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Cryosurgery - Introduction

Introduction and historical notes

James Arnott was the first, in 1845, to make use of the destructive effect of freezing in the treatment of cancer (Gage 1992). Frozen salt solutions (-18C and -22C) were used to treat advanced carcinomas of the breast and of the uterine cervix. The described benefits were lessening of pain, reduction in tumor size, haemorrhage and suppuration. Only at the end of the nineteenth century, however, research on liquid gases (oxygen, nitrogen, hydrogen) made such a progress that a mixture of them could be used in the treatment of skin disorders (Gage, 1992). Cryosurgery became a standard treatment (Zacarian et al., 1966) for malignant skin diseases, where the target tissues were more readily accessible and often smaller. In 1950 it was demonstrated by major experimental investigations that areas for destruction could easily be focused in the brain, heart and liver.

In 1961 modern cryosurgery received a major boost from the development of an automated cryosurgical apparatus in which liquid nitrogen circulated through an insulated metal sheath (Cooper, 1963). Important applications of cryosurgery in the treatment of Parkinson's disease followed in 1963. Cooper suggested that primary and metastatic liver tumors could be treated with cryosurgery and that freezing could produce an immunising effect. Between 1960 and 1970 a great number of cryosurgery experiments to treat cancerous cells were carried out, many on animals and in vitro. The formed cryolesions were circumscribed in situ and gradually reabsorbed by the body; and within six to eight weeks after the procedure they became fibrous scars. Furthermore, Gage and coll. (1982) demonstrated that large vessels had a tolerance for freezing and would not rupture. Cryosurgery thus began to be used for skin, lung, breast, prostate, intestine and pharynx tumors. In initial attempts to destroy liver tumors liquid nitrogen was applied directly to the surface of the liver (Orpwood, 1981; Bischof et al., 1993).

In the eighties two progressive techniques made hepatic cryosurgery generally more feasible: the use of vacuum-insulated probes and of intraoperative ultrasound. Liquid nitrogen produced temperatures below zero (-196C) inside the insulated probe in which it circulated and froze the borders of the tumour; only the edge of the healthy tissue surrounding each lesion was thereby destroyed. It is preferable to use a closed probe instead of an open one where liquid nitrogen comes in direct contact with the liver and may cause embolism.

The development of techniques employing intraoperative ultrasound has led to further cryosurgical applications. When using cryosurgery for malignant hepatic disorders the greatest difficulty lay in determining the exact volume of tissue to be frozen during treatment. The freezing area and the extent of damaged tissue in relation to the tumor margins had to be accurately defined in order to avoid total tissue destruction. Initially cryosurgery was monitored via thermocouples or electrodes (sensitive to changes in tissue impedance). Gilbert et al. (1985) demonstrated in vitro as well as in animals - and others subsequently in a small series of human subjects - , that the entire frozen area can be easily monitored by real-time intraoperative ultrasound. At the end of the eighties cryoprobes were developed in which liquid nitrogen circulated and produced an ice ball around each metastasis; during surgery the probes were controlled by ultrasound. These techniques proved themselves to be effective for tumor ablation. (Korpan N., 2002).

 



Cryosurgical probe testing

 

 



