G.Prochorov, V.Konusova, A.Simbircev, A.Popovitch
Clinical Hospital of Russian Academy of Science, St.Petersburg,
INTRODUCTION&OBJECTIVITIE: In an effort to enhance the T cells,
several strategies have recently been explored aimed at creating
therapeutic cancer vaccines. In case of tumor, as prostate cancer,
for which the relevant tumor antigens are unknown, this approach
has used the tumor cell itself as a source of antigen, modifying
it in vitro to express immunomodulatory proteins such as cytokines.
These studies have demonstrated in experiments that vaccination
with tumor cells modified in this way frequently leads to the generation
of systemic, tumor- specific immunity. In our opinion,the cryodestruction
of prostate cancer may be as an optimal model of so-called "specific
METHODS: In an ongoing pilot study the standard palliative (single
freezing) procedure of cryosurgical ablation of the prostate(CSAP)
has been carried out in 5 patients with T4N1-3M1 (D2) stage and
>6 months follow-up. Before it during 1-2 days we have injected
subcutaneously the solution of recombinant human interleukin-1-b
(rHuIL-1b) in dose 40 ng/kg (produced by Scientific Institution
of High Pure Bioproducts, St.Petersburg, Russia). In next day after
CSAP additionally we have performed the intratumor injection of
this agent (up to 10 ng). For enhancing of immune response we have
then continued this systemic immunotherapy during post-operative.
Follow-up included the routine clinical investigation, prostatic
specific antigen (PSA), X-rays and scintigraphy of scelet, computer
tomography and magnetic nuclear resonance imaging of abdominal and
pelvic cavity, thorough immunomonitoring.
RESULTS: In 3 cases we have investigated the clinical remission
of metastatic lesions, biochemical significant failure of PSA (from
83 to 125 ng/ml initially to 15 - 45 consequently), improvement
of quality of life, indirect features of increasing of tumor-specific
immunity (increasing of quantitative parameters of antigen activation;
enhancing of functional activity of lymphocytes, stimulation of
IL-2, IL-8 etc.). It was a very important proposal to support this
specific immune response not by means of consequential cryotherapy,
but the repeated immunotherapy by rHuIL-1-b. In 1 case we have reached
the partial immune response with regression of some metastases from
solid organs (not osteolytic origin). In 1 case with terminal stage
of D2 patient was died due to the polyorgan failure as the result
of the toxic complications of the intensive scheme of cry-chemotherapy.
CONCLUSION: Our initial results of pilot-study encourage about possible
efficacy of this therapeutic modality for advanced prostate cancer.
In comparing with previous studies the enhancing of tumor-specific
immunity may be achieved not at all by the consequential cryotherapy,
but the repeated course of systemic immunotherapy by rHuIL-1-b.
The continuation this study is needed to proven main idea futher.
THE CLINICAL APPLICATION OF CRYOIMMUNOTHERAPY FOR ADVANCED PROSTATE
P R O
- the cryogenic destruction of tumour and capacity to elicit an
antitumour immune response forms the basis for the concept of cryoimmunotherapy
- since cytoreductive cryosurgery leaves dead tissue in situ to
be resorbed over time, theoretically it can be likened to an vivo
tumour vaccine in which tumour heterogeneous antigens, perhaps slightly
changed or previously unexpected to the body's defense mechanisms,
can be recognized
- cryoimmune response may additionally be tumouricidal to metastases
- developments in genetic engineering, permitting increased immunogenicity
of tumours through transfection with expression vectors for various
cytokines and redirected attention also to the concept of cryo-immuno-chemotherapy,
provide further means by which to possibly enhance the local and
systemic cryodestruction of tumours
- insufficient knowledge of precise role of cytoreductive surgery
for advanced prostate cancer
C O N T R A
- prostate carcinoma is largely a nonimmunogenic cancer
- damage of immune response mechanisms leads to tumour escape from
- native immunological response may be as a typical inflammation
- concomitant destruction of immunocompetent cells
- antigen excess from multiple freezing at one setting may contribute
to tumour growth and metastases progress
T R I A L 1
Phase I (7 pats)-
- r H IL-I beta: 5ng/kg i.v. b.i.d. on days 1-5 of weeks 1-2; and
10ng/kg s.c. on days 1-5 of weeks 8, 16; plus
- EMP 600mg/m2 i.v. b.i.d. on days 2-7 of weeks 1-3; and 300mg/m2
orally on days 1-7 of weeks 6-10, 12-16; plus
- Cytoreductive cryodestruction of prostate cancer by single-freezing
cycle on days 3 of week 1
- Intralesional injection of rH IL-1b 10ng on day 3 ofweek 1 immediately
T R I A L 2
Phase II (3 pats )- similar design as trial 1 plus
- r H IL-2: 0,25 MU/m2 i.v. b.i.d. on days1-5 of week 1; and 0,5
MU/m2 s.c. on days 1-5 of weeks 6,11; plus
- intralesional injection of r H IL-2 0,1 MU on days 3 of week 1
immediately after cryo (together with r H IL-1b)
CONCLUSION AND FUTURE PROSPECTS
1.Initial results of this combined modality- cryo-immuno-chemotherapy
bring some hope to improve the efficacy of advanced stage therapy.
