Introduction

It is widely admitted that surgical resection is nowadays the only curative treatment of liver malignancies, whether primary or secondary. Liver resection can be partial or total, when followed by orthotopic liver transplantation particularly in selected cases of hepatocellular carcinoma(1). However, tumors are amenable to curative resection in only 10% to 20% of patients, with 5year survival of 25% to 39% in cases of liver colorectal metastases and in 12% to 39% for hepatocellular carcinoma (HCC)(2). The main reasons that preclude resection are multiple tumors involving both lobes, poor liver reserve in cirrhosis, tumors within the liver which are not easily accessible, or patients unfit to withstand either surgery or anaethesia (3,4). When resection is not feasible, percutaneous cryotherapy appears to be a good alternative in a certain number of cases.

History and principles

The first available data on cryotherapy go back to the early 1800s when it was used for freezing skin lesions. In 1963, Irving Cooper, a neurosurgeon treating Parkinson's disease and other neuromuscular disorders by means of cryosurgery, suggested extending the use of cryosurgery to liver tumors(6). Unfortunately, inadequate imaging to monitor the technique precluded its use at that time.

Cryosurgery's fundamental effect is based on the intentional application of subzero temperature generating in situ tissue destruction. Liquid nitrogen at a temperature of -196 °C is the most commonly used agent (2–7), although argon gas has also been used(7). It is delivered to the tumor via a vacuum-insulated cryoprobe that is inserted into it under ultrasonographic guidance. Then the frozen tissue is thawed. Cryogenic injury and cell death result from a combination of physiologic mechanisms including intracellular ice crystal formation, osmotic dehydration during cooling, denaturation of vital cellular enzymes, perforation of the cell membrane, microcirculatory failure(5), anoxia and cellular necrosis(4).

Although cryosurgery is not a selective treatment for the tissues, there appear to be different sensitivities of the different cells within the liver. Large vessels are protected from the cryogenic damage by the “heat sink” effect of flowing blood (5,7), while bile ducts are more likely to cryogenic injury.

Cryotherapy is more effective after more than one freezethaw cycle, and more destruction is seen at faster or slower cooling rates than 1–10 °C/min. Also, slow thawing of treated tissue is more cytotoxic to the frozen tissue(7).

Cryosurgery technique

The extensive use of intraoperative ultrasound (IOUS) has permitted development of the technique. First of all it allows the precise location of tumors within the liver, particularly in relation to vascular and biliary structures. It is a safe and precise method of guiding the cryoprobe into the lesion and visualizing the extent of freezing, easily identified as an hyperechoic rim with posterior acoustic shadowing(8). Although other techniques are currently in use, such as Magnetic Resonance(9) and CT scan, they are not as accurate nor as practical in assisting the process of cryosurgery since they are not real time scans. This makes the location of the tumor more difficult, and the freezing different phases are not easy to follow either.

Until recently, cryosurgery was performed through an open laparotomy, but recently considerable refinements in the delivery systems have made less invasive approaches possible in particular laparoscopic(10) and percutaneous techniques (11,12).

Specific aspects of percutaneous cryosurgery

Until recently the use of percutaneous cryosurgery was limited by the large diameter of the probes with subsequent risk of bleeding from their intrahepatic tract, as seen in open cryosurgery. Another technical problem was the freezing of the skin around the site of punction, since freezing was produced along the total length of the probe. In our preliminary experience(11), we were therefore obliged to use a coaxial plastic sheath (figure 1) or gauze swabs soaked in warm saline to protect the skin. New technological machines allow now to freeze liver tissue only at the tip of the probe, thus avoiding skin damage, and use small diameter cryoprobes, thus minimizing the risk of bleeding.

Figure 1

Illustration of the operative procedure of percutaneous cryosurgery. The cooling of the probe is apparent as frost accumulating on its external surface. The skin at the entry site is protected from freezing by a plastic sheath.

Indications

In general cryotherapy is to be proposed for documented primary or metastatic liver tumors, in the absence of extrahepatic metastasis, surgically unresectable disease and/or tumor involving surgically resected margins(4). Bilobar disease and multiple lesions can be treated safely this way since it avoids removal of surrounding tissue. However tumors occupying more than 50% of the liver are associated with unacceptable morbidity, and those greater than 6 cm in diameter are hardly treatable, since iceballs larger than 8 cm in diameter can not be obtained(13).