How cryosurgery works

Cryotherapy involves lesions in situ by freezing them so that they meet with coagulation necrosis and in time shrink to a fibrous mass. At temperatures below -20 C, the majority of cells die in immediate consequence of freezing internally and in the second place from vascular thrombosis or from exposure to concentrated electrolytes; however, experimental and clinical reports show that to bring about the death of certain types of cells temperatures of -40/50C are required.
Cryosurgery destroys tissues in a non-selective manner. There is evidence, moreover, that in certain organs healthy cells are possibly more sensitive than tumoral cells to frost damage. A study on human liver tissue by Bischof et al. (1993) indicates that cancerous cells may be more resistant to freezing than normal tissue cells.
Cryosurgery causes tissue destruction and cell death by means of various direct and indirect mechanisms.
Direct cell damage is the physical and chemical result of intracellular ice formation combined with extracellular ice formation and solute-solvent changes which first cause dehydration and then massive rehydration, followed by osmotic lysis of the cells.
Indirect damage arises non only when cells lose their integrity but also from alterations in the single-layer endothelium of the vascular lumen and from the consequent platelet aggregation and disseminated microthrombosis of the capillaries, resulting in ischaemic necrosis and hypoxaemia.
In the case of direct damage from rapid cooling, the mechanism is primarily triggered by the formation of ice crystals inside the cytoplasm.
In the case of indirect damage, the mechanism is triggered by the formation of osmotic contragradients in the different phases of cooling first and of warming afterwards. Actually, the freezing process starts with the generation of ice crystals in every interstitial compartment and therefore the withdrawal of their aqueous component that results in cell dehydration. Cell death takes place in the subsequent warming phase, when the cells are killed by a mechanism known as "solution" or osmotic effect. When the ice crystals in the interstitial tissues melt, the shrunken cells, that have high saline contents, attract water. But the damage to the membranes and to their compensatory mechanisms added to the instantaneousness of the phenomenon, cause the cells to swell so rapidly that they explode.
On the contrary, shrinking is not as strong during rapid freezing, as this produces intracellular crystals that exert a direct mechanical effect on the cell membrane. Bischof et al. (1995) described the mechanisms of cell damage around the cryoprobe and how this influences tumor destruction.
During cryosurgery three principal freezing areas develop in the ice ball around the tip of the cryoprobe: one close to the probe, where the freezing is rapid (temperature of approximately -100C); one in the middle of the ice ball; and a peripheral one where freezing occurs at a slower rate. A temperature gradient of 10C is created for every mm of tissue, reaching a temperature between 0C and -5C outside the ice ball. In the rapid freezing area intracellular ice forms, which is considered lethal for the cells. In the slower cooling peripheral area cellular dehydration occurs, followed by hyperdistension and vascular thrombosis. Both intracellular and extracellular ice is distributed over the intermediate area. The highest level of cytotoxicity is observed near the cryoprobe during the rapid freezing process and the intracellular crystallization that follows it. Cryosurgery generates no aftereffects in the proximity of the great vessels since the blood flow protects them against freezing ("heat sink effect"). Viceversa, the biliary ducts are not protected as well. In the case of lesions that are situated near the large biliary ducts, it would be better to use other methods, such as resection or radiofrequency, and so avoid the risk of causing biliary fistulae.
The choice in probe size depends on the dimensions and location of the lesion (McCarty et al, 1998). 3 mm probes generate a 3 cm ice ball, 5 mm probes produce 4 cm ice balls and 8-10 mm probes produce 5-7 cm ice balls. Flat probes are usually chosen for superficial lesions.
Cryoablation is carried out in a first cycle of variable duration, depending on what type of lesion must be treated. Generally, freezing takes more or less 8-20 minutes, after which the lesion is defrozen. A second freezing cycle is then undertaken in an analogous manner, to increase the effectiveness of the first.
The usefulness of repeating the freezing and warming cycles lies in the fact that frost damage is exponential. For example, if we assume that by lowering the temperature to -20C the number of cells that survive the thermal attack is 10-5, by repeating the freezing procedure the remaining cell survival is 10-10, which obviously means a relevant increase in treatment efficacy.
In the end the cryoprobes are reheated in order to accelerate their removal from the still frozen tissue.
If the procedure requires haemostasis, there are various solutions available. To give one example, Dr. Paganini (General Surgery Clinic - University of Ancona) has devised a method whereby the tissue is covered with a cellulose gauze. When the latter has been activated with a saline solution, a high frequency monopolar current is applied to it by means of an electrosurgical knife.
It is also possible to use different sorts of biological glue or haemostatic activators. As a rule, however, haemorrhagic instances are very moderate and tend to restrict themselves.
Beginning from 1997 (Seifert et al., 1998) an innovative cryosurgical system was set up: it makes use of the Joule-Thompson effect related to the expansion and consequent cooling of compressed gas. With a view to operating costs and practicality, these devices instead of liquid nitrogen use compressed argon gas that reaches a temperature of -185C. Argon can cool more quickly in the initial stages, but produces a smaller iceball than nitrogen, at least as far as the first systems went. Constant technological improvements have recently led to the design of an equipment that is just as efficient as the one employing liquid nitrogen, but is much handier.
Several devices with probes varying in shape and diameter have been created in the following years. Today there are 1mm, 2mm, 3mm, 5mm and 8mm probes available, as well as flat models for superficial lesions and straight or curved models that may also be employed in connection with CT guiding systems.
Systems that run on gas make it possible to produce equipment with multiple cryoprobes for simultaneous use. Their effects do not, however, differ significantly from those obtained by the system that runs on nitrogen.

Technical history

At the time when liquid nitrogen equipment was employed, there were three basic approaches to cryoablation: a direct cutaneous approach (pertaining to dermatology only), a second so-called "open" approach (and primary treatment) and the laparoscopic approach. Later, especially after argon gas equipment had come into use, the following percutaneous techniques were introduced: Rx-guided, CT-guided, MRI-guided and ultrasound-guided.
As for the liver, the open approach may still be the most appropriate in the treatment of multiple, non-confluent, lesions with a diameter anywhere between a few mm and 5-8 cm, which are located deeply within the hepatic parenchyma. The cryoprobe is placed in the nodule either by means of the Seldinger technique or directly. Laparoscopy is suitable for secondary hepatic tumors with no more than three lesions and with a diameter of 5 cm at the most; the cryoprobe is put into place by direct insertion. In the case of deep lesions the pathway to be followed must therefore be traced correctly, by employing special ultrasound transducers.
Histology of surgical lesions has been made the subject of description (Korpan N., 2001). Microscopic examination of the frozen portion of healthy liver reveals haemorrhagic coagulation necrosis of the single hepatocytes with small contracted nuclei and loss of nuclear detail. The cytoplasm is fuzzy and granular and has vague borders.The sinusoids are moderately congested and haemorrhagic. Tumor tissue similarly presents coagulation necrosis with loss of nuclear detail and cytoplasm reduction in the frozen areas. Post-cooling alterations in tumor tissue are more evident than in normal tissue, including definite histological changes with necrosis that may even occur after one freeze-thaw cycle only. There is an abnormal extracellular fluid increase in thawing cryolesions, too. Oedema and haemorrhage are probably responsible for most of the damage that is observed in cryolesions.
When the cryolesions are biopsied a week later they reveal complete destruction of the hepatic architecture and massive eosinophilic infiltration.
Hepatic cryosurgery has another great benefit, i.e. it does not provoke the production of local growth factors, which in their turn favour the accelerated growth of occult micro-metastases; the opposite of what happens after partial hepatic resection (Fisher and Fisher, 1959; Allen et al., 1998).
Freezing twice causes a greater cryodestruction than a single cycle does and is therefore more reliable from the oncological point of view. On the other hand, it can lead to potentially serious side effects such as thrombocytopenia following widespread intravascular coagulation. Besides, it is advisable to reflect carefully whether it is better to use one probe at a time vs. more probes simultaneously. Actually, in some cases - Cuschieri et al., 1995; Franco Lugnani (personal communication) - the second option has caused superficial fractures of the parenchyma, due to differing temperature gradients in each of the ice balls.
El-Shakhs and coll. (1999), have investigated the risk of tumor dissemination as well as the degree of freezing that is necessary to ensure an effective tumor cell destruction. The study was conducted on rats that had been injected with colonic carcinoma which developed in 4-6 weeks. Sixteen of the animals were treated with cryosurgery and sacrificed after 2-4 weeks. Pulmonary metastases were found in 75% of the untreated animals and in 38% of the ones that underwent cryotherapy. Peritoneal metastases were found in 42% of the animals under control and in 50% of the non treated animals. To be effective, freezing temperatures had to be at least -38C. It appears from these studies that cryotherapy does not bring on metastasis, but rather increases the number of T-suppressor lymphocytes.
Anyhow, it is evident that both in animals and human beings cancer originates and develops in different anatomical sites in ways that are independent from treatment.

