Liver cancer may divide into primary and secondary. Primary liver cancer begins in the cells of the liver itself. There are the following cell types:

• Hepatocellular carcinoma (HCC). It is the most common form of primary liver cancer in both children and adults. Worldwide, chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) is the most common cause of this liver cancer. Alcohol abuse is the common cause of cirrhosis, a disease that leads to irreversible scarring and neoplasm in the liver. Long-term exposure to aflatoxins can damage the p53 gene,and induce liver cancer.
• Cholangiocarcinoma. It begins in the small bile ducts within the liver.
• Hepatoblastoma.This rare type of liver cancer affects children younger than 4 years of age and may be caused by an abnormal gene.
• Angiosarcoma or hemangiosarcoma. These rare cancers begin in the blood vessels of the liver and are associated with exposure to industrial chemicals such as vinyl chloride or the drug thorium dioxide (Thorotrast).

Metastatic (Secondary) liver cancer is much more common, mainly arising from colon-rectal carcinoma and from the breast, lung, and gastrointestinal tract.i
Treatment review
Treatments for liver cancer depend on the extent (stage) of the disease as well as patient’s age, overall health, feelings and personal preferences. Liver cancer may be staged as ⅠtoⅣ. A stage I tumor is small and confined to one lobe of the liver. By stage IV, several tumors may exist in different lobes, or malignant cells may have spread to other parts of the body.
Since treatment opinion, liver cancer may also use the following stages to describe primary liver cancer in adults:

• Localized resectable. At this stage, the tumor is confined to one lobe of liver and can be completely removed in an operation.
• Localized unresectable. The cancer is found in only one part of liver, but can't be completely removed, either because the noncancerous portion of liver isn't healthy or the cancer is located near liver's main arteries, veins and bile ducts.
• Advanced. This stage of cancer has spread throughout the liver or to other parts of body, particularly the bones or lungs.
• Recurrent.This means the cancer has returned to liver or to another part of body after being treated.

The goal of any treatment is to eliminate the cancer completely. Standard therapies for adult liver cancer primarily include surgery, radiation therapy and chemotherapy. The best treatment for localized resectable cancer is usually surgical resection. Overall,the reported five-year cure rate for all HCC patients who have undergone hepatic resection is 30%-40%.Operative mortality is approximately 1% for noncirirrhotic patients and 10% for cirrhotic patients. Orthotopic liver transplantation has demonstrated a survival benefit in selected patients and is advocated as first-line therapy by some groups. However, the role of liver transplantation in patients with HCC remains controversial. Tumor in many patients usually recurs in transplanted livers within 6 to 24 months. In general, patients with tumors larger than 3 cm or with more than three nonules of tumors in the liver do poorly after transplantation. Radiation may be used to treat localized unresectable cancer. Radiation therapy following surgical resection is to help destroy remaining malignant cells. Systemic chemotherapy is generally not effective in treating liver cancer, but transarterial chemoembolization (TACE) is an important part of treatment for liver cancer.It isn't curative, but it can shrink tumors, which may provide symptom relief, and improve survival.
Only 5% to 10% of primary and secondary liver cancer are amenable to surgical resection. Liver ablation techniques have increased the number of patients who are suitable for curative treatment (table 1).
Table 1 Ablation therapy of liver cancer

• Alcohol injection.Percutaneous ethanol injection(PEI)has been shown to have response rates similar to those of surgical resection in patients with small tumors (<5cm) and is advocated as first-line therapy in patients who have small lesions and are not good operation candidates. The five-year survival rate for patients who have HCC smaller than 5 cm and are undergoing PEI approaches 50%.It may also be used to help reduce symptoms in cases of metastatic liver cancer. The most common side effect is leaking of alcohol onto the liver or into the abdominal cavity.
• Radiofrequency ablation. Using an ultrasound or CT scan as a guide, several thin needles of radiofrequency are inserted into small tumor, are heated with an electric current, destroying the malignant cells. Radiofrequency ablation is an option for small, nonresectable hepatocellular tumors and for some types of metastatic liver cancers. Although the procedure has a somewhat higher risk of serious complications than alcohol injection does, it appears to provide better outcomes.
• Cryosurgery (cryotherapy). This treatment uses extreme cold to destroy cancer cells. Cryosurgery is less invasive than regular surgery and have fewer complications,had a greater long-term survival benefit and is a useful means of controlling symptoms.
  

Overview of cryosurgery on liver cancer

Foremost among the most important areas in which cryosurgery is used are primary and secondary curative and inoperable liver tumors. Liver cryosurgery is a new method of treatment, in which the tumorous lesion is ablated in situ by means of a cryosurgical instrument. In recent years a new path has opened up for patients with liver tumors thanks to cryosurgery. The use of cryosurgery is now worldwide with the survey (1998) by Siefert et al. reporting 72 centres performing cryosurgery with a total of 2173 patients [1].It is only in Fuda Cancer Hospital Guangzhou, more than 1 000 patients with liver cancer, including 550 patients with primary liver cancer and 280 patients with secondary liver cancer, have received percutaneous cryoablation during from Mar 2000 to Oct 2005.

Currently, resection remains the therapy of choice in patients with liver cancer. However, very few of patients are actually eligible for resection. Cryosurgery helps to expand the indications for treatment. Although it is clear that inadequate evidence exists [2] regarding the efficacy of cryosurgery compared to resection, it appears to be an effective adjunct to surgery. Cryosurgery in the setting of unresectable liver cancer expands the possibility for radical intervention.

The different forms of liver cryosurgery are[3]:

• Liver cryoresection – the operative excision of pathological organ structures by means of a cold- producing clamp or scalpel.
• Operative liver cryoextirpation (liver cryoablation) – complete cryosurgical removal of a well demarcated focus or tumor in healthy tissue by way of a trocar or cryoprobe (cryoapplicator).
• Operative liver cryodestruction – a surgical intervention with the use of cold to partially remove a tumor in order to reduce the tumor mass.
• Laparoscopic liver cryosurgery (minimally invasive liver cryosurgery) – a cryosurgical procedure for removal of the liver tumor or tumor reduction using laparoscopy and other minimally invasive techniques.
• Percutaneous cryoablation- a minimally invasive liver cryosurgery,is performed under guiding of ultrasonography,CT or MRI.

Experimental basis for cryosurgery of liver tumor

Healey et al[4], then later Dulta et al [5,6] demonstrated in a series of dog models that cryosurgical destruction of liver tissue could be achieved without adverse effect on long term liver function. However, there were significant problems in both series. In Healey’s series, there was a significant death rate (11/34 of the animals) from major hepatic vein injury. In Dutta’s series, the major problem was with the development of fatal intraparenchymal cracks in the liver during the thawing phase of the cryosurgery. These problems would later be addressed by improvements in the instrumentation (vacuum insulated cryoprobes) and in instrument placement (intraoperative ultrasound). However, the experimental feasibility of hepatic cryosurgery was established.


