CRYOSURGERY AS PRIMARY TREATMENT FOR LOCALIZED PROSTATE CANCER: A COMMUNITY HOSPITAL EXPERIENCE DAVID S. ELLIS

ABSTRACT The technique and recent experience incorporating cryosurgery into our community practice for primary treatment of localized prostate cancer is described. Between December 2000 and December 2001, a total of 93 patients underwent targeted cryoablation for localized prostate cancer. Of the 93 patients, 18 had failed radiotherapy, and cryotherapy was used as salvage therapy. The remaining 75 patients underwent targeted cryoablation of the prostate as primary therapy. A single urologist using an argon-based cryoablation system performed the procedure. Cryoprobes and thermosensors were placed under transrectal ultrasound guidance via a transperineal route. A double freeze-thaw cycle was used with anterior-toposterior probe operation. Strategically placed thermosensors were used to monitor and control the freezing, and a warming catheter was used to protect the urethra. We achieved a nadir prostate-specific antigen level of ⱕ0.4 ng/mL in 84% of the entire population we studied (63 of 75 patients). Postsurgery complications were minimal. Incontinence developed in 4 patients, as did postsuprapubic catheter removal urinary retention. Erectile dysfunction developed in 28 of 34 patients who were potent preoperatively, with 6 of the 34 patients regaining potency after surgery. No rectourethral fistula formation occurred. Urethral sloughing was observed in 5 patients, 1 of whom developed a scrotal abscess during treatment of the sloughing. The use of cryoablation of the prostate for the treatment of localized adenocarcinoma of the prostate is feasible and can easily be transferred from the pioneering centers to the community hospitals without sacrificing safety or efficacy. UROLOGY 60 (Suppl 2A): 34–39, 2002. © 2002, Elsevier Science Inc.

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ith the increase in the aging population and improved diagnosis, the annual incidence of prostate cancer has increased steadily over the last few decades. Approximately 200,000 new cases of prostate cancer will be diagnosed during 2002 and ⬎70% of these cancers will be discovered while they are still localized.1 The standard treatment options for localized prostate cancer are radical prostatectomy, external-beam conformal radiotherapy, brachytherapy, and watchful waiting. The optimal treatment would offer a balance between efficacy and morbidity. Unfortunately, there is, as yet, no optimal treatment for localized prostate cancer. This is evidenced by the development of novel and modified From the Urology Associates of North Texas, Arlington, Texas, USA; and United States Medical Development, Irving, Texas, USA Reprint requests: David S. Ellis, MD, Urology Associates of North Texas, and United States Medical Development, 1001 Waldrop Drive, Suite 708, Arlington, Texas 76012. E-mail: [email protected]

34

© 2002, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

treatment options, such as brachytherapy, conformal 3-dimensional radiotherapy, and cryoablation, which have occurred in the last 3 decades.2– 4 Cryoablation represents a departure from the 3 foundations of modern cancer therapy: chemotherapy, radiation therapy, and surgery. As such, its adoption by the urologic community has been justifiably hesitant. Factors contributing to this hesitancy are: (1) the high incidence of morbidity before the incorporation of transrectal ultrasound guidance into the procedure5,6; (2) the high incidence of morbidity observed in the mid 1990s because of the use of urethral warmers that were not approved by the US Food and Drug Administration (FDA); (3) conflicting reports from separate studies on the efficacy and safety of the procedure (positive reports2,7,8; negative reports9,10); and (4) lack of long-term results.11 Cryosurgery continues to gain acceptance as an appropriate treatment option for localized prostate cancer with some compelling advantages over the conventional standard treatment options. Advan0090-4295/02/$20.00 PII S0090-4295(02)01682-5

tages include a low morbidity rate (both in absolute terms and compared with competing therapies), shorter hospital stays, negligible blood loss, less expense than competing therapies, and the ability to repeat the treatment without an increase in morbidity.2 The decision by our practice to investigate the role of cryoablation as a primary treatment for localized adenocarcinoma of the prostate was influenced by the emergence of acceptable 5-year results examining disease-specific survival,12 a 96% rate of patient satisfaction with the procedure,13 and advances in the technology and technique of the procedure.14 A growing concern of ours has been the prospect of poor transplantation of the procedure from the academic centers that had pioneered it to community hospital centers. This article reports on a community hospital experience where cryoablation was used as primary treatment for localized prostate cancer using an argon-based cryomachine. The cryoablation procedure has evolved significantly since its introduction in the early 1990s with the incorporation of temperature monitoring,15 improvements in probe placement strategies,14 and greater biologic understanding of the freezing process.16 This is the first report of preliminary safety and efficacy of a series of patients treated exclusively with the modern cryoablation procedure as it incorporates all these advances. MATERIALS AND METHODS PATIENT SELECTION From December 2000 to December 2001, 93 patients underwent targeted cryoablation of the prostate. All patients had biopsy-proven adenocarcinoma of the prostate and were subjected to presurgical prostate-specific antigen (PSA) testing, full routine clinical staging, and Gleason score evaluations. Bone scans were performed for patients who presented with either a PSA level ⬎10 or a Gleason score ⬎7. A positive bone scan is considered a contraindication for targeted cryoablation of the prostate, because it is a local therapy.