Clinical case studies of cryotherapy during the period 1990-2001

Steele et al (1990) published a work on 25 cases of metastatic colorectal cancer followed for a median of 20 months. Of these, 7 who had macroscopic residual tumour, died during follow-up. Of the 18 patients who were disease-free at the end of treatment, 11 had intra- or extrahepatic relapses, but not in the treated area. On the other hand the series of cases included treatments to the liver where the number of ranged from 3 to 6. In a subsequent publication (1991) 24 patients were described with a follow-up at 2 years characterised by a survival of 62.5% of which 29% were devoid of disease and 33.5% alive with disease. The same group published follow-up data at 5 years (1991) on 32 patients of whom 24 had colorectal metastases and a median follow-up of 2 years (5-60 months). Overall survival was 62% and disease-free survival was 24%. Survival in cases in which cryotherapy was conducted on all tumoural nodes was 78% in 18 patients, whilst the remaining 24 patients underwent incomplete resections.
Preketes et al (1994) measured the CEA levels in 33 patients with liver metastases and who received intratumoural CT. At a follow-up of 582 days survival was 54.5% and this correlated with a degree of CEA reduction after treatment.
Seifert and Morris (1998) studied prognostic correlation factors and cryotherapy in a trial on 116 patients, 85 of whom were assessed as having been radically treated by the method, with a median follow-up of 20.5 months. 37.1% of the patients survived with a median of 26 months and a survival of 82.4 % at 1 year, 32.3% at 3 years and 13.4% at 5 years. Factors which could be correlated with a favourable prognosis were: age less than 50 years, negative lymph nodes at the resection of the primary tumour, absence of extrahepatic metastases, liver metastases less than or equal to 3 cm, complete destruction of the treated areas, low initial CEA levels and return to normality in the postoperative phase, and absence of transfusion. That cancer is a systemic disease and that physical treatment is only palliative can be supported by the following observations: most of the intrahepatic recurrences take place in other sites in 20-85% of cases; hepatic metastases occur in 60% of cases, while recurrences in treated areas vary from 5% to 44% in patients based on the experience of the surgeons and on the topography of the tumour nodes.
Bilchik (1997) studied the cryoablation of hepatomas and of non-colorectal metastases by examining its effect on serum levels of tumour markers in 20 patients with primary liver cancer (N = 5) or liver metastases (N = 15) from breast cancer, neuroendocrine tumours, 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 tumour marker levels (median 77%) and a significant improvement in symptoms. One patient died of non-tumour 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 non-survivors (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). Cryosurgical ablation of non-colorectal hepatic metastases and primary hepatomas produces a profound reduction in serum levels of tumour markers. It is safe, provides excellent palliation of symptoms, and in selected patients can be performed with curative intent.
Korpan (1997) conducted a study on hepatic cryosurgery for liver metastases on 123 patients (87 men and 36 women). All the patients were followed over a long term, one group (n=63) being randomized for cryosurgery, and a second group (n=60) for conventional surgical techniques. Principally, a self-constructed cryogenic clamp was used for hepatic cryoresection with preliminary freezing of the margin resection by a cryosurgical system "Cryoelectronic-2" or "Cryoelectronic-4". Hepatic cryoextirpation and cryodestruction were performed by means of different probes of with differing disks from 5 mm to 55 mm with a volume of frozen zone of 40 cm3 to 180 cm3 for approximately 7 to 32 minutes. In most cases in group 1 and group 2, liver metastases derived from colorectal cancer. The hepatic cryosurgical procedures in the first group included cryoextirpation in 29 patients (46%), cryoresection in 20 patients (32%), and cryodestruction only in 14 patients (22%). Clinical and laboratory parameters showed that the curative effects were significantly higher in the first group than in the second group. The 3-year survival rate was 60% in the first group and 51% in the second group. The 5-year survival rate was 44% in the first group and 36% in the second group. Twelve patients (19%) in the first group versus 5 patients in the second (8%), survived 10 years. The disease-free survival was in 30% and 18% in the first group and the second group respectively. During a follow-up period, recurrence in the liver was observed in 54 patients (85%) in the first group and in 57 patients (95%) in control subjects. After a 10-year follow-up period in the first group and the second group, 9 patients (14%) versus 3 patients (5%) remained disease free, 3 patients (4%) versus 2 patients (3%) were surviving with disease, and 51 patients (81%) versus 55 patients (92%) died. The data obtained after 10 years suggest that cryosurgery is effective in the treatment of operable and inoperable hepatic metastases. The results show intraoperative tumour reduction and prolonged survival in these patients.
Pergolizzi et al. (1999) conducted a study in which they examined the case of a 68-year-old woman affected by liver cirrhosis for 10 years secondary to chronic active hepatitis C. A lateral segmentectomy was recommended but could not be done due to the severe cirrhosis. Cryosurgery followed by intraoperative ultrasonography was performed successfully. The patient developed recurrent disease at 58 months and died with disease at 62 months. Advanced instrumentation and intraoperative ultrasonography make cryosurgery a viable surgical therapeutic alternative in the management of patients with inoperable hepatocellular carcinoma.
