Prognosis of unnresectable hepatocellular carcinoma is very poor.In Japan,the median suvival for 229 patients received no specific treatment was 1.6 months[5].Although chemoembolization is associated with good objective responses in the tumor,a recent controlled trial showed that,by itself,chemoembolization offers no improvement in survival compared with supportive therapy alone[6].During the past years,much efforts have been paid to improve the survival of this disease[7]. In this trial,percutaneous cryoablation in combination with PEI showed more satisfactory therapeutic efficacy. 65 HCC patients,who received this combination therapy, were given a follow-up of median duration of 14 months.50.8 % of patients are currently free of disease with an average follow-up of 13.8 months. 33.8 % are alive although there are disease recurrences. 78% of the patients are alive,in spite of disease recurrence. Only12.3 % have died with their disease recurrence with an overall survival of 13.2 months.88.4% of patients who had CT scan available for review, had a shrinkage of tumor masses,and biopsy showed that the mass tissue had dead tumor cells or scar in much majority of patients. 91.3% of patients who had an increased AFP preablatively, had a decrease of AFP levels during postablative 3-6 months.
    Present result is comparable with those by other authors.Crews et al[8] 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[9] gave 4 patients with recurrent HCC after previous curative hepatectomy to treat with cryoablation.All patients were still alive with survival after cryoablation ranging from 12-23 month.Sheen et al[10] have demonstrated that the median survival for HCC patients after cryoablation was 36 months. Zhou et al[11,12] found 1-,3-,and 5-year survival rates of 78%,54%,and 40%,respectively,for 235 HCC patients received intraoperative cryosurgery.It is necessary to note that the cryoablation reported by those authors was mainly performed through intraoperative approach with a large invasion,while in present trial cryoablation was performed percutaneously,being minimally invasive and allowing for a rapid recovery.
    Cryoablation is a method of in situ tumor ablation.A circulated cryogen is used to target tumor tissue to induce irreversible tissue destruction at temperature below 40°C.Tumor cell death is caused by both direct and indirect mechanisms.The direct cellular damage is a result of intra- and extra-cellular ice crystal formation and solute-solvent shifts,which induce cell dehydration and rupture.The indirect effect results from vessel obliteration with resulting ischemic hypoxia[13,14].
    As alocal therapy,cryoablation carries certain advantages over other forms of HCC treatment[15].First,it is able to destroy only the tumor tissue in liver while sparing more noninvolved tissue,that is of particularly important significance to HCC patients,because the majority of these patients have cirrhosis and decreased reserve of liver function[16].Second,because of the warming effect of flowing blood,large blood vessels, such as in inferior vena cava and portal vein,are somewhat imperious to the effect of freezing.Therfore,tumors close to these venous system can safely undergo cryoablation,whereas resection of tumor close to large vascular structures is very difficult[17].Third, it is known that liver cirrhosis is basis of HCC development,if the entire liver is cirrhotic,then any part of the liver can develop new tumor.Perhaps liver cryoablation is more effective than surgical resection in treating multiple new tumors[13] .Forth,in contrast with other local ablation,such as radiofrequency,which is difficult to reliably destroy tumor greater than 5 cm in diameter,cryoablation is a promising means in the treatment of this larger form of tumor[2] Lastly,the rapid freeze-thaw process enhances necrosis and is purported to induce an autoimmune response against the surviving tumor cells[18].
    During cryoablation of tumor,there are three main areas of freezing:(1) in the center of iceball ,near the cryoprobe,where freezing is rapid and the temperature is lowest;(2)in the middle of the iceball,where the tissue experiences intermediate cooling rate;and (3)at the periphery of the iceball,where slow rates of cooling occur[18].The cytotoxic effect from rapid cooling is greatest in 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 may result in recurrence of disease. PEI has been used extensively for treatment of HCC.Ethanol diffuses into the cell and causes nonselective protein denaturation and cellular dehydration,leading to coagulation necrosis.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 tissue. It is obvious that combination of cryoablation and PEI had a complementary effects for preventing recurrence[18]. In present series ,PEI was given in 36 patients with tumor mass larger than 6 cm in diameter since 1-2 weeks after cryoablation,that may be contributory to the better outcome.Moreover, among the 17 patients who had recurrent tumor only 3 had recurrence at the original cryosite,that suggests the effectiveness of this combination therapy as well.
    Cryoablation is relatively safe modality[10].Transient intracryosurgical hypothermia and elevation of parenchymal hepatic enzymes are the most common side effects.The use of warming blankets and fluid warmers has been proven beneficial.Transient thrombocytopenia and hypoglycemia have been observed.Patients should be observed for possible coagulopathy when large tumor (greater than 5 cm) have been frozen.Pleural effusions may occur in tumor mass treated close to the dome of the diaphragm.Craking of the hepatic capsule may occur during the thawing process[13,17,19],that was seen in one patients in present series.It is one of the most serious complications of hepatic cryoablation, may be controlled with conservative therapies for majority of cases.Cryoshock ,that is manifested by varying degrees of acute renal failure,disseminated intravascular coagulation and adult respiratory distress syndrome, reported by some authors,was not seen in present series.It is shown that cryoshock occurs in proportion to the volume of tissue treated(greater than 40 percent) [15],and lesions over 6 cm were associated with a greater risk[20].However,lesions up to 10 cm in size were treated safely in present series.It is shown that this complication may be related more to the total duration of the cryoablation than to the volume of tumour treated[10]. Nevertheless,it is necessary to prevent the disastrous complication. DiurDiuresis with mannitol and alkalinization of urine should be used in all patients to avoid myoglobinuria and subsequent renal damage[8].PEI has proved safe,and no significant complication was associated with PEI in present series.
    In conclusion,this technique offers the possibility of curative treatment options for HCC that cannot be surgically removed owing to the anatomic location of the tumor and the presence of other comorbid conditions that otherwise preclude a major liver resection. Percutaneous approach has the advantage of being minimally invasive and allows for a rapid recovery,and does not bring appreciable complications.The integration of this technique with other adjuvant regional modalities,especially PEI,may be as an alternative to resection ,with the possibility of effecting long-term,disease-free survival in selected patients.