2.The cytoreductive cryodestruction may consider as a variant of
so-called "autovaccination" of heterogeneous disseminated
prostate cancer, particularly with capability to increase T-cells
response by main cytokines and to reduce the toxicity of chemotherapy.
3.In vivo injection genetic engineering IL-1 and IL-2 combined with
their systemic administration has been shown to eliminate/cease
the clinical manifestation- bleeding, pain, obstruction, tumour
growth and metastases progress.
4.The future prospects with possible goals of new researches are
to elucidate the individual immune response of patients with advanced
prostate cancer, identify tumour antigens, and isolate peptide antigens
that will elicit a strong cellular immune response. Other researches
may be aimed at defining the clinical parameters that can predict
responses to cryo-immuno-chemotherapy.
58-years man, with terminal stage of D2 prostate cancer with pulmonary
metastases and pneumonia was underwent by treatment under design
of Trial 1 on 30th October 1997. After 1 month general status
was stabilized, and the clinical remission of metastatic lesions
of solid organs was noted as well as, biochemical significant failure
of PSA (to 125 ng/ml initially to 45 consequently), improvement
of quality of life, the obvious signs of increasing of T-cell immunity
(cell contain providing activation markers- CD 25, HLA-II, CD 16;
enhancing of functional activity of lymphocytes, production
of IL-2, IL-8 etc.). It was a very important proposal to support
this specific immune response by repeated immunotherapy regimens
every 2- 3 months accordingly the rates of immune monitoring.
Follow-up -1 year: stable state, patient returned to occupational
duty (professor- physics, chair of research department), good quality
of life, normal voiding, PSA- 44 ng/ml.
Initial results of Phase I of Trial 1 (follow-up from 3months till
Regression of lymph nodes & metastatic lesions of solid organs
Stable status or non-progression of bone metastases 3 pats
Improvement of quality of life 4 pats
Elimination/ or ceasing of local symptoms 5 pats
Lethality- (with survival 0,5 and 11 months) 2 pats
German Experience with Ultrasound-Guided Percutaneous Cryoablation
of Prostate Cancer in 48 Cases
P. Derakhshani, S. Neubauer, M. Braun, W. Nayal, J. Zumb? U. Engelmann
Department of Urology, University of Cologne, Germany
Address for correspondence:
Dr. P. Derakhshani
Klinik und Poliklinik fuer Urologie
Universitaet zu Koeln
Joseph-Stelzmann Str. 9
Objectives: We present our experience as the first German center
to perform perineal cryoablation of localized prostate cancer in
a series of 48 consecutive patients.
Methods: We treated 7 patients staged T1, 21 with a T2-disease and
20 patients with a T3-tumor. 62.5 % of the patients received a neoadjuvant
hormonal downsizing. Follow-up ranged from 4 to 27 months with a
median of 15 ?5.7 months.
Results: Positive control biopsies after 6 months were obtained
in 0 % of T1-tumors, 16.7 % of T2-tumors and 26.7 % of T3-tumors.
PSA-persistence above 1 ng/ml was diagnosed in 14.3 %, 33.3 %, and
40 % respectively. Complications were acceptable. 22.9 % of the
patients had a prolonged urinary retention, requiring a TUR in five
patients ( 10.4 % ) to relieve obstruction. In 5 cases ( 10.4 %
) incontinence was found, in 2 of those patients mild urge incontinence
declined over time, in three cases moderate to severe stress incontinence
developed, two of those patients being pretreated with radiotherapy.
No fistulae were noted.
Conclusions: Cryoablation of the prostate is not a substitution
for radical prostatectomy but enables the surgeon to perform a radical
curative procedure in patients unfit for other radical forms of
treatment or unwilling to undergo these. Long-term follow-up and
prospective studies will be necessary to define the clinical significance
of this procedure.
Cryosurgery was initially used by James Arnott 1851 to treat gynecologic
malignancies with a mixture of salt and ice . In the following
decades cryosurgery was utilized especially in dermatology, where
skin tumors were treated by direct cryocontact.
The modern era of cryotherapy was initiated by Irving Cooper in
1966 by the development of closed system cryoprobes . Liquid
nitrogen circulated through a closed loop metal probe that was placed
in direct contact to the abnormal tissue. In urology cryotherapy
was first introduced by Gonder and Soanes, who reported the first
case of transurethral cryosurgical ablation of the prostate in 1966
. Other authors followed and the procedure , either transurethrally
or via an open perineal approach, had an experimental status in
the mid 1960磗 and 1970磗 in the treatment of benign prostatic hyperplasia
and prostate carcinoma [4,5,6,7,8]. Due to an unacceptable high
complication rate because of technical limitations and the transurethral
application this method did not gain wide utilisation.