Ravikumar et al[7] published a series of experiments that served as a model demonstrating the efficacy of cryosurgery in ablation of metastatic colorectal cancer. There were four series of experiments based on a rat model. The first series of experiments involved the implantation of colon cancer isographs in bilateral rat thighs. One thigh was subjected to cryosurgery while the other thigh acted as a control. Cryosurgery resulted in complete tumor destruction while the control side continued to have viable cells. In the second series of experiments, the colon cancer isographs were randomized to undergo single, double or triple freeze/ thaw cycles. Recurrences occurred in the single cycle group only. In the third series of experiments, the colon cancer isographs were pretreated with cryosurgery then implanted. Eight of nine isographs failed to show growth. Fourth, the rat model was changed to implanted colorectal liver metastases and then they were randomized to cryosurgery (two cycles), resection or sham laparotomy. In this last series, the overall results for both cryosurgery and resection were similar. These sets of experiments helped to establish that (1) cryosurgery was ablative to colorectal cancer cells with a two cycle freeze/ thaw sequence, (2) cryosurgery left almost all cells unviable, and (3) there was potential for the cryosurgical ablation to be as effective as surgical resection.

In a study from China, treatment results of the three percutaneous ablation,
namely local cryosurgery, acetic acid injection, and ethanol injection for transplanted HCC in mice, were compared. The tumor inhibition rates were 99.2%, 85.3%, and 72.8%, respectively. The rates for complete necrosis of the tumors were 100%, 60%, and 40%, with the survival time of 88.11+/-5.67, 86.67+/-7.26, and 72.89+/-12.86 days respectively. Cryosurgery may yield relatively better result than the other two methods[8].

Based on experimental studies using different low temperatures in vitro with
gelatine solutions as well as in vivo in the animal model with dog livers, the
following optimal parameters were determined for cryosurgery of parenchymal
organs, including liver surgery:

• Freeze temperature at -160oC to 190oC, with rapid freezing of the tumor required;
• Duration of a treatment session: 10-15 min;
• 2-3 freeze-thaw cycles;
• Spontaneous thawing, which must be carried out very slowly.

Indications of cryosurgery for liver cancer

In general, patients who are excluded from hepatic resection by a few criteria should be considered for hepatic cryosurgery. The general selection criteria used for hepatic cryosurgery are as follows [3,9]:

• Resection cannot be attained for anatomically unfavorable lesions and multiple lesions, which may be bilateral or may involve resection of too much functional hepatic parenchyma.
• Cryosurgery is used in combination with resection to achieve complete ablation.
• Lesions near the confluence of the bile duct would not be amenable to cryoablation if they were to be encompassed within the proposed area of cryoablation. Though the major vessels are “protected” by blood flow that prevents freezing of the vessel wall, no such protective mechanism exists in the bile ducts.
• The presence of ascites or advanced liver disease would preclude the patient’s ability to tolerate a laparotomy.This limitation is partially addressed by a laparoscopic and percutaneous approachs. Cryoablation of greater than 30%-40% of hepatic parenchyma is associated with increasing risk of complications, so that cryosurgery is limited to lesions involving less than 50% of the hepatic parenchyma.
• The patient should have an extensive work- up to rule out extra- hepatic disease. For metastasis colorectal cancer, any evidence of unresectable extrahepatic metastasis would be considered a contraindication to cryosurgery. The same principle would also apply to hepatocellular carcinoma. However, symptomatic patients may benefit from tumor burden reduction or “debulking” surgery.
• The patient who receives operative cryosurgery should have a good respiratory

reserve since the most widely used technique is to perform hepatic cryosurgery via a right subcostal incision. This incision may lead to post- operative mechanical respiratory limitations.

Pre-procedure of cryosurgery
Operative cryosurgery involves a significant physiological impact to the patient. Most patients undergo a significant laparotomy similar to that required for a hepatic resection. Thus, pre- operative work-up must be as rigorous as that typically used for a patient undergoing a major operation. In addition, many patients will be brought to the operating room for both a hepatic resection and cryosurgery.

Rigorous investigations to determine the patient’s candidacy for cryosurgery should be accomplished, such as ultrasound and CT. The patient should also have a biochemical work- up that includes evaluation of the complete blood count, coagulation parameters, liver function and renal function. In addition, preoperative measurement of tumor markers such as CEA (colorectal metastases) and alpha- feto protein (hepatocellular carcinoma) can be useful in prognosis as well to follow the response to therapy.

Procedure of cryosurgery
Open Liver Cryosurgery

In the open procedure, cryoextirpation is carried out on the operable liver tumor or cryodestruction on the inoperable liver carcinoma by application of the cryoapplicator (probe or needle) to the tumorous infiltrative liver parenchyma.

Access is established initially with a right sub costal incision positioned two finger breadths bellow the costal margin. Typically, a bilateral subcostal incision is used, or in some cases a “hockey stick” incision is used to spare the patient bilateral rectus muscle disruption. The liver is initially mobilized by dividing the falciform ligament back to the inferior vena cava, which allows maximum exposure of the liver. This maneuver can be critical to exposing the posterior segments of the right lobe. The rest of the liver mobilization is achieved by taking down the right and left triangular and coronary ligaments. An intra-operative ultrasound probe is now used to visualize the tumor(s) to be treated and visualize its relationship to the major vessels and bile ducts (if visible). Planning of the route with which to approach the tumor is done carefully with the priority maneuver being to avoid spearing the major vessels. The proposed surface entry point of the cryoprobe is then scored with electrocautery. If histological confirmation had not yet been achieved, tissue is now taken with a core needle biopsy under ultrasound guidance[3,10,11].

It is suggested that for tumors located in the upper part of the liver and close
to the inferior vena cava, the hepatic veins and the diaphragm, the abdominal
approach is uneasy, and transpleurodiaphragmatic access can be
employed[12].