The percutaneous technique also include patients at high operative risk whether due to their comorbid medical conditions or to local difficulties being expected after recurrence, in patients previously operated on. In fact adhesions from the liver to the peritoneum reduce the risk of intra-abdominal bleeding and help by giving a constant image on U.S. (11,12).

Good indications to percutaneous cryosurgery seem to be represented by irresectable tumors less than 5 cm in diameter with up to 3 nodules, or limited intrahepatic recurrence following previous hepatic resections.

Results

At present there is still little data available of results with percutaneous cryotherapy and only 2 preliminary studies including ours, have been reported (11,12). Consequently knowledge obtained from the open technique must be taken into consideration, since results of percutaneous cryotherapy should be assumed to be comparable to those observed with open cryosurgery.

Cryotherapy compares favorably with other types of curative regional treatment(3). From the different series of cryotherapy applied to liver malignancies, it appears to increase the number of cases with a potentially curative strategy, in patients initially considered to have unresectable lesions(2). Cryotherapy can be applied safely and effectively in the treatment of hepatocellular carcinoma(HCC). Zhou et al.(15) reported 31.7% five year-survival. Others, with a less aggressive approach have reported 30% survival at 2 years(7). In colorectal carcinoma (2,3,14) 62–64% survival after 2 years was obtained as opposed to 21% after the same period when not treated; and 30% after 5 years of which 19% were disease free(4). It has also been used in neuroendocrine liver metastases(3). Better results are obtained when cryosurgery is used with curative intention (2,3). In general the stay in hospital for percutaneous cryotherapy is less than 4 days.

After cryotherapy all patients are closely monitored, every 3 months with CT scanning and serum markers, AFP levels for HCC and CEA for colorectal metastases (8,13). Spiral CT scan is particularly useful for the detection of vascularized tissue inside the tumor, suggesting tumor persistence or tumor recurrence.

The current limitations of hepatic cryotherapy are largely due to incomplete tumor destruction. An iceball of one centimeter around the lesion is recommended. A high local recurrence rate is obvious from the literature with 40 to 78% recurrence for colorectal metastases (2,3,8) and 33% for HCC(2). However complete remission can be achieved in 11% to 28% of colorectal metastases treated, consistent with the above mentioned results on HCC from Zhou et al.(15).

Complications

Although there is still little experience with percutaneous cryotherapy, no complications have been described with this technique. Complications related to the procedure have been described only with the open technique. Some can be avoided by an specific anaesthetic management(14). Postoperative renal dysfunction, consistent with acute tubular necrosis and related to myoglobinemia and myoglobinuria (4,5,8) should be prevented by adequate intraoperative renal perfusion, alkalinization of the urine and osmotic diuresis (4,14). Warming blankets and fluid warmers should be considered to avoid clinically significant hypothermia (4,5,10,14), bleeding may occur during rewarming, especially if the iceball cracks (3,4,7,10,14). Biliary leak or subsequent stenosis, due to the great sensitivity of the bile duct system to freezing injury, has also been described (2,4,7,8). Other complications include: transient elevation of liver enzymes and leucocytosis (3,4,5), right subphrenic abscess (2,3), thrombocytopenia (4,5,14) and coagulopathy (4,14), pulmonary atelectasis and right pleural effusion (4,7,10,14), and hepatic cracking(4).

Figure 2

Ultrasound guidance and monitoring of percutaneous cryotherapy. a) the probe is inserted into the lesion. b) during the freezing cycle an hypoechoic “iceball” surrounds and obliterates completely the image of the nodule.

Figure 3

Computerized tomography (CT) scans of a second patient. a) Unenhanced preoperative CT showing a hypodense lesion in segment 8 (arrow), disappearing after contrast injection (not shown). Hepatocellular carcinoma was confirmed by ultrasoundguided biopsy. (more...)

Conclusion

Percutaneous cryotherapy is a useful tool when considering minimally invasive therapy and the non resective management of primary and some metastatic cancers (colorectal, neuroendocrine, etc. …). Using the same principles of in situ cytoreduction of tumors as in the open technique, thanks to improvements in cryoprobes, percutaneous cryotherapy compares favorably with other local methods. Alcohol injection does not diffuse effectively in hepatic metastases. As opposed to radiofrequency, cryotherapy allows visual monitoring of the area of tissue destruction. However adjuvant therapies are needed to ensure maximal tumor destruction and to reduce local recurrence (4,5,7).

References

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