Cryoablation of unresectable liver tumors or metastases in contrast
is an indication, where vast experience could be gathered in the
last decade [9,10,11,12].
Onik was the first to adapt cryotechnique to the urological application
in prostate cancer [13,14,15]. Especially the developments in high-resolution
transrectal ultrasound made this procedure potentially both safe
Strict selection criteria are necessary in cryosurgery of the prostate
as long term results are still missing. Therefore the European Study
Group of Urologic Cryosurgeons suggests the following indications:
· localized prostate cancer in high-risk patients with contraindications
to radical prostatectomy including patients refusing other forms
· progression after radiation therapy
· local recurrence after radical prostatectomy and
· in all cases a prostate volume less than 40 cc.
The efficacy of "downstaging" or "downsizing"
of prostate cancer using neoadjuvant hormone therapy remains a controversial
issue at this time, but the use of androgen ablation decreases the
size of the prostate gland, which facilitates cryosurgery and might
improve the results.
The guidelines of the European Study Group of Urologic Cryosurgeons
recommend downsizing by androgen deprivation in prostates larger
than 40 cc over a period of at least three months. Freezing equipment,
although very powerful with the new freezing devices, has a limited
capacity, and in certain instances large gland volumes prevent adequate
freezing of the prostate. By increasing the distance between the
cryoprobes, which is mandatory in large glands to achieve adequate
freezing of the peripheral zone, steep temperature gradients in
the interprobal regions result, which make complete necrosis of
all prostatic tissue less frequent. Lee et al.  suggested that
a negative biopsy rate of 93 % can be obtained on the first cryosurgical
procedure by downsizing all prostates in patients with glands larger
than 40 cc, those with a large tumor burden ( tumors 1.5 cc or greater
), and those with evidence of extracapsular extension [16,17].
Other factors also favor downsizing of the gland. Since percutaneous
prostate cryosurgery leaves dead tissue in situ to be resorbed over
time, efficient downsizing leaves less necrotic tissue to be resorbed,
reducing the potential for complications, particularly abscess.
The use of androgen ablative therapy also increases the deposition
of fat in the area of Denonvillier's fascia, making freezing of
the rectum less likely during the procedure.
As another argument for neoadjuvant androgen deprivation the margin
of error for the position of the cryoprobes, which in fact has much
improved with high-resolution transrectal ultrasound, is further
improved in smaller prostate volumes making freezing more efficient.
Material and Methods
Preoperative diagnostic tests include ultrasound-guided sextant-biopsy,
if necessary with biopsy of the seminal vesicles to determine the
exact location of the cancer. All patients with a PSA > 20 ng
/ ml receive a bone scan to rule out metastatic disease. In patients
with a PSA > 10 ng / ml a laparoscopic pelvic lymphadenectomy
is performed in accordance to the guidelines of the European Study
Group of Urologic Cryosurgeons. All patients with positive bone
scans or lymph node metastases are excluded from cryosurgery. In
our study in all patients with prostate volumes greater 40 cc, large
tumor volumes above 3 cc or signs of extracapsular invasion neoadjuvant
androgen deprivation was performed. It consisted of a course of
a LHRH analogue ( e.g. Leuprolin acetate ) as single agent or combined
with an antiandrogen ( e.g. Flutamide ) for at least three months.
Cryoablation of the prostate is performed as a single or two-step
procedure under general or regional anesthesia in accordance to
the technique described by Onik in 1991 using the Cryomedical Sciences
equipment [13,14,15]. We routinely administered intravenous prophylactic
antibiosis using ciprofloxacin 200 mg. Under permanent transrectal
ultrasound guidance five echogenic needles are placed into the prostate
using the ultrasound biopsy guide or the freehand-technique with
the patient being in the dorsal lithotomy position. The hyperechogenic
needles are inserted in the desired position and checked in the
transverse and sagittal planes with the ultrasound device. Dilators
with an isolating sheath are placed over guide wires.
An urethral involvement or bladder perforation by the dilators is
checked by flexible cystoscopy and if necessary the position of
the dilators is corrected. In the next step the cryoprobes are positioned.
In definite organ-confined disease usually five probes are mandatory.
If extracapsular disease is presumed, an extraprostatic placement
of an additional cryoprobe is possible. Several thermocouples can
be placed in or outside the gland to control the freezing procedure.
In our experience four up to six thermocouples are helpful to determine
the temperature at the prostatic capsule, which should be the border
for complete thermoinduced necrosis. Before freezing is initiated
an urethral warming device ( Cryomedical Sciences, Rockville, MD
) is placed to protect the urethra from thermo-induced damage. This
single step has led to a marked decrease of complications related
to sloughing and urethral damage as reported by several authors
After all cryoprobes are positioned, the temperature of the anterior
cryoprobes is simultaneously dropped to the maximum temperature
of about -195癈. Once the temperature has reached the therapeutic
range, careful monitoring of the growing iceball is accomplished
by real-time high-resolution transrectal ultrasound, and the freezing
is timed for approximately 10 - 15 minutes.