Application of the Cryoprobes: Under ultrasound guidance, the cryoprobe is directed in the direction of the chosen route into the lesion. Once the trip of the probe is confirmed to be in the middle of the lesion, the freezing process is initiated through introduction of high pressure of argon or liquid nitrogen. Ultrasound imaging is used intermittently during freezing process to monitor progress as well to ensure that a 1 cm margin is ensured around the lesion. The 1 cm margin is based on the same reasoning that is used in resection, namely that less than 1 cm margin are associated with a higher local recurrence rate . The ultrasound image of the advancing edge of the ice ball is striking and appears as a hyperechoic shadow with posterior acoustic shadowing (see Fig ). Once the hyperechoic shadow reaches the 1 cm margin point for 10 minutes, the circulation of argon or liquid nitrogen is interrupted to allow for the thawing cycle. The receding of the ice ball can be seen on intraoperative ultrasound and when this line recedes back 1 cm (i.e. the margin), the next freeze cycle is initiated. The reason for the incomplete thawing is to reduce the complication rate. The probe is left in place during the second thawing cycle until the temperature at the probe has risen to -20o C. The track left by the probe is then packed with a hemostatic agent. Each cycle should take approximately 15 minutes depending on the size of the ice ball being created.

At the end of the operation, the abdominal wall is closed in layers and a drain placed either subhepatically or subdiaphragmatically. Occasionally it will be necessary because of the interaoperative situation to place a rubber or a Robinson drain.

Laparoscopic Liver Surgery
With the patient under general anesthesia, a Veress needle is placed in the pneumoperitoneum and the optic endoscope is introduced into the abdominal cavity. After inspection of the abdomen, an inclusion is made in the right upper abdomen and a 12 mm working trocar introduced under endoscopic vision. Immediately thereafter a laparoscopic cryoapplicator (cryoprobe) is applied to the liver parenchyma in the area of the tumor or is implanted deeply into the tumor mass[13].

Thereafter the liver tumor is cryoextirpated in the usual fashion at a temperature of -160oC to 190oC with spontaneous thawing and freezing. Different special cryoneedles and cryoapplicators are used in this connection.

Percutaneous Liver Cryosurgery

The procedure is performed under ultrasound or CT monitoring. The Cryocare
System ( Endocare, Irvine, CA, USA),using Argon gas as a cryogen, is often used. The liver tumor is carefully punctured with a thin trocar and immediately next to it a cryoprobe is placed according to the Seldinger technique. Different cryoprobes with diameters between 2 and 20mm are used. Cryoneedles (cryoprobes) of the smallest caliber are preferred in order to spare the parenchyma to the extent possible. The probe tip should be placed in the middle of tumor mass. For cryosurgery for larger liver tumors several thin needles are implanted in the tumor mass at a distance of 2-3 cm from one another in the form of an equilateral triangle.

The freeze-thaw cycle is carried out automatically and, in turn, has duration of 15- 20 min, and has a visually clear demarcation from neighboring structures. The duration of the procedure and the number of treatment sessions must be individually set, depending on the individual clinical picture. Two-three freeze-thaw cycles are often required in order to carry out overlapping treatments of the entire tumorous infiltrate and to cryodestroy either the entire or a part of the tumor mass[14].

There are following three situations which should be paid attention:

• The first, deep-seated lesions, such as those in the posterior right lobe, may be better approached with commercially available guide wire-dilator kits. Using ultrasound guidance the wire is introduced to the middle lesion followed by a sheath and dilator. The stiffer dilator is removed and cryoprobe is placed within the sheath. The sheath is removed and the procedure is completed.
• The second, when a lesion(s) cannot be completely encompassed by one probe alone,the aim is to place these probes eccentrically and position the probes so that the outer extent of the expected cumulative ice ball is out to the requisite 1 cm margin. The probed will have overlapping areas of freezing, with the priority being the establishment of an adequate margin around the tumor. The freezing process can then be carried out simultaneously via the probes as detailed above.
• The final situation involves taking greater care when the lesion is in proximity to other organs especially the gallbladder, colon, duodenum, stomach and diaphragm.

Post-cryosurgery study

Because failure of cryosurgery is recurrence and metastases later, biochemical
and imaging studies at regular intervals is very important. Periodic CT or MRI
should permit early detection of metastases of liver and other organs (especially
lungs)[10].

It is necessary to point that the postoperative CT appearance of the liver in patients who underwent hepatic cryoablation without complications mimics that seen in the liver of patients with hepatic abscesses or infarcts, and needs to be carefully analyzed to avoid confusing normal findings related to the procedure with those related to procedural complications.According to Kuszyk et al[15], all cryolesions are primarily hypodense, 36% of lesions contained air, and 93% contained hemorrhage. 54% of lesions evaluated with i.v. contrast material showed peripheral enhancement. Cryolesions were primarily wedge shaped (54%), round (29%), or teardrop shaped (21%).The CT appearance of the liver in patients undergoing cryosurgery, it may be impossible to differentiate hepatic complications from normal postoperative changes on the basis of CT findings in many of these patients.

A more subtle sign of recurrence is an elevated serum AFP for HCC and CEA for colorectal liver matastases, although normal levels after cryosurgery do not necessarily preclude metastases.

Clinical comment

Hepatocellular Carcinoma

The data concerning the use of cryosurgery specifically in the setting of hepatocellular carcinoma is focused on open cryosurgery. Crews et al[16] reported that forty patients with hepatic malignancy underwent cryoablation and the estimated 18-month survival was 60% and 30% for patients with HCC and with colorectal metastasis, respectively. Lam et al[17] treated 4 patients with recurrent HCC after previous curative hepatectomy with cryoablation. All patients are still alive with survival after cryosurgery ranging from 12-23 mo (25-63 mo after the hepatic resection). Three patients showed evidence of recurrent disease and one patient was disease free. Sheen et al[18] have demonstrated that the median survival for HCC patients after cryoablation was 36 months. Wren et al[19]considered cryoablation to be primarily palliative but may provide a possibility of cure in selected patients. Twelve patients with cirrhosis with HCC (stage II, 2; stage III, 1; stage IVA, 7; stage IVB, 2) received cryoablation of all identifiable tumors. The mean survival has been 19 months after cryoablation and 29 months after diagnosis. Three of the 9 patients treated with curative intent died with recurrence at a mean of 17 months after cryoablation. Four patients are alive with recurrence at a mean of 19 months after cryoablation and 38 months after diagnosis. Two patients with stage II disease have no evidence of recurrence 10 and 32 months after cryosurgical ablation.

The largest experience is provided in Zhou et al.’s report from China(see table 2)[20]. They were able to demonstrate that cryosurgery can offer long term control of hepatocellular carcinoma. The overall 5 year survival of 39.8% compares favourably with resection data that shows 41.3% 5 year survival [21].

Table 2 Stratified results of cryosurgery for hepatocellular carcinoma based on Zhou XD et al.

Nakazaki et al[22]performed percutaneous cryoablation for 10 patients with HCC and 5 patients with liver metastases from colorectal carcinoma.The tumors of all cases were less than 3 cm in size. Results showed that 6 cases were CR(complete response),5 PR(partial response),2 NC(no change) and 2 PD(progressive disease).