Ruers et al. (2001) conducted a study on 30 patients to determine the long-term efficacy of cryosurgery as an adjunct to hepatic resection in patients with liver metastases, who were judged inoperable. Patients had to meet the following criteria: metastases confined to the liver and judged inoperable, ten or fewer metastases. Cryosurgery alone or combined with hepatic resection was performed. After localization of the liver metastases the cryoprobe was introduced under ultrasonographic guidance into the centre of the tumour. The volume of the tumour that can be frozen with one cryoprobe depends on the diameter of the probe. A cryoprobe with a diameter of 4-6 mm generally results in the formation of an ice ball of 4-6 cm. By introducing more than one probe, an area of approximately 10 cm in diameter can be destroyed. The time of freezing depends on the production of an adequate formation of ice, but generally one freeze period of 20 minutes, followed by thawing for at least 10 minutes is employed. Two freeze-thaw cycles were always performed for each lesion. The results showed a median follow-up of 26 months (9-73). The survival rate at 1 year was 76%, and beyond 2 years was 61%. The median survival was 32 months. The disease-free survival at one year was 35%, while at 2 years was 7%. Six patients developed recurrence at the site of cryosurgery; considering that the total number of cryosurgery-treated lesions was 69 the local recurrence rate was 9 per cent. It was thus concluded that in patients with colorectal liver metastases, local ablative techniques can be used as an effective adjunct to hepatic resection to obtain tumour destruction.
Malafosse et al. (2001) studied hepatic metastases from colorectal tumours which, it is noted represent the major cause of death of patients who have been treated for colorectal adenocarcinoma. Spontaneous survival rarely exceeds two years. The five-year survival rate after surgical resection varies from 20% to 45% according to important prognostic factors. The longer survival is observed in patients with fewer than four lesions, with lesions smaller than 4 cm, without extra-hepatic disease, and whose CEA level is normal. After resection, hepatic recurrence may occur that can be treated with repeat hepatectomy. Cryosurgery can be useful to patients who cannot be treated by means of surgical resection.
Goering et al. (2002) reviews the experience of 42 patients who underwent cryohepatectomy for 48 hepatic tumors between 1991 and 2001 with overall five-year survival rates of 82% at 1 year, 55% at 3 years and 39% at 5 years (median survival, 45 months). Local recurrence-free survival rates comparing resection only (25 cases) and cryosurgery with or without resection (23 cases), at 3 years were for the integrated treatment 24% versus 19%. The survival rates at 5 years of the two groups were 40% versus 37%. These data offer evidence in favour of combined surgery and cryotherapy with a palliative aim.
Menendez et al. (1999) conducted a trial on the use of cryotherapy in patients with soft-tissue sarcoma. Twelve patients with soft tissue tumours of the extremities were included. Cryoablation was performed by inserting cryoprobes into the tumours, through which liquid nitrogen and gaseous nitrogen were pumped to achieve two freeze/thaw cycles. The entire process was monitored with intraoperative ultrasonography. All patients had subsequent resection of the residual tumour. Patients were monitored clinically and metabolically for toxicity. Cryoablation was successfully performed on all 12 patients. Complications included peripheral nerve palsy (in 3 patients) and serious wound drainage (in 3 patients). There were no cases of wound infection, deep venous thrombosis, pulmonary embolism, or metabolic abnormalities. All 3 cases of peripheral nerve palsy needed to stay in hospital, 2 cases for 1 week and 1 for 4 months. The authors concluded that Cryosurgical ablation of soft tissue sarcomas is technically safe and feasible. This method can be used in conjunction with other modalities in the treatment of patients with these tumours. The complications associated with cryoablation of sarcomas are minor or transient, and the procedure is well tolerated by patients.
Seifert and Morris (1999) conducted a questionnaire-based statistical analysis of the complications experienced by 299 patients, out of whom only 134 replied. Seventy-two of the returned questionnaires were from centres specialising hepatic surgery and 62 prostatic surgery. The most serious complication, namely cryoshock was observed in 1% of 2173 patients (1%) and was responsible for death in 6 of 33 cases (18.2%). Shock was extremely rare in prostate cryotherapy (2 of 5432 patients, 0.04%) and did not contribute to the overall mortality. Other complications reported in this survey concerned hepatic insufficiency (12%), haemorrhage (12%), acute myocardial infarction (21%), pneumonia or sepsis (6%), and other incidents statistically non exceeding 3% including hepatorenal syndrome, hepatic insufficiency with pneumonia, bleeding diastasis, portal vein thrombosis, bowel obstruction, acute pancreatitis, peritoneal tuberculosis, pulmonary embolism, and complications arising from thoracentesis.
Kovach et al. (2002) between 1995 and 1999 performed 10 ultrasound-guided cryosurgical procedures on 9 patients with pancreatic cancer which was beyond curability. Four patients had a concurrent gastrojejunostomy, 2 had a splanchnicectomy, and 1 underwent a concurrent hepatic cryosurgical procedure. No mortality, morbidity, pancreatitis or fistulas were observed. The results concerning pain were good, as the palliative procedure was directed towards this symptom.

