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THE CLINICAL APPLICATION OF CRYOIMMUNOTHERAPY FOR ADVANCED PROSTATE CANCER


November 1998
V.Mouraviev,
G.Prochorov, V.Konusova, A.Simbircev, A.Popovitch
Clinical Hospital of Russian Academy of Science, St.Petersburg, Russia

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 autovaccination".

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 CANCER
P R O
- the cryogenic destruction of tumour and capacity to elicit an antitumour immune response forms the basis for the concept of cryoimmunotherapy (R.J.Ablin)
- 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 immune surveillance
- native immunological response may be as a typical inflammation process
- 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 after cryodestruction

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.
 Case report
 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 1 year)
 Regression of lymph nodes & metastatic lesions of solid organs 4 pats
 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
Dec 1998

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
50924 KOELN
Germany
Phone: +49-221-478-4687
Fax: +49-221-478-6256
Email:I p.derakhshani@uni-koeln.de

Abstract:
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.

Introduction
Cryosurgery was initially used by James Arnott 1851 to treat gynecologic malignancies with a mixture of salt and ice [1]. 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 [2]. 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 [3]. 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 and effective.
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 of therapy
· 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. [17] 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 Staging
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.

Cryosurgical Technique
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 [19,20,21,22,23,24,25].

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 postoperatively.

Patients
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 G3 respectively.

Androgen Deprivation
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.
Postoperative 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 [20]. 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.
Results

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 deprivation.
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 therapy.
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.

Discussion
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 [26]. Radical prostatectomy is widely considered as the "gold standard" for the treatment of organ-confined prostate cancer [18]. 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 be performed:
· 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 voiding dysfunction
· 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 the procedure
· 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 [29].

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 [30]. 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 [30]. Cespedes et al. reported on significant incontinence rates after cryotherapy in preradiated patients [32]. 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 [32]. Long reported on even higher complication rates in preradiated patients [33]. 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 rates.

Sosa et al. reported on data of a multicenter study including nearly 1500 patients and presented the complication rates [25]. 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 [20]. 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 [33]. 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.
Conclusions

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.
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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 biopsy
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 = 48 )

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 removal)
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 )

 

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