Now the cryosurgery for unresectable HCC is mainly performed percutaneously.
During from Mar 2000 to Oct 2005, the cryoablation for 550 patients with HCC were performed in Fuda Cancer Hospital Guangzhou. In 550 cases, 152 patients received percutaneous cryoablation alone and were followed-up for 4 years. The tumors in all 152 cases were unresectable. The patients with liver failure were excluded. The results are as Table 3.The 1-,2-,3-,and 4-survival rates are 86.4%,72.9%,51.6% and 45.4% respectively. The HCC smaller than 5 cm has better survival.

Table 3 Percutaneous cryoablation in 152 patients with HCC

Liver metastasis from colorectal adenocarcinoma

In patients who have had colorectal cancer, approximately one quarter of the patients will develop isolated metastases to the liver but of these patients, only 10%-20% will qualify for a resection. In the group that undergoes resection, there can be extended survival of up to 50%. Unfortunately, there are still many patients with metastases isolated to the liver who by virtue of anatomy or number of tumors will not be a resection candidate. Cryosurgery offers an alternative treatment for these patients.

A review of the literature in 1977 by Tandan et al[2] demonstrated the efficacy of cryosurgery for colorectal hepatic metastases. Although some limitations of the data made it impossible to clearly determine the efficacy of cryosurgery compared to resection, it was noted that some patients were surviving long term after cryosurgery with approximate 2 year survivals ranging from 30 to 64%. It was clear though that further study would be needed to better define the actual benefit of cryosurgery and also to better define the prognostic factors for hepatic cryosurgery.

Korpan [23] followed-up, prospectively over a period of ten years, patients with liver metastases. The patients were randomized into one of two groups. The first group received cryosurgery in some form either alone or in combination with surgical resection. The second group underwent conventional surgery alone (no additional cryosurgery). Both groups then had adjuvant 5-FU/Leucovorin chemotherapy after surgery for the colorectal liver metastases. The total number of patients was 123. Table 4 summarizes their results. Several important observations were made in their study. Firstly, the five year survival rate in the group who had surgery alone (36%) was consistent with the results of trials using surgery alone for colorectal liver metastases (20-49% (20). Cryosurgery resulted in a significantly higher survival of44% compared to the group who had surgery alone. From this, the authors concluded that cryosurgery may play a role as an adjunct to resection in the setting of resectable colorectal liver metastases. Secondly, in the cryosurgical group, 14 patients (22%) were discovered to have unresectable disease and subsequently underwent a cryoablative procedure (only) for these lesions. In the non-cryosurgical group, 12 patients were discovered at laparotomy to have unresectable disease and were explored only. The patients who underwent cryosurgery did not have a complete tumor ablation (between 90-97% tumor destruction) but did achieve a higher mean overall survival than those who underwent exploratory laparotomy only.

Table 4 Hepatic cryosurgery on colorectal hepatic metastases[23]

Weaver et al[24]reported that forty-seven patients with documented metastases limited to the liver from colorectal adenocarcinoma were treated with cryosurgery with or without resection from Nov 1987 to Feb 1992 and were followed until Feb 1994. The actual survival at 24 months was 62%. Eleven percent of these patients had no evidence of disease at a median follow-up of 30 months.

Weaver et al[25] further studied the usefulness of cryosurgery in the setting of the unresectable liver metastases. They chose patients who were deemed unresectable due to location and / or number of lesions and excluded patients with >50% liver involvement, cirrhosis, lesions >6 cm and total number of lesions >10. A total of 136 patients underwent 158 cryosurgical procedures. The overall group had a median survival of 30 months. Twenty patients in the series required multiple cryosurgery for recurrent hepatic disease. These results compare favorably to older studies looking at the natural history of unresectable liver matastases (mean survival between 4 to 13 months) and at newer studies looking at survival after aggressive chemoradiation (mean survival 20 months) [26] and hepatic artery infusion (mean survival 13-19 months) [27-29].

Seifert et al[30] performed a multivariate analysis on their series of 116 patients who had colorectal liver metastases treated with cryosurgery. Their overall median survival was 26 months, comparable to the previously mentioned study. Two years later,Seifert JK et al[31] further assessed the efficacy of hepatic cryotherapy for liver metastases in a prospective case control study. 54 cryosurgical procedures were performed on 49 patients with liver metastases. Patient, tumor, and operative details were recorded prospectively. Liver metastases mainly originated from colorectal cancer. In 76% of patients with preoperatively elevated serum CEA and colorectal metastases it returned to the normal range postoperatively. Overall median survival patients was 23 months, and survival in patients with colorectal metastases was 29 months.

Brooks et al[32] reported that the results of synchronous liver resection and cryotherapy ablation for colorectal metastases where complete resection is not possible by conventional liver surgery alone. Ninety-three patients with colorectal metastases underwent synchronous liver resection and cryotherapy. Data were available on 86 patients with a median follow-up of 18 months (range 1-83). The median number of metastases at initial surgery was four (range 2-11) and the number of lesions treated by cryotherapy ablation was two (range 1-8). Eighty-four per cent had a hepatic artery catheter inserted at surgery and at least one cycle of post-operative hepatic artery chemotherapy. One-, three- and five-year survival was 85%, 43% and 19% respectively, with a median survival of 33 months (95% confidence interval 19.9-42.1). Site of recurrence was recorded and presented. The results show that patients with liver metastases that are not amenable to resection alone can achieve worthwhile median survival with synchronous liver resection and cryotherapy ablation.

Onik et al[33]reported that 57 patients with unresectable hepatic metastases were treated with cryosurgery (with at least a 6-month follow-up). The number of lesions treated ranged from 1-16 with a mean of 4.6. Forty-three patients (73%) had bilobar disease, while 25 patients (42%) were treated with a combination of resection and cryosurgery. The disease-free survival rate (patients with normal CT scans and CEA levels) was 27% with a mean follow-up of 21 months.

Huang et al[34]evaluated the efficacy of percutaneous cryoablation for treating irresectable colorectal liver metastases. Liquid nitrogen cryoprobes were inserted percutaneously into metastases using the Seldinger technique under CT guidance.Single-probe treatment were performed with either 3.6- or 6.3- mm cryoprobes(ice-ball volumes 18 and 59 cm3,repectively),or dual-probe treatment with two adjacent 6.3-mm probe(ice-volume 205 cm3).Treatment involved a single freeze-thaw cycle.Fifteen patients received 25 single-probe treatments and seven patients received 14 dual-probe treatments.The treatment-related mortality rate was zero and complications occurred after 6 of 39 treatments.Liver metastasis growth was significantly delayed for 2 months after dual-probe but not single-probe treatment.Serum CEA level had an immediate rise,followed by a fall.Cryoablation stimulated an immune upregulation that was significantly greater after dual-probe treatments.