As the freezing continues the posterior probes are activated and
the iceballs from each cryoprobe coalesce, so that the whole gland
including capsule and extraglandular regions of interest can be
frozen to a complete necrosis.
Ultrasonographic monitoring shows the hyperechogenic edge of the
iceball to document this area and the thermocouple system registers
the tissue temperatures in the capsular region. When the 15 minutes
freeze cycle is completed, the cryoprobes are turned off for 10
minutes, stopping the flow of liquid nitrogen. The cryoprobes are
not artificially warmed during this thaw cycle to allow a slower,
natural thaw. A second freeze cycle in the above manner completes
the surgical procedure. After complete thawing of the prostate and
removal of all probes and thermo couples a transurethral foley catheter
is placed to ensure adequate bladder drainage for two to three weeks
We performed the procedure in 48 patients between October 1995 and
August 1997. Mean patient age was 67.2 years ( range: 56 - 76 years
). All patients underwent complete preoperative screening, as described
above. Indication for cryosurgery predominantely was localized prostate
cancer without prior surgery or radiation therapy in 95.8 % of the
cases ( 46 / 48 ), 2 patients ( 4.2 % ) developed PSA progression
with active tumor cells in the prostatic biopsy after radiotherapy.
In patients with organ-confined prostate cancer the reason for not
performing radical prostatectomy was high comorbidity in 80.4 %
( 37 / 46 ) ( predominantely risk of cardio-pulmonary complications
) and 19.6 % ( 9 / 46 ) of the patients refused radical prostatectomy.
Regarding the staging 14.6 % ( 7 / 48 ) of the patients had a T1
tumor, 43.8 % ( 21 / 48 ) had a T2- and 41.7 % ( 20 / 48 ) had a
T3-disease. Histopathological grading was done according to the
guidelines of the WHO. A total of 13 patients ( 27.1 %) had a grading
of G1, 45.8 % ( 22 / 48 ) of the patients had a G2-tumor and 27.1
% ( 13 / 48 ) were G3-tumors. The postoperative follow-up ranged
from 2 to 25 months. The staging and grading of patients with a
follow-up of at least six months including PSA-follow-up and control-biopsy
after six months are shown in Table 1. 17.5 % ( 7 / 40 ) had a stage
T1-disease, 45 % ( 18 / 40 ) were staged T2 and 37.5 % ( 15 / 40
) were staged T3.
Grading for patients with a follow-up > six months was 30 % (
12 / 40 ), 45 % ( 18 / 40 ) and 25 % ( 10 / 40 ) for G1, G2 and
In our study androgen deprivation was completed before performance
of cryosurgery in 30 of 48 patients ( 62.5 % ). Indications for
neoadjuvant androgen deprivation were gland volumes of more than
40 cc in 18.8 % ( 9 / 48 ), tumor volumes larger than 3 cc in 8.3
% ( 4 / 48 ), or evidence of extracapsular invasion in 10.4 % (
5 / 48 ). In all other cases ( 25 % ) hormonal therapy was given
by the diagnosing urologist as medical treatment and was continued
until cryosurgery was performed. The preoperative hormonal therapy
consisted of a 3 - 10 month course of a LHRH-analogue alone or combined
with Flutamide as an antiandrogen. Androgen deprivation was stopped
with performance of cryosurgery to obtain sufficient PSA-follow-up.
In all cases PSA was followed postoperatively in three-month intervals.
Ultrasound-guided control-sextant-biopsies were obtained after six,
12 and 18 months, or if PSA-progression occurred. PSA-failure was
defined as PSA remaining above 1 ng / ml at six months postoperatively.
As the current literature on this topic is controversial, we also
included our results on PSA-values below 0.5 ng / ml ( Table 2 and
3 ), which might be the future goal to be achieved by cryosurgery,
as the probability for tumor persistence is significantly lower
with PSA-levels below 0.5 ng / ml . At six months all patients
completed a questionnaire to receive data about postoperative complications
and quality of life. Questions regarded potency, continence, voiding,
other complications, overall satisfaction and health status.
Mean operating time ( Figure 2 ) was 115 ?36 min ( range: 65 - 215
min ). Follow-up ranged from 4 to 27 months with a median of 15
?5.7 months ( Figure 1 ). 40 of 48 cryotreated patients had a six
month control-biopsy and a PSA follow-up ( Table 2 ). 65 % ( 26
/ 40 ) of those patients were pretreated with neoadjuvant androgen
In the T1-group we found a PSA-failure in 1 of 7 patients ( 14.3
% ) and no positive biopsies after six months. 6 of 18 patients
( 33.3 % ) with a T2-disease had a PSA-failure and in 3 of those
( 16.7 % ) active tumor cells were found in the postoperative sextant-biopsy.
In the T3-group 6 patients ( 40 % ) had persistence of PSA above
1 ng/ml and in four cases positive biopsies resulted ( 26.7 % ).
