranging between 8% and 40%. These results are probably due in part to the use of RFA to treat METs that are too large for this type of ablation. Given the characteristics of metastatic tissue discussed above, percutaneous RFA with curative intent should probably be reserved for METs with diameters no larger than 2.5 cm. If larger METs are treated with this method, local recurrence must be expected in more than 30% of the cases.

Long-Term Results in Hepatocellular Carcinoma Patients

The long-term results reported after RFA treatment of HCCs are summarized in Tables 85A.5 and 85A.6. In our own RFA series, cumulative disease-free and overall survival was similar to those observed by others after RFA, percutaneous injection therapy, or surgical resection. Meaningful comparison of the mortality data and survival curves reported after surgical and nonsurgical treatment of HCC is virtually impossible, because only perfunctory descriptions are provided of recurrences occurring after the initial treatment. Most reports simply do not mention the characteristics of first recurrences (location, extension, etc.), how this recurrence was managed (with the same method used to treat the original tumor or with one or more other techniques), or the outcome of the treatment; even fewer details are provided on subsequent episodes of recurrence. Comparison of results reported for surgical and nonsurgical series is further complicated by the fact that cases of tumor understaging and/or positive resection margins are generally excluded from analyses of survival in surgical series, whereas cases of this type—understaged disease, tumors with persistent viability after two treatments—are usually included in the nonsurgical series (Hanazaki et al, 2000; Helling & Woodall, 2007; McCormack et al, 2005; Shimozawa & Hanazaki, 2004; Torzilli et al, 1999).

Randomized controlled studies have demonstrated that RFA is superior to chemical ablation methods in terms of both local tumor control and survival (Bouza et al, 2009; Brunello et al, 2008; Orlando et al, 2009). These findings suggest that, when possible, RFA should be the first choice for nonsurgical ablation of HCCs. RFA was also directly compared with surgical resection in two randomized clinical trials, and neither revealed any significant differences between the local tumor control or survival rates associated with the two approaches (Chen et al, 2006; Lu et al, 2006).

Recently, HCC nodules with diameters larger than 3 cm have been treated with a cluster of cooled RF needle electrodes and a multiple-insertion technique (Goldberg, 1998a). Complete responses were observed in 61% of the nodules up to 5.0 cm in diameter and in 24% of larger nodules. These results were to be expected, because tumor volume increases exponentially with its diameter, and larger diameters are also associated with higher frequencies of daughter nodules, capsule infiltration, and neoplastic thrombosis of the portal vessels close to the tumor. Better results have been obtained with more conventional RFA electrodes during gelatin-sponge occlusion of the hepatic artery flow (see Physical Principles below). A complete response rate of 82% was achieved with this approach in 62 HCC nodules, with a mean diameter of 5.6 cm. The local recurrence rate was 19%, and the overall intrahepatic recurrence rate was 45% at 1 year (Rossi et al, 2000). RFA is now recognized as a potentially curative treatment for HCC nodules up to 3 cm in diameter, and some investigators maintain that it should be considered the treatment of choice for these cases (Choi et al, 2007; Livraghi et al, 2008; Shiina, 2009).

Long-Term Results in Patients with Metastases

Table 85A.6 shows the long-term results of RFA for resectable and unresectable CRC liver METs. Survival rates range from 33% to 46% at 3 years and from 22% to 30% at 5 years (Abdalla et al, 2004). These rates are worse than those reported after surgical resection, but it is important to recall that surgery is used in a more select population with fewer risk factors for mortality. RFA can now be considered an approach capable of improving survival in patients with limited but inoperable metastatic liver disease (Otto et al, 2010; Seidenfeld et al, 2002). RFA alone or combined with resection has also proved to be superior to other nonsurgical therapies in patients with multiple liver METs (Abdalla et al, 2004). Finally, some investigators suggest that RFA can be used as a part of a “test of time” approach. Use of RFA as the first option for limited hepatic METs would reduce the need for surgical resections by producing complete and persistent tumor necrosis in some patients. In others, RFA would be followed by new intrahepatic and/or extrahepatic METs, which means that surgery would have been a useless ordeal for the patient. And in a few, post-RFA recurrence will be limited to local regrowth at the site of the ablated MET, and in these cases, surgical resection may prove worthwhile (Livraghi et al, 2003a).