During from Mar 2000 to Oct 2005,205 patients with colorectal hepatic metastases received percutaneous cryosurgery in Fuda Cancer Hospital Guangzhou.There were 128 cases who were followed up for median duration of 38 months(range 8-63),and results showed 82%,65%,53%,35% and 18% in 1-,2-,3-,4- and 5-year survival, respectively.

Liver metastases from neuroendocrine Tumors

Neuroendocrine tumors make up a much smaller proportion of patients presenting with liver metastases. In this group of patients, the natural history is somewhat less virulent but they can often be very symptomatic because of the hormonal production of the neuroendocrine malignancy. Previous studies of aggressive surgical resection for metastatic neuroendocrine tumors of the liver suggest that cure is rare but not impossible and cytoreduction effects a measurable improvement in symptoms and delays need for medical therapy [35-39]. However, some patients who do not meet the criteria for resection, cryosurgery should be attempted. Table 5 summarizes the results of larger series of hepatic cryosurgery in which metastatic nueroendocrine tumors were also treated.

Table 5 Results of cryosurgery for neuroendocrine liver metastases

Two studies [40,41] looked specifically at hepatic cryosurgery for neuroendocrine metastases. These results confirm the efficacy of cryosurgery for non-resectable hepatic neuroendocrine metastases. Though the natural history of neuroendocrine tumors even with metastases confers a much better prognosis overall than hepatoma or colorectal metastases, symptomatology is known predictor of poor prognosis. In both series, cryosurgery was effective in generating at least a partial decrease in the symptomatology of these patients. These previously symptomatic patients then went on to have long term survival which was more consistent with the natural history of asymptomatic patients.

Liver metastases from other malignancies

It was reported that non-colorectal and non-neuroendocrine metastases treated by hepatic cryosurgery have included breast, gastric, melanoma, ovarian, renal, small bowel, and pancreatic. There are too few numbers in any series to allow for any useful analysis.

Bilchik et al[42] evaluated cryoablation of hepatoma and noncolorectal hepatic metastases by examining its effect on serum levels of tumor markers in 20 patients with primary liver cancer (N = 5) or liver metastases (N = 15) from breast cancer, neuroendocrine tumors, ovarian cancer, and thyroid cancer. All patients had failed conventional therapy and had no evidence of extrahepatic spread. After cryosurgery, 17 patients had a significant decrease in tumor marker levels (median 77%) and a significant improvement in symptoms. One patient died of nontumor causes, and five patients died of recurrent disease. Median interval to death or last follow-up was 28.3 months overall (range, 2-45 months), 17.9 months for nonsurvivors (range, 2-44 months), and 35.2 months for survivors (range, 26-45 months). Median survival was 32 months following curative surgery (range, 16-45 months) and 25 months following palliative surgery (range, 2-42 months).


During from Mar 2000 to Oct 2005,75 patients with liver metastases from other
malignancies have received percutaneous cryoablation in Fuda Cancer Hospital
Guangzhou(Table 6),and have got better outcome in 75 percent of patients.

Table 6 Cryoablation for non-colorectal and non-neuroendocrine metastases

＊ S:Solitary or ≤ 3 tumors,M:Multiple (3＞tumor
＊＊NSCLC 17 cases,SCLC 3 cases

In general,a patient with a predicted good natural history would benefit the most from any additional and localized therapy to the liver such as cryosurgery. These patients include those with a longer disease free interval, absence of extra-hepatic disease, single metastasis, and long time stable disease (on or off other therapy such as chemotherapy).

In the meantime, cryosurgery of noncolorectal hepatic metastases can provide
excellent palliation of symptoms, and in selected patients can be performed with
curative intent.

Complications and adverse effects

Because the size of the iceball created during the cryosurgery procedure can be carefully controlled, cryosurgery has the advantage of being a focal technique that spares much more noncancerous liver tissue than surgical resection. The major complications of open hepatic cryosurgery are the same as those of hepatic resection: hemorrhage, pleural effusion, bile leak fistula, perihepatic abscess, and hepatic failure. In addition, there is a risk of coagulopathy when large tumors are frozen using multiple freeze-thaw cycles. In general, operative morbidity is related to the volume of frozen tissue, the number of freeze-thaw cycles, and number of cryoprobes[43]. Percutaneous cryoablation is a miniinvasive technique, and has fewer complication compared with open cryosurgery.

Seifert and Morris [44]made a world survey on the complications of hepatic
and prostate cryotherapy in 1999.A questionnaire was sent to all cryotherapy
users (n = 299). Altogether 134 completed questionnaires were returned
(44.8%). Seventy-two centers had experience with hepatic cryotherapy and 62 with prostate cryotherapy. They suggested that hepatic cryotherapy is safe.

Niu et al made a survey of adverse effects for 1500 patients who received
percutaneous cryosurgery in Fuda Cancer Hospital Guangzhou,and results are
as Table 7.
Table 7 Adverse effects of percutaneous cryosurgery

Intra-operative pitfalls

Injury to major vessel: The injury may be induced by thrombosis if the major vessel is within the zone of freezing and a direct injury during the placement of the probe. Thrombosis of a major vessel is unusual since blood flow through it gives the vessel a protective “cold sink”. Guiding of ultrasound should be carefully used to map out a probe route that avoids the major vessels, which may lie in close proximity to the lesion. The porta hepatic, the inferior vena cava and the hepatic veins where they join the inferior vena cave should be identified prior to cryosurgery in cases where the lesion is close to a major vascular structure[10].

Post-probe removal bleeding: After freezing there can be a significant blood loss from either the probe tract or from cracks in the parenchyma of the liver. In most cases, bleeding will occur during the thaw cycle of the procedure. Bleeding (unless it is massive) can be controlled with a combination of compressive maneuvers. For bleeding during open cryosurgery,hemostatic material can be used to pack the tract tightly but care must be taken not to induce parenchymal fracture during packing. Manual compression of the probe tract can also be successful in arresting the hemorrhage but persistence of up to 20 minutes of compression may be needed to achieve control.

Parenchymal fracture: Surface cracks can also occur secondary to the freezing process especially in situations where a large area is being frozen using multiple probes. It can also occur during probe removal especially if one torques on the probe while trying to remove it. Preventative measures include waiting for the probe to reach at least -20oC and a soft rotational action on probe removal may help decrease the chance of parenchymal fracture. If subsequent bleeding occurs, it can be controlled with parking or hemostatic agents, and if massive bleeding can’t be controlled with above modalities, it is necessary to suture operatively.