EQUIPMENT All procedures were performed using the Cryocare System (Endocare, Inc., Irvine, CA), a cryosurgical device with 8 cryoprobe ports and an integrated temperature monitoring system consisting of 8 thermosensor sockets. The system relies on circulating argon and helium gases in its probes to freeze and thaw tissue, respectively. The freezing process is regulated by varying the flow rate (50% to 75% to 100%) of argon gas to the individual cryoprobes. As the high-pressure argon gas circulates in the probes, it lowers the temperature at the cryoprobe tip to below freezing, forming an ice ball around the probe tip. A biplane transrectal ultrasound probe (B-K Medical, Copenhagen, Denmark) with biplane 5.0 to 7.5 MHz transducers was used in all patients to guide accurate probe placement and to monitor the freezing process. Thermosensors (or TEMPprobes, Endocare, Inc.) were strategically placed around the periphery of the gland in all patients to permit objective temperature determination at critical locations. A coaxial flexible UROLOGY 60 (Supplement 2A), August 2002

urethral warming catheter (Endocare, Inc.) that permits continuous circulation of warmed water was used in all patients to protect the urethra, bladder neck, and external sphincter from the lethal ice during the procedure.15 A computerized data acquisition system was used to continuously monitor and record the temperatures of all thermosensors simultaneously. Temperatures in the system are displayed graphically on a real-time basis by sampling the thermosensor temperatures once every second. Temperature records are stored in a data file that can be retrieved for later review.

CRYOABLATION PROCEDURE All cryoablation procedures were performed at Arlington Memorial Hospital (Arlington, TX) or Baylor Medical Center (Coppell, TX), by a single urologist. In contrast to medical centers where the urologist and interventional radiologist work jointly as an intraoperative team, the urologist at our centers performed the procedures alone, using both surgical and hands-on sonography expertise. This is possible for any urologist, provided he or she has solid sonographic imaging skills. The procedure is an evolved version of that reported by Lee et al.16 in 1994. Preoperative patient management, positioning, prepping, and suprapubic catheter placement are identical to those recently described by Donnelly and Saliken17 for salvage cryosurgery after failed radiation therapy and are not included for brevity. Cryoprobe placement, operation strategy, and thermosensor placement strategy differ slightly during primary treatment of prostate cancer and warrant a detailed description. Usually, 6 cryoprobes are used which, except for large (⬎35 cm3) or small glands, allow sufficient but not excessive freezing of the gland. The procedure is performed with the goal of exposing all prostate tissue to temperatures at or below the point where uniform necrosis is known to occur. Research has shown the optimum ablative temperature for prostate cryosurgery to be ⫺40°C.18 Laboratory studies of cryoprobe performance19,20 combined with clinical observations14 have led to the compilation of 4 guidelines for cryoprobe placement, developed jointly by expert cryosurgeons, as follows: (1) cryoprobes should not be placed ⬎1.8 cm apart, (2) cryoprobes should not be placed ⬎1.0 cm from the margin of the prostate, (3) the distance between the urethra and any cryoprobe should not be ⬍0.8 cm, and (4) the posterior cryoprobes should be placed such that their separation is less than twice the distance to the posterior capsule of the prostate. The cryoprobes are placed roughly in the locations as outlined by Donnelly and Saliken.17 Because of sonographic shadowing beyond the proximal ice ball edge, the cryoprobes are operated from anterior to posterior. Cryoprobes are not inserted directly. Rather, a simple dilator system (FastTrac, Endocare, Inc.) is used to insert a sheath into which a probe is placed once all sheaths have been inserted into the gland. Thermosensor placement takes place after all the sheaths have been placed but before the warming device is inserted into the urethra and before the cryoprobes are inserted into the sheaths. There are 5 thermosensors that are placed, 3 of which ensure that adequately cold temperatures have been reached within the prostate and 2 of which ensure that collateral freezing does not occur in the sensitive anatomy adjacent to the prostate. To ensure that sufficiently cold temperatures have been reached, 1 thermosensor is placed in each neurovascular bundle and 1 is placed at the apex of the gland. Prophylactic thermosensors are placed in the external sphincter and just anterior to the rectal wall at Denonvilliers fascia. Goals during the procedure are to achieve temperatures as follows: (1) at least as cold as ⫺40°C in the neurovascular bundles, (2) not colder than ⫹15°C at the external sphincter, (3) not colder than ⫺40°C at Denonvilliers fascia when the 35