Table 1. Synopsis of literature on hepatic cryosurgery

 

First Author,

Year

N

Tumour type

Operative approach

Treatment

Median follow-up (months)

Median survival

Disease-free survival

Ravikumar

1991

32

CCR, HCC, O

Lap

C, C/R

24

62% (in general, at 24 months)

24% (at 24 months)

Onik,

1991

18

CCR

Lap

C

23,

mean

21.4, mean of patients with complete remission

22%

Preketes,

1994

33

CCR

Not stated

C/H, C

 

19

 

Weaver,

1995

47

CCR

Lap

C, C/R

26

26

11% (at a median follow-up at 30 months for disease-free patients)

McKinnon,

1996

11

CCR, O

Lap

C, C/R

 

73% (in general, at 29 months)

 

Shafir,

1996

39

CCR, HCC, O

Lap

C, C/R

14,

mean

65% (in general, at a median follow-up )

51% (at a median follow-up )

Korpan,

1997

123

CCR, HCC, O

Lap

C, R

 

60% at 3 years

44% at 5 years

19% at 10 years

30% at 3 years

14% at 10 years

Adam,

1997

63

CCr, HCC

Lap

C, C/R

68% one lesion only treated

16,

mean

Only CCR

77% at 1 year

54% at 2 years

(median not reached)

Only CCR

20% at a median follow-up

Johnson,

1997

42

CCR

Lap

C

14

43% at 14 months

100% at 14 months

(C ) 14.3% at 14 months

(C/R) 71.4% at 8.4 months

Crews,

1997

40

CCR, HCC, O

Lap

C

15

20(CCR)

7.5 (CCR)

Yeh,

1997

24

CCR

Lap

C

19

32.7, mean (median not reached)

23.5, mean

Stubbs,

1998

30

CCR

 

C, H

 

18.2

 

Haddad,

1998

31

CCR, O

Lap

C, C/R

 

18

 

Lezoche,

1998

18

CCR, O

Lap

C

 

78% at 11 months

 

Dwerryhouse,

1998

32

CCR

Lap

C/R, C/R/H

23

29

14 months (C/R)

11 months (C/R/H)

Weaver,

1998

136

CCR

Lap

C, C/R

 

30

 

Schder,

1998

8

CCR, HCC

Perc

C

11.9, mean

 

 

Heniford,

1998

12

CCR, O

Lap

C

11, mean

83% at a median follow-up

58% at a median follow-up

Dale,

1998

12

CCR, O

Lap

C, C/R (6/12 patients received C)

17, mean

100% at a median follow-up

50% at a median follow-up

Pearson,

1999

54

CCR, HCC, O

Lap

C

15

 

 

Wallace,

1999

137

CCR

Lap

C, R, C/R, not treated

14

27(C )

20(C/R)

 

Seifert,

1998

116

CCR

Lap

C, C/R, C/R/H

20.5

26

 

Seifert,

1999

85

CCR

Lap

C, C/R, C/R/H

22

30

11

Seifert,

2000

49

CCR, O

Lap

C, C/R

13

23 (29 for CCR)

43% at follow-up

Bilchik,

2000

240

CCR, HCC, O

Lap

C, C/R

28

 

 

Rivoire,

2000

19

CCR, O

Lap

C

28, mean

26

16% at 4 years

Ruers,

2001

30

CCR

Lap

C, C/R

26

32

17% at follow-up


Abbreviations:
CCR: colorectal cancer; HCC: hepatocellular cancer; O: other; C: cryotherapy;
HA: hepatic arterial perfusion; R: resection; Lap: laparotomy; Perc: percutaneous

Table 2. Recurrence sites following cryotherapy

SITE

PERCENTAGE

CRYOTHERAPY SITE

5-44%

LIVER ONLY OR OTHER

20-85%

EXTRAHEPATIC

6-60%

LIVER/EXTRAHEPATIC

20-59%



Table 3. Complications following cryotherapy

COMPLICATION

PERCENTAGE

LIVER FRACTURE

5-28%

HAEMORRHAGE

3-6.7%

COAGULOPATHY

0.9-4.4%

ACUTE RENAL INSUFFICIENCY

2.4-4%

BILE COLLECTION/BILE LOSS OR FISTULA

2.5-15.3%

ABSCESS

3-22.5%

PLEURITIS

3.7-17%

PNEUMONIA

2-10%

DEATH

0.9-7%


As for laparoscopy or percutaneous treatment, current data are not sufficient to discriminate indications in favour of one or the other. Heniford (1998) studied 12 patients that were operated in laparoscopy, with a follow-up of 11 months, an overall survival rate of 83% and disease-free survival in 58% of cases. Edwin and coll. (2001) treated 8 patients during laparoscopic resection, employing either percutaneous or laparoscopic cryosurgery in two of the cases,. There are no data available on the usefulness of the two procedures.

 

Prostate cancer and cryosurgery

Prostate cancer is the second cause of death in males. The conventional treatments for confined prostate cancer (which does not extend beyond the gland) include surgical removal and radiation treatment. Unfortunately these treatments can result in serious complications. The histological examination of surgically-removed tissue often shows that the cancer has spread beyond the borders of the gland. Surgical resection does not always remove the cancer completely, as has been reported in 50-60% of radical prostatectomy procedures. Radiation therapy is associated with a failure rate of 50-80%. Cryotherapy is an emerging alternative technique for the treatment of prostate cancer.

Cryoablation of the prostate consists in the controlled freezing of the gland in order to destroy both the cancerous cells and the native prostatic cells.