Post –operative adverse effects

Routine precautions and post-operative care for the patient with a laparotomy are employed. This would include chest physiotherapy, adequate pain control using epidural analgesia or patient controlled analgesia devices (PCA), and monitoring of urine output. Standard blood work would include a postoperative complete blood count, electrolytes, renal function (creatinine and blood urea nitrogen), coagulation factors (INR, PTT), and liver enzymes (AST, ALT, ALP, GGT, BILI).

Complications induced by cryosurgery can be classified into intraoperative, immediate and delayed. Understanding and recognizing these complications will allow one to initiate treatments that can help ameliorate the consequences of the complications.

Intraoperative complications were partially discussed above and are mainly related to hemorrhage. These include probe placement-related major vascular injury, probe removal bleeding and parenchymal fracture. A further intraoperative complication that can occur with cryosurgery is hypothermia.This complication can be ameliorated with the use of body warmer devices. If a significant cryosurgery is being offered (for example, multiple lesions or one large lesion), the use of two body warmers for the upper and lower torso is advisable. Myoglobinuria can also manifest intraoperatively at the time of the thaw cycle. It is discussed below.

Immediate complications include those that can occur during the early post-operative period after the cryosurgery. These can include acute renal failure, biliary fistula, hepatic abscess, coagulopathy, transient biochemical derangements, pleural effusion, acute respiratory distress syndrome and the most serious, the “cryoshock” phenomenon [45].

Pleural effusion is a common complication and is thought to be a sympathetic process reacting to the inflammation caused by the cryoablation of the liver tumor. Most are asymptomatic and spontaneously resolve. Treatment will be based on the amount of respiratory compromise caused by the effusion.

Biliary fistula results form damage to the endothelial lining of a bite duct adjacent to the area of hepatic cryosurgery. The risk of this has been reported from 0.5% to 10%[46,47]. Controlling the biliary drainage and eliminating any distal biliary obstruction are the mainstays of treatment. These strategies established 100% healing of biliary injuries in the series from Weaver et al[48] Prophylactic measures proposed include the use of metallic stents (to allow for contiguous re-epithelialization after injury) as well as intra- biliary circulation of warmed saline. The potential biological “protective” effect on an adjacent tumor warmed by this saline irrigation technique has not been explored. A potentially life threatening biliary complication is arteriobilious fistula formation leading to hemo-bilia [47].

Infection related to the cryosurgical procedure may occur. Riley et al.showed[49]
that among 158 hepatic cryosurgery in 150 patients, the following 12 infections were directly related to the cryosurgical procedure: hepatic abscess[50], intraperitoneal abscess [6], ascending cholangitis [5], and an intrahepatic device infection [4]. Hepatic abscess, as a more common infectious complication, can occur early or late and occurs in the area of necrosis caused by hepatic cryosurgery. The incidence in the series from Siefert et al is low (0.6%)[45]. Interestingly, Sarantou et al[45] reported one abscess occurring 3 months post-cryosurgery following a dental procedure. Treatment involves antibiotics to the appropriate organism and to drain the abscess cavity percutaneously.

Transient biochemical derangements are the most benign of the complications, involving subclinical rise in liver enzymes, leukocytosis, thrombocytopenia and myoglobinuria. These changes usually resolve over a period of days without clinical consequences. However, these changes can also progress to more severe complications if they do not resolve. Thrombocytopenia may be part of the cryoshock phenomenon (DIC) and myoglobinuria may result in acute renal failure. To monitor these changes, serial blood work should be ordered. Myoglobinuria is common without serious consequences in most cases.

The etiology of coagulopathy is multifactorial following hepatic cryosurgery and involves hypothermia, thrombocytopenia or worse as part of the cryoshock phenomenon. Treatment is addressed to each of the factors. Hypothermia is treated with warmers as described above. Thrombo-cryopenta associated with coagulopathy can be treated with a platelet transfusion or the addition of 1-desamino-8-D-arginine vasopressin (DDAVP). The true etiology of this thrombocytopenia is not determined but there seems to be correlation with the number of freeze-thaw cycles and number of lesions cryoablated [50,51].

Acute renal failure can be a major problem post hepatic cryosurgery. In the world review by Seifert et al., renal failure accounted for 12% of the mortality in the group of patients who died following hepatic cryosurgery. The etiology is thought to be from the myoglobinuria (which can occur during the thawing cycle) that is complicated by acute tubular necrosis. Similar to thrombocytopenia, observations have been made relating the incidence of acute renal failure to the volume of frozen liver and the number of complete thaw cycles. Prophylaxis is important and adequate diuresis with a judicious combination of fluid infusion and mannitol initiated at the start of the thaw cycle is critical. Weaver et al[25] also suggested the use of furosemide and urinary alkalinization.

Acute respiratory distress syndrome (ARDS) can also occur following hepatic cryosurgery, and recent work from Blackwell et al. (18) has shown a significant difference in the incidence of lung injury following 35% cryoablation versus 35% hepatic resection in a rat model. Cryoablation resulted in the release of pro-inflammatory factors (NF-kappa-B dependent cytokines) that was detected in both liver and lung tissues, but in the hepatic resection group there was no increase in these pro-inflammatory factors. The authors concluded that the production of specific pro-inflammatory cytokines was a unique feature of cryoablation and not resection.

The cryoshock phenomenon is characterized by multi-organ failure (ARDS, liver failure, renal failure, shock), severe coagulopathy, and disseminated intravascular coagulation (DIC). This is basically a coalescence of the aforementioned complications following hepatic cryosurgery, and in fact many refer to the manifestation of an individual characteristic (e.g., acute renal failure) as an “incomplete cryoshock phenomenon”. The etiology of cryoshock phenomenon may be related to tumor lysis. Firstly, many of the characteristics of cryoshock occur proportionally to the amount of tissue destruction. Secondly, lower volume cryosurgery, such as that administered to the prostate, has a much lower incidence of cryoshock phenomenon. The overall prevalence of cryoshock phenomenon was not common (1%) but the consequences were severe causing death in 29% of patients who manifested the cryoshock phenomenon. It also accounted for 18.2% of the total mortality rate. Treatment is supportive, using the same strategies as described above for the individual components of cryoshock phenomenon (renal failure, coagulopathy, etc.).

Delayed complications occur at a much more distant time after hepatic cryosurgery, usually occurring well after the patient has returned home. More common problems include ventral hernia after open cryosurgery(common to all laparotomies). Tumor recurrence at a cryosurgical site can also be considered a complication of incomplete ablation. Delayed hepatic abscess can also occur, as mentioned above.