Correlation to grading ( Table 3 ) showed a PSA-failure in 2 of
12 patients ( 16.7 % ) and a positive biopsy in 8.3 % ( 1 / 12 )
of the G1-tumors. 38.9 % ( 7 / 18 ) of G2- and 40 % ( 4 / 10 ) of
G3-tumors showed PSA-failure. Positive six month biopsies were obtained
in 16.7 % ( 3 / 18 ) and 30 % ( 3 / 10 ) of G2- and G3-tumors respectively.
Regarding the hormonal pretreated patients in the T2-group one patient
with a positive biopsy had prior hormonal ablation, in the T3-group
also one patient with a treatment failure was hormonally pretreated.
Up to now the number of patients is not sufficient to draw general
conclusions and further follow-up will show, if there is a benefit
for pretreated patients compared to those without neoadjuvant hormonal
Postoperative erectile dysfunction was noted for up to 6 months
by 77.1 % of patients ( 27 / 35 ) who were potent preoperatively.
After six months impotence persisted in 68.6 % of patients ( 24
/ 35 ) due to cryoinduced destruction of the neurovascular bundles.
The postoperative complication rate was acceptable ( Table 4 ).
We found mild to moderate dysuria within the first weeks after removing
the transurethral catheter in 35.4 % ( 17 / 48 ). No patient required
further treatment related to dysuria.
In 16.7 % ( 8 / 48 ) we recognized a slight to moderate perineal
or scrotal hematoma, which
resolved spontaneously in all cases.
11 of 48 patients ( 22.9 % ) suffered from prolonged retention of
more than three weeks and in 5 of these patients ( 10.4 % ) a secondary
TUR-P was necessary to relieve obstruction.
In the first group of 25 patients we routinely used a suprapubic
catheter to ensure adequate drainage from the bladder. Lately due
to experiences from other investigators we advocate transurethral
drainage for two to three weeks. Only in patients, who had moderate
or severe obstructive symptoms preoperatively, we consider placing
a suprapubic tube to ensure adequate bladder drainage after removal
of the foley catheter, as obstruction tends to worsen in the first
weeks after cryosurgery.
We did not have significant problems with sloughing, a fact which
might be explained by the consistent utilisation of the standard
CMS urethral warming catheter.
Currently 2 patients suffer from moderate to severe stress-incontinence
probably due to sphincter damage ( both patients being radiation
failures ). 3 other patients had mild to moderate urge incontinence,
which resolved spontaneously in 2 without causal treatment in less
than 6 months.
An epididymitis developed in 2 patients and was treated conservatively.
One patient had a perineal abscess, which developed 3 month postoperatively.
The abscess was treated by open-surgical incision and drainage.
Further follow-up in this patient was uneventful.
With 35,000 men dying annually in the U.S. from prostate cancer
treatment of this disease is of particular interest to urologists,
both clinical and investigative . Radical prostatectomy is widely
considered as the "gold standard" for the treatment of
organ-confined prostate cancer . Nevertheless it is not an option
for every single patient, as comorbidity or personal wishes of the
patient might be a contraindication to open-surgical procedures.
Established therapeutic alternatives are external beam radiation
and seed implants with a reported low morbidity. As in other fields
of urology minimal-invasive procedures have gained increased interest
in urologic oncology. With cryoablation of the prostate minimal-invasive
therapy of prostate cancer is available and under investigation
since 1991 [13,14,15].
Improvements in cryotechnique and progress in transrectal high-resolution
enable the surgeon to achieve the curative target of thermoinduced
destruction of the whole gland in high-risk patients. After initial
uncertainty about technical considerations due to various reports
on the feasibility and resulting complications and efficacy of the
method, there is a common consensus about the basic technique to
· a double-freeze technique using at least four to five cryoprobes
should be mandatory
· in case of apical cancer a pull-back of the probes between the
freeze-cycles seems favorable
· in case of extracapsular invasion an additional cryoprobe might
be placed in the region of interest to allow extraprostatic freezing
· a company-manufactured urethral warming catheter has to be utilized
to protect the urethral epithelium and to prevent sloughing and
· the use of thermo-couples has not been established in all centers,
although we believe, that they are a useful tool to assist in performing
· follow-up should be done in a standardized fashion as addressed
by other authors
Cohen et al. reported on data of 119 patients with a PSA follow-up
and biopsy controlled therapeutic efficacy [27,28]. He had a positive
biopsy rate of 13.3 to 21.7 % depending on tumor stage. Regarding
neoadjuvant androgen deprivation he could prove a distinct benefit
for the pretreated patients. However the limited number of patients
and the relatively short follow-up does not allow general conclusions
to be drawn. In 1997 Cohen et al. presented their data on 38 patients
with a follow-up of four years .
All of those patients were treated using the CMS urethral warming
device and showed a minimal complication rate of 9.2 % sloughing
and a less than 2 % incontinence rate. The therapeutic results seem
to be favorable: 11.4 % ( 4 / 35 ) of the patients have a positive
biopsy, all of those being staged T3 and 50 % having a pre-treatment
PSA greater than 10 ng / ml.