 

In 1968, Soanes and Gonder first performed cryoablation of the prostate and achieved tissue necrosis. In 1970, Bonny reported he had performed cryosurgery with an open perineal approach on 229 patients. In 1988, Onik reported that monitoring the freezing process was feasible by using real-time ultrasound. In 1994, Lee and coll. introduced a more specific cryosurgical technique, basing it on advanced cryotechnology under transrectal ultrasound guidance. To be judged suitable for cryoablation (Crittenton Center of Cryotherapy) candidates must be examined prior to the procedure by means of transrectal ultrasound and prostate biopsy. Knowledge of the exact location and size of the tumor, as well as of the condition of its surroundings e.g. the seminal vesicles, is fundamental to make the treatment succesful. To achieve a high level of accuracy in the procedure, ultrasound equipment with colour-Doppler must be employed. Patients will also undergo bone and pelvic x-rays that assess the absence of metastases far from the surgical site. If distant metastasis or lymph node involvement are diagnosed, the patient is considered unsuitable for cryosurgery. Prior to cryotherapy the patient is subjected for 3-6 months to an antiandrogen therapy which reduces or blocks the stage of the neoplastic cells. On the day before cryosurgery routine blood examinations and an x-ray are required. Most patients will spend the night before surgery in the hospital. Cryosurgery is performed under either general or spinal anesthesia. Usually five to eight punctures are made in the perineum (the region between rectum and scrotum) and a guiding needle is inserted under ultrasound direction in pre-selected locations of the prostate. The guiding needle will then be dilated so that the cryoprobe may be inserted. During the procedure the temperature is monitored via multiple thermocouples placed in strategic points around the gland. Once a warming device has been put into place to protect the urethra, the freezing process may commence. To make sure tissue destruction is effective, at least two freezing cycles will be carried out. The entire prostate will be frozen, including the tumor and the surrounding tissue. The patient is discharged the following morning; he will carry a Foley catheter which will have to stay in place for two to three weeks. After three months patients must return for follow-up ultrasound and PSA control. It is indispensable that further PSA and biopsy controls are performed 6 months, 1 year and 2 years after cryosurgery. Between February, 1993 and February, 1998 at the Crittenton Center of Cryotherapy 603 cryoablations were carried out on 585 patients. Results were good in 485 patients with a median follow-up of 26 months (6-48 months). Sixty-five cases were found to be biopsy-positive which indicated residual cancers and failure of cryosurgery; this corresponded to a percentage of about 13.4%. Where the cancer was confined to the prostate (T1-T2 or stage A, B) the failure percentage was 9%; where it was not, the failure percentage was 25%. Postoperative evaluation showed that 85% of the patients had a PSA level of less than 0.5 ng/mil. Although complications from cryosurgery are the same as from surgery and radiotherapy, their percentage is relatively low.

The most important complication reported is the fistula (abnormal communication between rectum and prostatic urethra), which occurred in 0.25% of patients who underwent cryotherapy. All these patients except one had been submitted to radiation therapy prior to cryosurgery. According to the questionnaires completed by the patients, urinary incontinence resulted in 4.3% of subjects who had never before been treated for prostate cancer. It was reported however that the percentage increased to 11 in those who had had radiotherapy and to 31 in patients submitted to radical prostatectomy. A known side effect of cryotherapy is impotence. It is a consequence of the fact that the tissue surrounding the prostate is intentionally frozen in order to destroy any cancerous cells that might have leaked out of the prostatic capsule. The study showed that only 15% of the patients remained potent (defined in: to have a sufficient erection for penetration) and a further 23% recovered partially. When compared with reports on radical prostatectomy and radiotherapy these figures are essentially the same for all three therapies. Other minor complications include: urinary flow obstruction in 9% of the patients, pelvic pain in 11% and scrotal swelling in 17%. These aftereffects usually disappear after three months. Ninety-six percent of the patients stated that if an operation again became necessary they would choose cryosurgery.

Ghafar et al. (2001) examined the case of 38 men with an average age of 71.9 years who between October, 1997 and September, 2000 underwent cryosurgery for recurrent prostate cancer after the failure of radiation therapy. All patients suffered a return of biochemical disorders, defined as an increase in prostate specific antigen (PSA) and were biopsy-positive. Bone x-rays showed no presence of metastasis. Before cryotherapy was carried out the patients followed an antiandrogen therapy for three months. After cryotherapy the PSA level decreased in 31 patients (81.5%). After one year 86% of the patients was biochemically recurrence-free according to the Kaplan-Meier curve and after two years 74%. Reported side effects included rectal pain in 39.5% of the patients, urinary tract infection in 2.6%, incontinence in 7.9%, hematuria in 7.9% and scrotal oedema in 10.5%. There were no cases of rectourethral fistulae and urinary retention. This study therefore supports cryosurgery as a safe and effective treatment for patients that do not benefit from radiation therapy.

Clarke et al. (2001) investigated their assumption that the combination of chemotherapy and cryosurgery would result in cell death and would so represent a more effective treatment of prostate cancer. A human prostate cancer (PC-3) model was exposed to 5-FU for 2 and 4 days prior to freezing (from -5 to -100C), or to a combination of the two treatments; each of the options was controlled for a period of 2 weeks after the treatment. Research on the mechanism of cell death was conducted through DNA sequencing. As for chemo-therapy, cultures were exposed to 5-FU (2-4 days). As for cryotherapy, cultures were exposed to temperatures of -5/-25C, that caused an initial loss of vitality between 5% and 70%. Cultures that were exposed to temperatures of -25/-80 C showed an initial loss in cell activity between 90% and 99% and cell repopulation after 12 days. Cells were then frozen at -100C which resulted in a 100% loss of activity and no signs of recovery. The combined therapy caused a loss of cell activity similar to that of sole freezing at -5/-25C. At temperatures of -40/-80C the same therapy achieved a complete loss of cell vitality. DNA analysis after 48 hours revealed that the cells that had been treated with 5-FU died from apoptosis, whereas the cells that had been treated with cryotherapy died from frost-rupture and necrosis. The three causes for cell death were all present after the combined treatment. These results show that the chemo-cryotherapy combination may be an alternative treatment for the control and eradication of prostate cancer.