Discussion
Prognosis of unresectable liver cancer is very poor. Typically,median survival for
unresected tumors is three to four months. In Japan, the median survival
for 229 patients with HCC received no specific treatment was 1.6 months[52]. During the past years, great efforts have been made to improve the survival of the patients with this disease[53].

Advantages of cryosurgery for liver cancer

Cryoablation is a method of in situ tumor ablation. As a local therapy, cryoablation carries certain advantages over other forms of liver cancer treatment[54].

• First, it is able to destroy only the tumor tissue in liver while sparing more noninvolved tissues, which is of important significance to HCC patients, because the majority of these patients have cirrhosis and decreased reserve of liver function[55].
• Second, because of the warming effect of flowing blood, large blood vessels, such as inferior vena cava and portal vein, are somewhat imperious to the effect of freezing. Therefore, tumors close to these venous system can safely undergo cryoablation, whereas resection of tumors close to large vascular structures is very difficult[56]
• Third, it is known that liver cirrhosis is a basis of HCC development, if the entire liver is cirrhotic, any part of the liver can develop new tumors. Liver cryoablation is more effective than surgical resection in treating multiple new tumors[57] .
• Forth, in contrast with other local ablations, such as radiofrequency, which is difficult to reliably destroy tumors greater than 5 cm in diameter, cryoablation is a promising means in the treatment of this larger form of tumor[58].
• Lastly, the rapid freeze-thaw process enhances necrosis and helps induce an immune response against the surviving tumor cells[59].

Tumor dissemination by hepatic cryosurgery

One experimental report has indicated that hepatic cryosurgery may enhance tumor dissemination. El-Shakhs et al[60] investigated the risk of tumor dissemination by hepatic cryosurgery. Rat hepatic tumors were produced by direct injection of rat colonic carcinoma cells. The control untreated animals (n = 12) were sacrificed after induction of liver tumors at 4 and 6 weeks. The animals in the treatment group (n = 16) underwent cryosurgery 2 weeks after tumor induction and were allowed to recover before sacrifice 2 and 4 weeks later. Pulmonary metastases were identified in 9 of 12 (75%) control animals at postmortem examination (2 and 6 weeks after tumor inoculation) and in 6 of 16 (38%) rats in the treatment group at sacrifice 2 and 4 weeks after cryosurgery (p = 0.11). Peritoneal deposits were observed in 5 of 12 (42%) control animals at postmortem examination and in 8 of 16 (50%) of the treated animals at the time of cryosurgery (p = 0.95). The results do not support the suggestion that hepatic cryosurgery enhances tumor dissemination.

Combination of cryosurgery and other modalities

1.Adjuvant chemotherapy after cryosurgery(cryochemotherapy):It is showed that freezing facilitates chemical agents such as bleomycin penetration into cells making it toxic to surviving cells after cryosurgery at concentrationa that are non-toxic systemically[61]. Bilchik et al[62] evaluated their 6-year experience(July 1992-July 1998) in 153 patients with unresectable hepatic colorectal metastases refractory to systemic 5-fluorouracil (5-FU) who underwent cryosurgery with or without postoperative adjuvant chemotherapy(hepatic arterial floxuridine (FUDR),systemic CPT-11).Overall median survival was 28.4 months from the date of diagnosis of liver metastases and 16.1 months from the time of cryosurgery. After cryosurgery alone,median survival was 13 months,which was significantly shorter than the post-cryosurgery survival of 23.6 months with adjuvant CPT-11 and 21.2 months with Hepatic FUDR(p<0.007).

2.Combination of cryosurgery with transarterial chemoembolization (TACE) : Sequential combination of TACE and resection has been proved as an effective modality for larger liver cancer. TACE may ablate a significant portion of the tumor, but has high rate recurrence. Cryosurgery may permit successful ablation of liver cancer but can be complicated by hemorrhage and also associated with a significant risk of recurrence. Therefore, the combination of the two techniques might be beneficial[63].

Clavien et al[64]evaluated in a prospective study the efficacy of combination of
TACE and cryosurgery in 15 cirrhotic patients with unresectable HCC.All but one
patient underwent one or several sessions of TACE before cryosurgery.The patient
who did not undergo preoperative TACE required reoperation for hemorrhage.At a
mean follow-up of 2.5 years,three patients had recurrence of disease,and 13 of 15
patients were alive with the longest survival time being 5 years. The actuarial
survival rate at 5 years was 79%.

From Mar 2001 to Jun 2004, three hundred and sixty patients with HCC the sequential treatment of TACE-percutaneous cryoablation in Fuda Cancer Hospital Guangzhou. Intrahepatic tumor masses were larger than 5 cm in size. 220 patients had single mass in liver and others had multiple masses but which numbered less than 5. The tumors of all patients were considered to be unresectable through comprehensive comment. Transarterial chemoembolization was completed according to routine method. Two weeks later, if CT scanning showed good response, percutaneous cryoablation should be given, otherwise, the chemoembolization should be completed again (generally no more than 3 times). The cryoablation was performed with the Cryocare system(Endocare, USA) by using argon gas as a cryogen. One month after cryoablation,the chemoembolization of one or two times may be further performed if necessary. Results: Among the follow-up period of median 21 months(6-36 months),ultrasound and /or CT showed that a complete response(CR) was seen in 30 cases (8.3%),partial response (PR) in 228 cases(63.3%),no change (NC) in 66 cases (18.3%),and progressive disease(PD) in 36 cases (10.0%). Alpha-fetoprotein(AFP) was significantly decreased and decreased into normal range, in 86.9% and 62.0%, respectively, of 229 patients with pre-therapy elevation of serum levels of this protein. Out of 258 patients with CR and PR,26.7 % had intrahepatic recurrence, but only 15.9% developed a cryosite recurrence. There were 113 cases who died during the follow-up period, and the death reasons included widespread metastasis in 45 cases,rupture of esophageal varices in 24 cases, spontaneous peritonitis in 23 cases,hepatic encephalopathy in 14 cases and other non-liver cancer-related causes in 7 cases[65].

3.Combination of cryosurgery with alcohol injection: During cryoablation,
freezing occur in three main areas:(1) the center of iceball near the cryoprobe, where freezing is rapid and the temperature is lowest;(2) the middle of the iceball, where the tissue experiences intermediate cooling rate; and (3) the periphery of the iceball, where slow rates of cooling occur[59].The cytotoxic effect from rapid cooling is the greatest in the center of the iceball, while cells at the periphery of the iceball may survive, particularly if the tumor abuts a large intrahepatic blood vessel that abrogates the effects of tissue cooling. The surviving tumor cells result in the recurrence of the disease. Percutaneous ethanol injection(PEI) may cause nonselective protein denaturation and cellular dehydration, leading to coagulated necrosis of tumor. Subsequent fibrosis and small vessel thrombosis also contribute to cellular death. Therefore, after cryoablation which could destroy much majority of tumors, PEI used at periphery of tumor can destroy residue tumor tissues. It is obvious that combination of cryoablation and PEI had a complementary effects for preventing recurrence.

