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Федеральное государственное бюджетное учреждение науки
"Институт токсикологии Федерального медико-биологического агентства"

Институт теоретической и экспериментальной биофизики Российской академии наук.


Адрес редакции и реквизиты

199406, Санкт-Петербург, ул.Гаванская, д. 49, корп.2

ISSN 1999-6314

Российская поисковая система

ТОМ 2, СТ. 24 (стр. 144) // Июль, 2001 г.


А.Ю.Баранов, В.Н.Кидалов. Лечение холодом. Криомедицина.
СПб, Изд-во "Антон", 1999, 271 С.

А.В.Максимов, В.В.Кирьянова. Аэрокриотерапия. Учебное пособие.
СПб, СПбМАПО, 2000, 12 С.

Cryotherapy of hepatic tumors

Cryoablation in treatment of livers lesions


G. A. Pistorius
Dept.of Surgery, University of Saarland, D-66421 Homburg/Saar

Background: Up to 25% the patients with malignancies (e.g. colorectal cancer) will present with synchronous liver metastases at the time of the original operation and 50% of all patients with colonic cancer develop liver involvement ultimately.

Surgical resection continues to be the gold standard in the treatment of hepatic metastases. Unfortunately, only 20 - 25% of these patients will have resectable hepatic metastases due to the number and location of the tumors. The outcome of primary and secondary tumors is poor when resection can not be achieved.
In the last years different techniques of local tumor destruction have been developed. Cryotherapy is apart from interstitial therapy, the only modality which allows the treatment of critical resection margins.

Patients: Between 8/1993 and 12/2000 cryotherapy was performed in 145 patients (liver metastases 127, primary hepatic tumors 18) using the new developed cryosurgical system CRYO 6 (ERBE Company, Tubingen, Germany). The mean age was 62,9 years. Patients included 94 males and 51 females. 74 patients underwent open cryotherapy alone, 55 patients were treated with cryotherapy in combination with resection and 16 had a percutaneous approach.

Results: 19 patients (13,1%) developed therapy related complications (hemorrhage 6,2%; thrombopenia 3,4%; cryoshock 2,1%), 16 patients (11%) showed general complications. The complication rate was significantly higher with primary tumors compared to metastases (41,2% vs. 9,5%). Therapy related mortality was 1,6% with metastases and 2,8% in all patients. The mean survival time was 36.9 + 2,9 months.

Conclusion: Cryotherapy is safe and increases the number of patients with unresectable liver malignancies in whom surgery can aim at eradicating the tumor. Cryodestruction of the resection margin reduces the number of palliative resections and will optimize surgical treatment.

В кн.: Достижения криомедицины. Санкт-Петербург, Изд-во "Наука", 2001.С.113-114.


Prokhorov G.G., Litvinov O.A., Prokhorov D.G.
Clinical Hospital of Russian Academy of Sciences. Saint-Petersburg, Central Research Institute for X-ray and Radiology Russia

This report generalize our 3-year experience with cryosurgery of liver tumors. In the period with 1997 for 2000 10 patients (7 men and 3 woman) were entered into this study. The liver was exposed with laparotomy and tumors were subjected to one or two freezing-thawing cycles using liquid nitrogen (temperature -196 N) delivered by five electrodes by a diameter of 3,85 mm. The cryoablation was monitored with intraoperative ultrasonography. The histologic characteristics of the tumors were, as follows: lesions of colorectal cancer, 6 patients; lesions of stomach cancer, 2 patients. The follow-up period ranged from 71 about 446 days ( median follow-up 233,7+? 43,3 days). 6 patients in the period from 2 about 10 months have died. Two patients are alive, one of them lives more than year with attributes of a relapse of disease in a liver. In given clause we estimate opportunities and efficiency of cryosurgery in the treatment of the large size livers lesions.

The average age of the patients has made 57,5 years (from 46 till 65 years). The diagnosis of livers lesions was established on the basis of the data of ultrasonography and computed tomography. Cryodestruction was carried out in cases, when the attributes of unresectable tumors of a liver took place ( 1, 9 ): multiple lesions, tumors localization in immediate proximity from major vessels, such as the portal vein and the cava vein, heavy accompanying pathology not allowing to execute a resection of a liver. Preoperative clinical and biochemical analyses of blood, liver function tests, coagulation test , abdominal computed tomography and liver ultrasonography were performed in all patients. Bilateral anatomic location were detected in 5 cases, 3 patients had a single node. In 4 cases lesions amazed the eighth segment in a mouth of hepatic veins and involved in a process a wall of the cava vein. Synchronous lesions were at 3 patients, metachronous - at five. Computed tomography and ultrasonography were used in radiologic evaluation of tumor response and recurrence. We did not perform regional or systemic chemotherapy after cryodestruction.