In addition 75 % of patients with a positive biopsy did not receive
neoadjuvant androgen deprivation therapy ( ADT ), whereas 25 % had
prior ADT. The PSA values were below 1.0 ng / ml in 52.6 % ( 20
/ 38 ) and below 0.4 ng / ml in 39.5 % ( 15 / 38 ) of the patients
at 45 months.
Bahn et al. found a reduction of the prostate volume from 33.3 cc
to 21.3 cc in a series of 130 patients of whom 114 were treated
by neoadjuvant hormonal therapy . A comparison in biopsy- or
PSA-results between pretreated and not pretreated patients was not
performed. Overall there were positive biopsies after three, six,
or 12 months in 7.7 % ( 10 / 130 ), 3.3 % ( 3 / 91 ), and 2.3 %
( 1 / 43 ) of the patients respectively. Patients with a Gleason
score of eight or nine showed a significantly higher positive biopsy
rate ( 28.6 % ) than patients with a well to moderately differentiated
tumor ( 5.2 %, 12 % ). Mean PSA levels in patients with a negative
control biopsy decreased from 12.6 ng / ml ( (16.1 ) preoperatively
to 0.35 ng / ml ( (0.75 ) at three months, 0.54 ng / ml ( (1.1 )
at six months, and 0.43 ( (0.78 ) at 12 months. The complication
rate was low with an impotence rate of 41 % ( 11 / 27 ).
In our study we found biopsy results and PSA values in similar ranges
as reported in the literature. Follow-up though, as with most studies
published, is very limited due to the limited time the technique
is available. Until conclusions regarding the efficacy of this method
can be drawn, a much longer follow-up is mandatory, although the
short-term results seem promising. In addition the lingering effects
of neoadjuvant androgen deprivation may be playing a role in low
PSA failures in early follow-up.
Lately reports were published about high complication rates in preradiated
patients [30,31,32,33,34]. Bahn et al. had an incontinence rate
of 11 % ( 3 / 27 ) in preradiated patients and five of 210 patients
with urethrorectal fistulas, four of those patients being radiation
failures . Cespedes et al. reported on significant incontinence
rates after cryotherapy in preradiated patients . Persistent
urinary incontinence occurred in 28 % ( 30 / 107 ) of the patients
utilizing a factory-manufactured urethral warmer. Of 28 patients
undergoing cryosurgery using an alternative self-made urethral warmer
13 ( 46.4 % ) had incontinence and 15 ( 54 % ) had significant obstruction
or retention. The reasons for this are speculative. Prior radiation
therapy probably causes microvascular damage, leading to increased
tissue slough and obstruction.
Similarly, a compromised vascular supply to the sphincter may increase
radiation-induced damage and undermine the healing process with
resulting incontinence . Long reported on even higher complication
rates in preradiated patients . The incontinence rate increased
significantly from one percent ( 1 / 105 ) in primary cryotherapy
to 69.6 % ( 16 / 23 ) in patients after salvage cryotherapy.
Concluding from this extensive data the indication for cryoablation
in radiation failures should be seen critical and sharply defined,
and the patient has to be extensively informed about possible complication
Sosa et al. reported on data of a multicenter study including nearly
1500 patients and presented the complication rates . An initial
impotence rate of 100 % was found. 6.8 % of all patients had urinary
retention longer than 4 weeks post cryosurgery. The incontinence
rate differed from 6.8 % for stress- and 11 % for urge-incontinence.
The authors found urinary tract infections in 6,4 % and a prostatorectal
fistula only in 1.4 %.
In contrast, Cox et al. found a significantly higher complication
rate in a group of 63 patients . An explanation for this discrepancy
might be the ongoing learning curve, which is very important in
cryosurgery. Many studies, which differentiated between the first
procedures and the last procedures found remarkable differences.
At the 1997 Meeting of the AUA in New Orleans data of 150 procedures
were shown in a presentation by Long et al., 18 of those were done
for radiation failures . After 6, 18 and 24 months PSA-values
of less than 0.3 ng / ml were found in 71-82 %, after 48 months
the PSA-value was less than 1.0 ng / ml in 68 % of the patients.
In conclusion the indication for cryoablation of the prostate should
be limited to high-risk patients and patients refusing radical prostatectomy.
With follow-up being four years, data exist about mid-term efficacy
and survival of patients treated with cryosurgery [27,28,29,33].
In a large number of patients the clinical effect of cryosurgery
of the prostate seems to be similar to radiotherapy. Nevertheless
those studies were mostly clinically based and prospective randomized
controlled trials are still missing, before final conclusions can
be drawn. Only those trials would be able to compare cryosurgery
to other treatment modalities, e.g. radiotherapy.
