|
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 (-18°C and -22°C) 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 (-196°C) 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).
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 -40/50°C 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 -100°C); one in the
middle of the ice ball; and a peripheral one where freezing occurs at a slower
rate. A temperature gradient of 10°C is created for every mm of tissue,
reaching a temperature between 0°C and
-5°C 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 -20°C 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 -185°C. 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 -38°C. 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
|
|
|
Schüder,
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 -100°C), 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/-25°C,
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 -100°C 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/-25°C. At
temperatures of -40/-80°C 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:
-
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:
-
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:
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)
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.
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.
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.
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.
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).
|