Cryodestruction was carried out on a standard technique by an open way ( 1, 4 ). Operative access to a liver carried out by a right subcostal incision . The liver was examined bimanual and peritoneal cavity was explored to rule out extrahepatic disease. An intraoperative ultrasound unit (" Aloca -630 ", "Philips-360") was used to obtain real time of the entire liver. The 5 mHz linear-array transducers were used for this scanning. 3,85 mm probes of trocar desing were used for hepatic cryoablation. Plate probes by a diameter of 40 mm applied to freeze livers surface lesions. The probe was driven by a cryosurgical system LCS 3000 Candela USA that circulates the liquid nitrogen (temperature -196 C) through the probe. A site of probes in the lesions, and also process of freezing - thawing supervised with intraoperative ultrasonography. Cryosurgical ablation was utilized with placement up to 5 cryoprobes simultaneously to expand ice ball over all metastases. Intraoperative ultrasound measured ice ball formation, the aim being to achieve a 1 cm ice ball marging around the lesion. With this purpose it was necessary to carry out change of positions of electrodes. The maximal size of a tumor, which allowed to execute adequate cryodestruction of lesion by simultaneous installation probes by a diameter of 3,85 mm did not exceed 40 mm. The freezing portion of each freezing-thawing cycle took 15 - 20 minutes, and thawing took approximately 20 - 25 minutes. The spontaneous thawing a little bit extended time of operation, however allowed to save stocks of nitrogen in the cryosystem, that is important at the large tumors sizes for adequate cryodestruction. Single or double freezing-thawing cycles carried out for each lesion. The choice of a cryodestructions mode in each concrete case depend on general number of lesions, their sizes, and it anatomic localization, also a condition of the patient during operation, combination of cryodestruction with other kinds of operations. The probe was withdrawn after complete warming and the tract was packed with an absorbable knitted fabric. The livers wounds were sutured to minimize bleeding. From 8 patients a single freezing-thawing cycle was conducted up to 7 patients, double freezing-thawing cycle was performed in 1 case. RESULTS
In the period with 1997 for 2000 8 patients entered into this study. Their average age has made 57,5 years (from 46 till 65 years). In all cases the tumors of a liver carried metastatic character. The histologic types of tumors included metastases of a colorectal cancer in 6 patients, metastases of a stomach cancer in 2 patients. Metachronous lesions were at 5 patients, synchronous - at 3. In all cases there were adenocarcinoma of different kind of . To all patients cryodestruction carried out through 3 - 48 months after resection of a primary tumor. The basic clinical data on the patients are submitted in the table 1.

Number of the patients 8
Average age 57,5 years
Woman 3
Man 7
Percentage hepatic replacement by tumors ( PHR )  
< 25 % 2
25 - 50 % 4
> 50 % 4
Liver disease only 6
Liver and extrahepatic disease 2
Number of lesions present ( mean ) 6,25 +(-) 2,4
Range 1 - 19
Average diameter of lesions 3,31 +(-) 0,48 см
Range 0,8 - 13 см
Follow up in days 233,7 +(-) 43,3 days
Range 71 - 446 days