Physical Principles

The term microwave (MW) refers to electromagnetic radiation with frequencies ranging from 900 to 2450 MHz. MW radiation is emitted by the tip of a bipolar antenna electrode placed within the tissue. Microwaves cause rapid vibration and rotation of water molecules within the tissue, which immediately generates frictional heat that persists for the duration of energy delivery. The uniform distribution of this heat in all directions results in coagulative necrosis, and charring near the tip of electrode limits further heat diffusion in the tissue. The thermal lesions produced are spherical to elliptical in shape. Their diameters vary with the power delivered, the electrode caliber, and exposure time. With a 14-gauge electrode, a power output of 60 W, and an exposure time of 120 seconds, the maximum and minimum diameters of the thermal lesions were 2.4 ± 0.4 cm (length) and 1.6 ± 0.3 cm (width). Corresponding diameters achieved with 30 minutes at 40 W were 3.6 cm (length) and 2.6 cm (width) (Seki et al, 1994).

Technique

The technique of MWA is quite similar to that described above for RFA (Seki et al, 1994). Percutaneous MWA is usually performed as an inpatient procedure after an overnight fast. General anesthesia or deep sedation is induced, and a thin (14- to 16-gauge) MW antenna is advanced directly into the tumor nodule under US guidance. The antenna is connected to the MW generator, which is activated to deliver 60 to 90 W of power. Delivery times vary from 2 to 30 minutes, depending on tumor size. In general, tumors less than 2 cm in diameter can be ablated with one or (more commonly) two electrode insertions; for larger tumors, multiple insertions are necessary. The same precautions described for RFA apply to MWA. The changes revealed by US consist of the appearance around the tip of the electrode of a hyperechoic area with a posterior acoustic shadow. This zone increases in size with exposure time and ultimately involves the entire tumor. The hyperechogenicity diminishes rapidly after the generator is switched off and disappears completely within 8 hours of the procedure.

Complications

The complications reported after MWA are quite similar to those listed above for RFA. Table 85A.7 shows the mortality and complication rates observed in the various published series. Mortality ranged from 0% to 8.3%, and complication rates from 2.6% to 14% were reported.

Local Tumor Control

MWA can produce complete tumor necrosis. Histologic examination revealed no viable tumor in 180 (92.3%) of 192 treated HCC nodules that were biopsied after MWA and in 5 (90%) of 6 HCC nodules that were surgically resected after MWA (Seki et al, 1999). None of these nodules were more than 3 cm in diameter. For HCCs of this size, the complete ablation rate is reportedly quite good, more than 90%, but it is significantly lower for larger tumors. The local recurrence rates reported by several investigators after MWA of hepatic tumors ranged from 2% to 37%, as shown in Table 85A.8.

Long-Term Results

Several clinical studies have investigated the usefulness of MWA in the treatment of HCC. The long-term results observed in these studies are summarized in Table 85A.8. The overall survival rates 3 years after the procedure ranged from 50.5% to 90%, and at 5 years from 17% to 70%. The Fifteenth Nationwide Follow-up Survey conducted by the Liver Cancer Study Group of Japan found 1-, 2-, 3, and 5-year survival rates of 94.2%, 84%, 72.9%, and 44.1%, respectively, in 1751 patients whose HCC had been treated with MWA (Ikai et al, 2004). The effectiveness of MWA and that of RFA have also been compared in randomized trials (Ohmoto et al, 2009; Shibata et al, 2002). No statistically significant differences were observed between the two treatment methods in terms of local efficacy, but RFA tended to be associated with slightly better local recurrence and complication rates; however, since RFA was introduced in 1999, use of MWA has steadily decreased, even in centers where it was once widely used (Shiina et al, 2002).

Limited data have been reported so far concerning the long-term results of MWA of liver METs (see Table 85A.8). Some investigators have reported promising results in their initial experience with several types of primary tumors (Abe et al, 2005; Liang et al, 2003). In another randomized study comparing MWA and surgical resection in patients with multiple CRC liver METs, no statistically significant differences were observed in the survival rates of the two groups (Tanaka et al, 2006).

Collectively, the data cited above indicate that MWA is an effective method for the treatment of hepatic tumors. Its major limitation is the relatively small size of the thermal lesions it produces. To ablate most tumors, multiple overlapping lesions must be created; because this requires multiple electrode insertions, it is unlikely that percutaneous MWA will be widely used to treat hepatic tumors, unless equipment and electrodes can be modified to produce a larger zone of coagulative necrosis with small caliber electrodes.