Wong et al[66]investigated the role for combination of cryosurgery with alcohol
ablation in the treatment of patients with HCC. Twelve patients with biopsy proven hepatocellular carcinoma underwent ultrasound-guided cryosurgical ablation of their liver tumor. Postoperative alcohol ablation was performed on those patients who were found to have residual tumor or recurrence after the cryosurgical procedure. Most patients had advanced disease according to the TNM staging system.The 1-year survival rate for the entire group was 50% and the 2-year survival rate was 30%. At last follow-up, 1 patient with an 8-cm tumor was disease free for 3 years and another patient with a 13-cm tumor was disease free for 2.5 years. Both of these patients had Stage IVA disease. It is showed that follow-up treatment with alcohol ablation is an important adjunct in treating residual tumor and controlling recurrences.

Between March 2001 and January 2003,percutaneous hepatic cryoablation for 65 patients with unresectable HCC was performed in Fuda Cancer Hospital Guangzhou. Among those patients 36 patients with tumor mass larger than 6 cm received PEI 1-2 weeks after cryoablation. The results is showed in Table 8 . During follow-up duration of 14 months in average with a range of 5 to 21 months, 33 patients(50.8%) were free of tumors,22 patients (33.8%) alive with tumor recurrence: two had bone metastases, three were found to have lung metastases, and the remaining 17 recurrences occurred in the liver, of whom only 3 developed a cryosite recurrence. The low recurrence of original sites suggests the effectiveness of this combined therapy[14].

Table 8 Status of 65 patients with unresectable HCC after cruosurgery

Comparison between radiofrequency and cryosurgery

It is suggested that radiofrequency is a safe, well-tolerated treatment for patients with unresectable hepatic malignancies compared with cryosurgery. Pearson et al [67]showed that. 40.7% complication rate of cryosurgery in contrast to 3.3% complication rate of radiofrequency,and early local tumor recurrence was more frequent following cryosurgery. However, in general, both radiofrequency and cryoablation are safe and well-tolerated.The effectiveness for local tumor eradication depends on many factors, including tumor size, location, number, and type. The choice of ablation modality is based on user and institutional biases. Now it is proved that there are the relative advantages and disadvantages of each technique. Radiofrequency ablation of malignant hepatic neoplasms can be performed safely, but is currently limited by size (<3 cm). Cryosurgical ablation is more effective for larger unresectable hepatic malignant neoplasms. Bilchik et al[68] evaluated both techniques in 308 patients with liver tumors not amenable to curative surgical resection. Median ablation times for lesions greater than 3 cm were 60 minutes with radiofrequency and 15 minutes with cryosurgery(P<.001). Local recurrence rates for lesions greater than 3 cm were also greater with radiofrequency (38% vs 17%). Radiofrequency ablation combined with resection or cryosurgery resulted in reduced blood loss (P<.05), thrombocytopenia (P<.05), and shorter hospital stay compared with radiofrequency alone (P<.05).It is suggested that combination of both techniques may be a good option for patients with unresectable liver cancer.

Assessment of prognosis after cryosurgery
Identifing prognostic indicators may allow better selection or stratification for adjuvant therapies of patients(Table 9 ).

Table 9 Prognostic factors for cryosurgery in liver cancer
Favourable Prognostic Factors on Multivariate Analysis

• Low presurgical serum tumor markers
• (AFP in HCC and CEA in colorectal liver metastases)
• Small diameter of cryoablatde tumor(< =3 cm)
• Absence of untreated extrahepatic disease at laparotomy
• Absence of nodal involvement at primary resection
• Complete cryotreatment
• Good to moderate differentiation of the primary resection
• No receiving blood transfusion intraoperatively
• Ultrasonography showing hyperechoic tumor masses in liver

Seifert and Junginger[69] showed that in patients with colorectal liver metastases, multiple or large (>4 cm) liver tumors, patients undergoing cryotherapy combined with liver resection and patients receiving blood transfusion intraoperatively, especially when exceeding 4 units packed red cells, had a significantly impaired survival in univariate analysis. In multivariate analysis (Cox regression) the amount of intraoperative blood transfusion was the only independent prognostic indicator. Therefore intraoperative blood transfusion should be avoided by refinement of surgical technique whenever possible.

Seifert et al[70] investigated the prognostic value of echogenicity of colorectal liver metastases in patients receiving hepatic cryotherapy. The echogenicity of liver metastases was assessed intraoperatively in 48 patients undergoing cryotherapy for in situ destruction of colorectal liver metastases. Thirty-three patients who were found to have hyperechoic metastases,had a favorable outcome, with a median survival time of 50 months, as compared with a median survival time of 24 months in the 15 patients with hypoechoic metastases (P = 0.0074).

Seifert et al[70] showed that age less than 51 years, absence of involved nodes at primary resection, small diameter of liver metastases, and low preoperative serum carcinoembryonic antigen levels were associated with a favorable outcome.

Fluorine-18-deoxyglucose positron emission tomography (FDG-PET) seems to have a significant impact in measuring treatment efficacy directly after local ablative therapy and has an added value in patient follow-up because it reveals recurrences earlier than conventional diagnostic modalities. Langenhoff et al [71]showed that during a mean follow-up period of 16 months,80% of FDG-PET-positive lesions had a local recurrence and none of the FDG-PET-negative lesions developed a local recurrence. In all patients with recurrence in the liver outside of the treated area, previously negative FDG-PET scans became positive. Extrahepatic recurrence was also associated with positive FDG-PET. It is suggested that the time point of detection of recurrence by FDG-PET is considerably earlier than the detection by CT.

Conclusion
Minimally invasive therapies are gaining increasing attention as an alternative to standard surgical therapies in the treatment of liver cancer. One such option is cryosurgery which is feasible with operative, laparoscopic or percutaneous approach. Its benefits over surgical resection include the anticipated reduction in morbidity and mortality, low cost, suitability for real time image guidance, the ability to perform percutaneously,and the potential application in a wide spectrum of patients, including nonsurgical candidates. Cryosurgery in combination with resection or as sole treatment,can result in radical treatment for patients with liver cancer formerly considered unresectable. Although resection remains the gold standard in treatment of liver cancer, cryosurgery may be as a complement to hepatic resection in those patients in whom liver resection can not achieve complete tumor clearance. Combination of cryosurgery and other techniques (such as radiofrequency) can further increase therapeutic efficacy.

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