The combined operations were executed in 3 patients. Сryoablation was combined with cholecystectomy in 1 patient , with nephrectomy in 1 patient, with cryodestruction of pelvis metastases in 1 patient. The median hospital stay was 14 days (range 2 - 18 days). There were no intraoperative and postoperative complications . The duration of operations was 5 hours 42 mines + 39,1 mines (from 3 hours 45 mines to 9 hours 25 mines). Average blood loss was 650 + 197,3 ml (ranged from 400 to 1200 ml). The intraoperative bleeding from the probe tract was controlled by packing with an absorbable knitted fabric. Patients spend from 2 to 3 days in the intensive care unit. Transient elevation of liver enzymes (more than in 7 times on 2 - 3 day after operation) and leukocytosis (up to 18 thousand) were observed. Those levels normalized by the 10 postoperative day. The patients had temperature high as 38 - 39 C for 6 - 7 days after operation, in 1 case for 20 days as a reaction on cryoablation with negative cultures for any sings of systemic sepsis or purulent complications. Serum leak for 14 days was seen in 1 patients who had undergone cryoablation of large surface lesion(the lesions diameter 10,8 cm).
A perioperative complication occured in case when a double freezing- thawing cycle was carried out. One patient died over 5 days after thromboembolie. Second patient died over 12 hours after operation due to cryoshock. He had bilateral lesions localisation and percentage hepatic replacement by tumors 25- 50 %. As known ( 2, 3 ) intraoperative coagulation disturbances can be exacerbated by general hypothermia, and warming device surrounding the patients body and administer warming fluid and plasma (300-600 ml) was routinely used. But long term hypothermia ( duration of operation was 9 hours 25 mines, there were 12 freezing-thawing cycles, the patients temperature in the end of operation was 32 C) led to coagulopathy and multiple organ failure. On our data within first three hours of operation there were a general decrease of temperature of a body of the patient not less than on 1,5 C. In process of increase of duration of operation and increase of duration of general hypothermia temperature of a body was reduced more considerably.
The follow-up period ranged from 71 about 446 days (without the account of the patient died from cryoshock), median follow-up - 233,7 + 43,3 days. Two patients are alive up to the present moment, 6 patients died of recurrent tumors from 71 to 280 days after cryoablation.
The most important prognostic indicators were the size tumors treated expressed as percentage hepatic replacement ( PHR ) ( 3 ), anatomic lesions localization and combination liver disease with extrahepatic disease. For a PHR < 25 % ( n = 2 ) the median survival was 323 + 123 days. Both patients were alive. One of them had residual disease. He underwent bowel resection of colorectal cancer recurrence 8 months following the cryosurgical procedure. It was detected recurrence tumors in places of lesions cryodestruction and in the over parts of the liver. Both patients was performed single freezing-thawing cycle of cryoablation. It is obvious, that in a case of recurrence of a primary tumor the clinical effect of lesions cryoablation is reduced and it is not necessary to expect for substantial growth of median survival of the patients. The follow-up period of the second patient are 200 days, and now there are no tool attributes of progressive growth metastases in a liver.
Of the 6 patients with colorectal metastases one had evidence of residual disease ( extrahepatic pelvic disease ) documented at the time of cryosurgery. Two patients had percentage hepatic replacement > 50 %, two patients were with PHR 25-50 % and had from 10 to 19 lesions. One of patient with PHR > 50 % had large lesion in pelvis (diameter 10 cm). He was performed a single freezing-thawing cycle cryodestraction livers metastases combined with cryoablation pelvic lesion. The patient lived after operation 9 months. The follow-up period the second patient with PHR > 50 % and central localization of metastases was 71 days.
Of the 2 patients with stomach metastases one had evidence of residual disease ( extrahepatic nodal disease ). Both patients had percentage hepatic replacement by tumors 25 - 50 %. Long-term disease control was not achieved in any of these cases.
We used 3,85 mm cryoprobes to increase safety in the passage of probes through the liver and reduce blood loss. But we had to perform lesions cryoablation in several positions of probes to expand ice ball over all metastases when it had been more 40 mm in diameter. In patients with PHR 25 - 50 % and > 50 % only single freezing-thawing cycle cryotherapy could be available .Our trying to do double freezing-thawing cycl cryoablation led to cryoshock. Median survival in patient with PHR > 25 % was 198 + 36,2 days, that correlated with untreated hepatic metastases median survival ( 6, 7, 8 ).
Our data suggested that single freezing-thawing cryodestruction of large metastases in the liver have not essential increased survival rate. Our experience has shown that double freezing such largest lesions can lead to ensuring of cryoshock. Than is more lesions diameter , than is more their amount, than closer they are located to major vessels, such as vein cava , hepatic veins , the worse results of cryoablation. Bad prognostic indicators are also a combination liver disease with extrahepatic disease and a recurrence of primary tumor. The performance of cryoablation of the livers lesions located closely to a mouth of hepatic veins and involve in a process a wall of the vein cava does not result in damage of veins wall because of powerful bloodstream in the vessels.
Finally we suspected that the good clinical effect from the cryodestruction is possible to expect at the patients with colorectal cancer livers lesions with percentage hepatic replacement by tumors less than 25 % and absence extrahepatic metastases at performance of double freezing-thawing cycle.

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Original text.

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