Physical Principles

Laser light, which has a wavelength of 800 to 1064 nm, is delivered to the tissue through the tip of a bare, flexible, quartz laser fiber (300 to 600 µm in diameter) where it is scattered, reflected, and absorbed to varying degrees, depending on its specific wavelength and the specific optical properties of the tissue. The production of heat stems from interaction between the photons of low-intensity laser energy and molecular chromophores—hemoglobin, myoglobin, bilirubin, the cytochrome pigments in mitochondria, and so on—structures ubiquitous in human tissues. This distinguishes laser thermal ablation (LTA) from RFA and MWA, which produce heat by inducing ionic and molecular friction, but the results are the same: lethal thermal injury. Temperatures between 45° C and 55° C ultimately lead to cell death if the heating is persistent. In contrast, temperatures that exceed 60° C cause immediate and irreversible cellular death with protein denaturation, breakage of chemical bonds in DNA and RNA molecules, and loss of integrity in the lipid layers (Head & Dodd, 2004; Izzo, 2002).

Use of high-power laser energy results in vaporization and rapid tissue charring around the tip of the fiber. Although temperatures near the light-emitting portion of the laser fiber can range from 300° C to 1000° C, the presence of coagulated tissue around the tip drastically reduces the optical penetration of the light into adjacent tissues and thereby limits heat diffusion. As a consequence of overheating and charring, the areas of thermal necrosis produced with LTA are often less than 1 cm in diameter. If low-power laser energy is used, tissue heating occurs slowly, which decreases vaporization and tissue carbonization around the tip of the laser fiber. This approach produces a zone of radiant and conductive tissue heating that enlarges progressively, and the area of thermal necrosis ranges from 1.0 to 1.5 cm in diameter (Germer et al, 1998).

Obviously, the relatively small volume of LTA thermal lesions limits the clinical applicability of this thermal ablation technique. To overcome this problem, a variety of strategies have been proposed. The use of sapphire-tipped laser fibers significantly reduces the occurrence of carbonization at the fiber tip, but it does not significantly increase the size of the thermal lesions (Vogl et al, 2002). The use of interstitial fibers, quartz fibers with flat or cylindrical diffusers at the tip, reduces tissue carbonization and produces thermal lesions ranging from 2.3 to 5 cm in diameter (Khan, 2008). Cooled laser application sheaths, designed to reduce temperatures around the laser fiber tip, allow the use of higher power output without carbonization and produce larger thermal lesions (Vogl et al, 2002); however, diffusers increase the caliber of the laser fiber, and water-cooled sheaths require insertion of a coaxial dilation system introduced through an 18-gauge puncture. The beam-splitting multiple-fiber LTA device offers further improvement in thermal lesion size. Most of these systems use four parallel fibers positioned 1.5 to 2 cm from each other. The simultaneous activation of all four fibers produces a thermal lesion that is larger than the sum of the individual lesions produced by each fiber, because killing temperatures are also reached in the overlapping peripheral zones. This laser device can produce thermal lesions from 4 to 7 cm in diameter; however, positioning the multiple fibers in the tumor nodule is a highly complex procedure that requires training and a great deal of practice. In addition, even for skilled investigators, it is almost impossible to place the fiber tips correctly within the three-dimensional space, and in most cases, the thermal lesion produced will be irregularly shaped.

Technique

Like other thermal ablation methods, LTA can be performed percutaneously, laparoscopically, or during open surgery. The percutaneous technique is identical to those described above for RFA and MWA, and US is the technique most commonly used to insert the Chiba or Chiba-like needle into the tumor. When the needle tip is in the correct position, the laser fiber is passed through the needle and advanced, until its tip lies about 1 cm beyond that of the needle. Laser energy is then delivered for 6 to 10 minutes.

The appearance of the thermal lesions on US is the same as that described for other methods of thermal ablation. The technique used with the beam-splitting multiple-fiber laser device is basically the same, but it involves the placement four Chiba-like needles as guides for the four laser fibers. With single and multifiber techniques, the pullback technique can be used to create multiple lesions (Pacella et al, 2009).

Unlike other thermal ablation methods, LTA can be performed under the guidance of MRI. This approach allows real-time monitoring of the temperatures reached in the tissue undergoing ablation. Several MRI sequences have been evaluated for this purpose (Botnar, 1998; Matsumoto et al, 1994; Vogl et al, 1995). The simplest and most widely used is the T1-weighted sequence. The T1 values of a tissue decreases linearly with increasing temperatures (up to about 55° C). However, conventional MRI significantly limits access to the patient, so percutaneous insertion and placement of laser fibers is often done under US or CT guidance, and the patient is then transferred into the MRI scanner to monitor the treatment. This limitation may be overcome by the use of open MRI systems, which are becoming more and more common (Izzo, 2002).