Izawa et al. (2001) carried out a research (between July, 1992 and January, 1995) on 145 patients whom they treated with cryotherapy for prostate cancer. After treatment biopsies were taken in 107 cases and resulted positive in 23 (21%). Among patients whose disease had been at an initial clinical stage T1-2N0M0 and whose PSA level had not exceeded 10 ng/mil, there was a high percentage of negative biopsies. The best candidates for cryotherapy were patients affected by locally recurrent prostate adenocarcinoma after external beam radio-therapy. The authors asserted that to optimize local control, the cryotherapy technique should consist in two subsequent freezing cycles and be performed with at least 5 cryoprobes. The postoperative PSA level signals clearly whether the treatment has been a success or a failure.

 

Cryomyolysis of uterine fibromas

Garzetti and coll. of the Gynaecology and Obstetrics Clinic of the University of Ancona reported (Rome 2002) on 61 cases of uterine fibromas submitted to laparoscopic cryomyolysis treatment between January, 1998 and December, 2001.

Cryomyolysis can be proposed as an alternative to laparoscopic myomectomy in cases of large (>5cm) and multiple (>2) intramural fibromas in women over 40 years, whose reproductive cycle has been concluded, but who wish to avoid a future hysterectomy.

Its purpose is to destroy the myoma, thereby causing tumor atrophy: it is a mininvasive technique if compared to myomectomy and requires less time as well as less training for the operator.

 

Criteria for inclusion:

  • age between 40 and 45 years

  • single or multiple nodular uterine fibromatosis, 5 fibromas at the most and dimensions smaller than 10cm (ultrasound assessment with 3.5 Mhz transvaginal and/or transabdominal probe)

  • uterine annexes within the normal range

  • written informed consent;

Exclusion criteria:

  • indication for total hysterectomy

  • previous myomectomy or other uterine surgery with the exception of Caesarean section

  • blood creatinine >= 1.5

  • contraindications for laparoscopic procedure

  • contraindications for the use of GnRH analogues

  • unwillingness to cooperate in follow-up

Before undergoing laparoscopic cryomyolysis, of the 61 patients considered:

  • 26/61 (41.6%) reported menometrorrhagia
  • 14/61 (22.9%) was symptom-free and fibroma/s was/were discovered incidentally during ultrasound examination for other reasons conducted incidentally

  • 17/61 (27.8%) reported dysmenorrhoea

  • 4/61 (6.5%) reported pelvic pain

The results of the performed treatments are summarized in the following table:

The study therefore showed:

  • an overall reduction in average myoma size of 39.72% 32.7%

  • an overall reduction in average myoma volume of 60.28% 20.73%

From a symptomatological point of view:

At the follow-up the initial symptoms had disappeared in all patients except 3; in 2 patients menometrorrhagic symptoms persisted and became more serious, so that they had to undergo a laparohysterectomy elsewhere, and in one patient the menometrorrhagic symptoms were replaced by slight intramenstrual spotting.

 

Prostatic tumours

Out of all the experience gathered in Italy on prostate cancer treatment, we quote a report delivered by Prof. Muzzonigro et al. at the World Endourology Meeting in 2002.

Sixty patients (averagely 71.6 years old) underwent treatment with ultrasound- and thermoguided transperineal percutaneous cryoablation of the prostate. Preoperative clinical stages: 21 (35%) cT1-2, 19 cT2b (32%), 20 cT3a (33%). PSA 14.7 ng/ml 10. One patient suffered from recurrence after definitive radiotherapy, one after failure of prior cryoablation.

The patients underwent postoperative assessment through PSA, testosteronemia and ultrasound examinations, and through prostatic biopsies at 6/12/24 months.

At the time the study was presented, for 51 of the patients the follow up had lasted more than 6 months (median 21, 6-52): in 25 patients (53%) the PSA was <0.5ng/ml, in 12 (23.5%) between 0.5-1.0 ng/ml and in 12 (23.5%) it was > 1ng/ml. Eight of the 51 patients(15.7%) resulted biopsy-positive: five of them also had an increasing PSA, whereas in the remaining three the PSA levels were stable. Furthermore three of the 51 patients (5.9%) were in biochemical progression (PSA >1) although their biopsies were negative.

Complications were impotence in 75% of the cases and temporary stress or urge incontinence (16%). Subsequently two of these patients continued using a napkin a day as a safeguard against sporadic urine leakage.

In the first 30 days 30% of the patients endured minor complications such as haematuria, oedema and infection. Later on, some suffered retarded episodes of perineal pain (6/60) or sloughing syndrome (8/60) and/or had to undergo a TURP for the removal of necrotic tissue that obstructed the lumen of the prostatic urethra (6/60).

CONCLUSIONS

By way of a final summary, it is possibile to draw the following observations from all the above listed literature:

Cryoablation, especially if carried out with a percutaneous technique under CT or ultrasound guidance, is a mininvasive treatment for parenchymatous tumours, that causes the patient nearly no discomfort and allows for a rapid postoperative recovery and therefore a very short stay in the hospital.

The standard of mininvasiveness with respect to traditional surgery applies also when open or laparoscopic techniques are used.

In some cases cryosurgery may offer patients the opportunity to be treated effectively even when other therapies either cannot be performed or do not have the same efficacy.