In Europe, the effort was undertaken to gather patient data from
different centers performing cryoablation of the prostate under
defined conditions and technical considerations. Still the only
way to establish this innovative technique for a sharply defined
group of patients is to compare it in a standardized fashion to
radiotherapy. This task is currently developed by the AUA in cooperation
with the centers using cryotherapy in the U.S.. The results will
be very interesting to follow.
Cryoablation in radiation-failure should be regarded as experimental
due to a high complication rate. Nevertheless the studies cited
above showed good efficacy in treating radiation failure of prostate
cancer, so that this option can be included in the therapeutic concept
after a thorough information of the patient before salvage-cryotherapy.
Neoadjuvant androgen deprivation improves technical limitations
of the cryoprocedure especially in large glands. The hormonal therapy
should be administered to patients with prostatic volumes greater
than 40 cc for at least 3 months prior to cryosurgery. The efficacy
can be monitored by transrectal ultrasound measurements and PSA-follow-up.
When neoadjuvant androgen deprivation is indicated it should be
performed as complete androgen blocking using LHRH analogues and
antiandrogens for greater efficacy.
Further follow-up is necessary to determine effects of neoadjuvant
hormonal therapy before cryosurgery on treatment results, PSA-follow-up,
biopsy results, and survival rates.
1.Arnott J: On the treatment of cancer by the regulated application
of an anesthetic temperature. London: J Churchill 1851:32-54.
2.Cooper IS, Hirose T: Application of cryogenic surgery to resection
of parenchymal organs. N Engl J Med 1966; 274: 15.
3.Gonder MJ, Soanes WA, Shulman S: Cryosurgical treatment of the
prostate. Invest Urol 1966; 3: 372-378.
4.Jordan WP jr, Walker D, Miller GH jr, Drylie DM: Cryotherapy of
benign and neoplastic tumors of the prostate. Surgery 1967; 125:
5.Flocks RH, Nelson CM, Boatman DL: Perineal cryosurgery for prostatic
carcinoma. J Urol 1972; 108: 933-935.
6.Loening S, Hawtrey C, Bonney W, Narayana A, Culp DA: Cryotherapy
of prostate cancer. Prostate 1980; 1: 279-286.
7.Thiel KH, Braun HP: Die Kryochirurgie nach Sesia in der Behandlung
von Blasenentleerungsst鰎ungen des Mannes. Zschr Urol 1974; 66:
8.Peters HJ; Popa G; Ludwig G; Potempa J: Fr黨- und Sp鋞ergebnisse
nach kryochirurgischer Behandlung der Blasenhalsobstruktion.
Urologe [A] 1975; 14: 137-143.
9.Cozzi PJ, Englund R, Morris DL: Cryotherapy treatment of patients
with hepatic metastases from neuroendocrine tumors. Cancer 1995;
10.Cuschieri A, Crosthwaite G, Shimi S, Pietrabissa A, Joypaul V,
Tair I, Naziri W: Hepatic cryotherapy for liver tumors. Surg
Endosc 1995; 9: 483-489.
11.Onik G, Kane R, Steele G, McDermott W, Khettry U, Cady B, Jenkiny
R, Katz J, Clouse M, Rubinsky B, et al: Monitoring hepatic cryosurgery
with sonography. AJR Am J Roentgenol 1986; 147: 665-669.
12.Onik G, Rubinsky B, Zemel R, Weaver L, Diamond D, Cobb C, Porterfield
B: Ultrasound-guided hepatic cryosurgery in the treatment of
metastatic colon carcinoma. Preliminary results. Cancer 1991; 67:
13.Onik G: Transperineal prostatic cryosurgery under transrectal
ultrasound guidance. Semin Intervent Radiol 1989; 6: 90-96.
14.Onik GM, Cohen JK, Miller R, Merlotti LA, Halpin DE, Porterfield
R: Treatment of non-organ confined prostate cancer with percutaneous
prostate cryosurgery. Radiology 1993; 189: 277.
15.Onik GM, Cohen JK, Reyes GD, Rubinsky B, Chang Z, Baust J: Percutaneous
radical cryosurgical ablation of the prostate under transrectal
ultrasound guidance. Cancer 1993; 72: 1291-1299.
16.Lee F, Siders DB, Newby JE, McHugh TA, Solomon MH: The role of
transrectal ultrasound-guided biopsy and androgen ablation therapy
prior to radical prostatectomy. Clin Invest Med 1993; 16: 463-483.
17.Lee F, Bahn D, McHugh T, Onik GM, Lee F jr.: Ultrasound-guided
percutaneous cryoablation of prostate cancer. Radiology 1994;
18.Walsh PC: Radical retropubic prostatectomy. In Walsh PC, Retik
AB, Stamey TA et al. (ed): Campbell磗 Urology. Philadelphia,
Saunders, 1992, pp 2865-2886.
19.Cozzi PJ, Lynch WJ: Experimental and clinical observations of
urethral warming catheters for transperineal cryosurgery of localized
prostate cancer: low morbidity is achievable. J Urol 1997; Suppl.