Complications

The complications reported after LTA are also quite similar to those observed after the other percutaneous methods of thermal ablation. Table 85A.9 shows the LTA mortality and complication rates reported by several investigators. Mortality ranged between 0% and 0.8%, and complication rates were between 0% and 2%.

Local Tumor Control

LTA has been shown to be effective in producing complete ablation of tumor nodules, and as expected the probability of success depends on the size of the tumor. Increasing size is associated with decreasing rates of complete ablation; therefore all three major methods for thermal ablation can produce complete ablation in more than 90% of HCC nodules, as long as their diameters do not exceed 3 cm. As shown in Table 85A.10, the local recurrence rates reported by several investigators vary widely after LTA of hepatic tumors, from 2% to 37% (Eichler et al, 2001).

Long-Term Results

The long-term results of LTA of HCC and METs are summarized in Table 85A.10. In terms of survival, the best results were those of Vogl and coworkers (2004), who reported 3- and 5-year survival rates of 49% and 33% after LTA treatment of liver METs; however, the wide variability of the results and the limited number of reports make these data of limited value. Some investigators have reported promising 3- and 5-year survival rates after LTA of HCC (61% and 34%, respectively). On the whole, LTA is an effective method for treating hepatic tumors, but it has two major limitations: First, the small size of the thermal lesions obtained with a single laser fiber reduces the applicability of the technique and necessitates multiple treatment sessions to ablate most tumors. Second, the multiple-fiber technique is a much more complex procedure that requires a high degree of skill and experience. It also tends to produce irregularly shaped thermal lesions, therefore LTA technology needs to be improved before it gains worldwide use. At present, the available data on local recurrences and long-term survival are inadequate to allow any meaningful conclusions on the future of LTA.

Physical Principles

Cryoablation kills tumor cells by the induction of hypothermia rather than hyperthermia. The mechanisms underlying the cellular damage produced by cryoablation depend on the freezing rate. Rapid cooling near the cryoprobe tip produces an ice ball. Water molecules are trapped within the cells and are transformed into ice crystals, which aggregate and cause cell death.

Technique

Cryoablation has been practiced during open surgery for more than 40 years. Recently, needle-like cryoprobes 3 mm in caliber have been developed that can be used for percutaneous tumor ablation, which is generally performed under US guidance (Mala, 2006); general anesthesia is typically used, because the procedure lasts longer than 30 minutes. The tip of the cryoprobe is placed in the deepest part of the tumor under US guidance, and the freeze-thaw cycle begins. On US, the ice ball appears as an increasing hyperechoic rim with a posterior acoustic shadow. Multiple cryoprobes must be inserted to ablate tumors larger than 3 cm in diameter. In this way, ablation areas larger than 5 cm in diameter can be created (Bilchik et al, 2000).

Complications

Cryoablation is associated with a higher rate of complications than other thermal ablation techniques (Seifert & Morris, 1999). One event that is peculiar to this type of ablation is cracking of the liver parenchyma, resulting in hemorrhage. Another typical complication is a syndrome known as cryoshock, which involves pulmonary, renal, and coagulation abnormalities in a variety of combinations (Head & Dodd, 2004). The severity varies, and the syndrome may include diffuse intravascular coagulopathy. Severe hypothermia can occur with either intraoperative or percutaneous cryoablation, and this can be lethal when the tumor being treated is large (Sarantou et al, 1998). Other complications are similar to those reported for the other thermal ablative methods. Table 85A.11 shows the mortality and complication rates reported by several investigators after cryoablation of hepatic tumors; they range from 0% to 4% and from 1.5 % to 29%, respectively.

Local Tumor Control

Cryoablation can completely destroy hepatic tumors, but the complete response rates, as shown in Table 85A.12, are lower than those reported for RFA or MWA. Local recurrence rates (6.4% to 58%) also seem to be higher than those observed after RFA.

Long-Term Results

In several centers, cryoablation has been used to destroy liver tumors, for the most part liver metastases from CRC. Only limited initial experiences have been reported for HCC, but for these tumors, RFA has surpassed cryoablation in terms of local tumor control (Adam et al, 2002). The long-term results documented in several studies are shown in Table 85A.12, but these data are characterized by a degree of variability that precludes any meaningful assessment of the efficacy of cryoablation.

The major drawbacks of cryoablation are the large caliber of the cryoprobes, which are not suitable for percutaneous insertion, and the long exposure times required to ablate even small tumors. These aspects need to be substantially improved before cryoablation can compete with the other thermal ablation methods.