Cryoablation is a normal (though not the only) treatment in the following cases and has the following features:

A) KIDNEY TUMOURS

  • Open, laparoscopic, percutaneous techniques

  • Treatment repeatability

  • Enables freezing of tumours situated in the proximity of the collecting system

  • Does not hamper kidney functions in the long term and does not lead to urinary extravasation or caliceal fistulae.

  • Ideal for mixed and central exophytic lesions.

  • Nephron-sparing, independently of the local thermal conditions.

B) PULMONARY AND THORACIC TUMORS

  • Open, thoracoscopic, percutaneous techniques

  • Treatment repeatability

  • Possibility to freeze inside trachea and bronchi, whilst reducing any complications to a minimum

  • Effective treatment even when lesions are situated close to the large vessels

  • Nearly all pulmonary areas are treatable

  • Indicated for patients with reduced pulmonary function

  • Possible for otherwise inoperable patients

  • Debulking of voluminous and metastatic tumors with a possible effect of activating the immunity system, and consequent improvement of the overall prognosis.

C) LIVER TUMOURS

  • Open, laparoscopic, percutaneous techniques
  • Treatment repeatability

  • Ice clearly visible and the possibility to monitor procedures by ultrasound, CT or open coil MRI in order to treat the tumor without harming the sensitive surroundings.

  • Possibility to treat peripheral or capsular lesions under local anaesthetic using a CT or ultrasound guided percutaneous technique, causing the patient minimum pain and discomfort.

  • Possibility to either treat multifocal and bilobar disease simultaneously or treat large lesions with multiple probes.

  • Possibility to efffectively treat lesions even in proximity of the large vessels

  • Possible for otherwise inoperable patients

  • Debulking of voluminous and metastatic tumours with a possible effect of activating the immunity system, and consequent improvement of the overall prognosis.

D) PROSTATE TUMOURS

  • Ultrasound-guided transperineal percutaneous technique
  • Treatment repeatability

  • Possibility to treat prostate tumors of all grades and stages

  • Definitive treatment for locally-confined tumors

  • Possibly definitive treatment even for locally advanced tumors

  • Great effectiveness for high grade tumors (Gleason 8/9/10)

  • Can be utilized when radiotherapy fails

  • Low complication rate

  • Effective obstruction removal so that no further surgery is required

  • Possible in otherwise inoperable patients

  • Debulking of voluminous and metastatic tumors with a possible effect of activating the immunity system, and consequent improvement of overall prognosis

  • Saving of welfare money since patients who would otherwise need radiotherapy can benefit from a less expensive treatment

  • Possibility of sparing patients chronic hormone treatment and therefore saving of welfare money.

  • Very short hospital stay

  • Can also be applied in "minor" ORs so that the employment of major ORs is no longer indispensable.

E) PALLIATIVE INTERVENTIONS

  • Open, laparoscopic, percutaneous technique

  • Repeatability of treatment

  • Marked pain reduction for patients with bone metastases without the increase of short-term pain which arise when other methods are used

  • Maintenance of the collagenous architecture of the nerve endings can enable the immediate reduction of pain with the associated metastatic disease.

  • Treatment of large zones and geometrically difficult tumours in a single treatment with multiple probes and high visibility in the soft tissues.

CRYOSURGERY THEREFORE HAS THE FOLLOWING SPECIFIC CHARACTERISTICS WHICH ARE EXCLUSIVE WITH RESPECT TO OTHER ABLATIVE MINI-INVASIVE TREATMENTS, TYPICALLY, BUT NOT SOLELY, USABLE IN PERCUTANEOUS TREATMENTS (PERCRYO)

  • HIGH VISIBILITY UNDER CT-GUIDANCE OR ULTRASOUND GUIDANCE

The very high degree of visibility of PerCryo, under image guidance, can diminish the quantity of tumour inadequately treated. With CT-imaging, the ice ball is visible with a drop in attenuation of 40 Hounsfeld units and with ultrasound the ice appears with a hyperechogenic rim and posterior shadow cone which can be easily identified.

Improved monitoring during the procedure results in a more reliable verification of the ablation zone.

  • REDUCED ALGOGENESIS DURING AND AFTER THE PROCEDURE

The formation of ice by PerCryo is a natural anaesthetic. It enables a wide variety of patients to be treated with minimal discomfort during the procedure, to simplify patient sedation requirements, to use less analgesics and assists in a more rapid recovery.

  • IT DOES NOT DESTROY COLLAGEN

PerCryo leaves the tissue architecture intact. This permits treatment in the area near to the critical structures, such as the collecting system of the kidney or the area near the trachea. In this way, tissue architecture is spared and allows the system to function after treatment.

  • ICE PROPAGATION IS PREDICTABLE AND REPRODUCIBLE

The reproducible growth of the ice in the PerCryo procedure and the predictability of success enable the procedure to be highly controllable with a high degree of consistency of results. The reproducibility of ice formation can be easily planned, and then safely monitored.

  • MULTIPLE CRYOPROBES MAY BE USED SIMUNTANEOUSLY

During the PerCryo procedure, multiple probes can be used simultaneously. This gives PerCryo a large volume of tissue ablation, plus the ability to treat multiple tumours concurrently.

Furthermore it is important to note that a single probe (CryoProbe) can create an ice-ball of 4x6cm, that up to eight probes can be used simultaneously and that several devices can be used to monitor and control them individually and independently.

PerCryo has the widest range of uses with respect to any other ablation treatment. It is approved for benign tumour ablation, palliative interventions and the ablation of cancerous lesions (FDA).

 

 
 
 
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