20.Cox RL, Crawford ED: Complications of cryosurgical ablation of
the prostate to treat localized adenocarcinoma of the prostate.
Urology 1995; 45: 932-935.
21.Kohn IJ, Seidmon EJ, Hanno PM, Pontari MA: Voiding dysfunction
following cryosurgery of the prostate. J Urol 1997; Suppl. 157:
22.Zippe CD: Cryosurgical ablation for prostate cancer: a current
review. Sem Urol 1995; 13: 148- 156.
23.Zippe CD: Cryosurgery of the prostate: techniques and pitfalls.
Urol Clin N Am 1996; 23: 147- 163.
24. Shinohara K, Connolly JA, Presti JC jr, Carroll PR: Cryosurgical
treatment of localized prostate cancer (stages T1 to T4): preliminary
results. J Urol 1996; 156: 115-121.
25. Sosa RE, Martin T, Lynn K, Cryosurgery Users?Group: Cryosurgical
treatment of prostate cancer: a multicenter review of complications.
J Urol 1996; Suppl. 155: A361.
26. Boring CC, Squires TS, Tong T: Cancer statistics 1993. CA Cancer
J Clin 1993; 43: 7-26.
27. Cohen JK, Miller RJ, Rooker GM, Merlotti L: Two-year prostate-specific
antigen and biopsy results after cryosurgical ablation of the prostate
(CSAP) for localized adenocarcinoma of the prostate. J Urol 1996;
Suppl. 155: A360.
28. Cohen JK, Miller RJ, Rooker GM, Shuman BA: Cryosurgical ablation
of the prostate: two-year prostate-specific antigen and biopsy results.
Urology 1996; 47: 395-401.
29. Cohen JK, Miller RJ, Rooker GM, Benoit R, Merlotti L: Four-year
PSA and biopsy results after cryosurgical ablation of the prostate
(CSAP) for localized adenocarcinoma of the prostate. J Urol
1997; Suppl. 157: A1634.
30. Bahn DK; Lee F; Solomon MH; Gontina H; Klionsky DL; Lee FT Jr:
Prostate cancer: US-guided percutaneous cryoablation. Work in progress.
Radiology 1995; 194: 551-556.
31. Fernandez AZ, Durham NC, Leal JJ: Incontinence following cryoablation
of prostatic carcinoma in radiation treatment failure patients -
the need for cryosurgical probes of various length. J Urol 1997;
Suppl. 157: A1135.
32. Cespedes RD, Pisters LL, von Eschenbach AC, McGuire EJ: Long-term
follow-up of incontinence and obstruction after salvage cryosurgical
ablation of the prostate: results in 143 patients. J Urol 1997;
33. Long JP, Fallick ML, Rand W: Cryoablation (CP) for patients
with T1-T3 PCA. J Urol 1997; Suppl. 157: A1122.
34. Moul JW: Editorial: radical prostatectomy and cryotherapy -
some answers, more questions. J Urol 1997; 157: 256-257.
Table 1: Staging and grading of patients with > six months follow-up
( n = 40 )
Clinical Stage G1 G2 G3
T1 3 3 1
T2 6 9 3
T3 3 6 6
Table 2: Correlation of PSA-failure and biopsy results to pathological
staging six months postoperatively (n=40)
Clinical Stage n PSA > 0.5 ng / ml PSA > 1 ng / ml positive
T1 7 28.6 % ( 2 / 7 ) 14.3 % ( 1 / 7 ) 0 % ( 0 / 7 )
T2 18 44.4 % ( 8 / 18 ) 33.3 % ( 6 / 18) 16.7 % ( 3 / 18)
T3 15 46.7 % ( 7 / 15 ) 40 % ( 6 / 15) 26.7 % ( 4 / 15)
Table 3: Correlation of PSA-failure and biopsy results to pathological
grading six months postoperatively ( n = 40 )
Grading n PSA > 0.5 ng / ml PSA > 1 ng / ml positive biopsy
G1 12 25 % ( 3 / 12 ) 16.7 % ( 2 / 12) 8.3 % ( 1 / 12 )
G2 18 55.6 % ( 10 / 18 ) 38.9 % ( 7 / 18 16.7 % ( 3 / 18 )
G3 10 40 % ( 4 / 10 ) 40 % ( 4 / 10) 30 % ( 3 / 10 )
Table 4: Complications after cryoablation of the prostate ( n =
impotence ( < 6 months) 77.1 %( 27 / 35 ) ( 35 pt. potent preop.)
impotence ( > 6 months) 68.6 %( 24 / 35 ) ( 35 pt. potent preop.)
dysuria 35.4 % ( 17 / 48 )
prolonged retention 22.9 % ( 11 / 48 ) ( >3 weeks after catheter
secondary TUR 10.4 % ( 5 / 48 )
scrotal hematoma 16.7 % ( 8 / 48 )
incontinence 10.4 % ( 5 / 48 )
epididymitis 4.2 % ( 2 / 48 )
perineal abscess 2.1 % ( 1 / 48 )