thermosensor is placed at the posterior prostatic capsule, and (4) not colder than 0°C at Denonvilliers fascia when the thermosensor is placed at the anterior rectal wall. Once all cryoprobes are placed, the freezing process is started with the anterior probes, with 50% of argon gas flow. This continues until the anterior ice balls begin to merge. After 2 to 5 minutes of anterior ice formation, the posterolateral cryoprobes are activated at 50% to 70%. Operation of these probes shuts off the blood supply to the prostate. Once adequate thermosensor temperatures are reached at the neurovascular bundles, probes 5 and 6 are activated at 25% to 50% argon gas flow. At this stage of the freeze cycle, the ice ball at the posterior of the prostate needs to be intently monitored to ensure adequate freezing of the gland and protection against freezing of the rectal wall. This is accomplished with the combined use of sonographic visualization and careful monitoring of the thermosensor located in Denonvilliers fascia. Although the incidence of rectourethral fistula formation is extremely rare in modern cryoablation practice, such watchful vigilance serves as insurance against the occurrence of rectal injury. There are 2 criteria that are relied on to determine the completeness of the freeze cycle, which usually lasts about 10 minutes: (1) the targeted lethal temperature (typically ⫺40°C) reading in the thermosensors positioned in the neurovascular bundles and at the apex of the gland, and (2) extension of sonographic freezing to outside the gland in all visible dimensions without injury to the rectal mucosa.21 It must be noted that both these criteria must be met; either on its own is insufficient. Temperature monitoring is necessary as ultrasound is unable to image temperature and can, in fact, overestimate the size of the ice ball because of refraction.22 Sonographic confirmation that the ice ball has enclosed the entire posterior margin of the prostate and has not intruded into the rectal mucosa is imperative. Once the freeze is complete, probes are switched to the thaw mode, which circulates helium gas through the probes and results in an increase in temperature at the cryoprobe tip (active thaw). Once cryoprobe temperatures are above freezing, the flow of helium gas is stopped, and the remaining ice ball is allowed to thaw by the warmth of the body (passive thaw). Some surgeons further facilitate the thawing process by adding warm water to the rectum. When the prostate is completely thawed (no ice visualized sonographically), the second freeze-thaw cycle is initiated in the same manner as the first. After the second freeze-thaw cycle, the cryoprobes and thermocouples are thawed and removed, insertion sites are sutured, and the urethral warmer is removed before transport to the postanesthesia care unit.

FOLLOW-UP PROCEDURES Most patients (95%) were discharged the day of surgery. Then, 4 to 7 days after the procedure, the patient is instructed to plug the suprapubic catheter and to try to void per urethra. The catheter is removed when postvoid residuals are consistently ⬍100 mL. After the procedure, all patients have PSA levels checked at 6 weeks, 3 months, 6 months, 9 months, 12 months, and then every 6 months thereafter. Biopsies are conducted at 1 year and 5 years, and earlier if indicated by an increasing PSA level. Patients are evaluated in the office at the times of their PSA tests.

RESULTS Retrospective analysis was performed on 75 consecutive patients who underwent 75 targeted cryoablation procedures for the primary treatment 36

TABLE I. Patient demographics Range: n (%) Age (yr) Average ⫾ SD Median PSA Average ⫾ SD Median

70.0 ⫾ 5.0 72

Gleason score Average ⫾ SD Median

T-stage Median

8.5 ⫾ 6.0 7.3

⬍10: 17 (23) ⱖ10: 58 (77) Total: 75 (100)

6.7 ⫾ 0.9 7

2–6: 34 (45) 7: 31 (42) 8–10: 10 (13) Total: 75 (100)

T1c

T1–T2a: 59 (79) T2b–T3: 16 (21) Total: 75 (100)

PSA ⫽ prostate-specific antigen.

of biopsy-proven adenocarcinoma of the prostate between December 2000 and December 2001. Patient demographics are summarized in Table I. For analysis, the patients were divided into favorable and unfavorable risk groups. A patient with favorable disease characteristics was defined as a patient with a PSA level ⬍10 ng/mL, a Gleason score ⱕ6, and a T-stage ⱕT2a. Of the 63 patients for whom the PSA nadir was ⬍0.4 ng/mL, 22 (35%) were classified as favorable, and the remaining 41 (65%) were classified as unfavorable. The median follow-up time was 3 months. The procedures were well tolerated, and no postoperative deaths occurred. Incontinence was defined as severe (requiring ⬎2 pads per day) or mild (stress urinary incontinence or incontinence requiring ⬍2 pads per day). Of 75 patients, 1 patient was incontinent preoperatively. Of the remaining 74 patients, 1 patient (1.4%) developed severe incontinence and 3 patients (4%) developed mild incontinence. Urinary retention after suprapubic catheter removal was observed in 5 of the 75 patients (6.7%). Transurethral resection of the prostate was required in 1 of these patients (1.3%) and was performed 4.5 months after the procedure, while short-term intermittent catheterization was required in 2 of the others. No rectourethral fistula formation was seen. Urethral sloughing occurred in 5 of the 75 patients (6.7%) and was managed nonoperatively with catheter drainage in 4 patients. The only patient treated operatively (5 weeks after the procedure) for urethral sloughing developed a scrotal abscess and Fournier gangrene, which was aggressively treated surgically and medically. Altogether, 34 of the 75 patients were potent preoperatively. Erectile dysfunction developed in UROLOGY 60 (Supplement 2A), August 2002

TABLE II. Comparison of 3-month prostate-specific antigens (PSA) in 1990s prostate cryosurgeries and the present study Patients, total (no. tested)

Study Onik et al., 1993 Miller et al.,7 1994 Coogan and McKiel,27 1995 Bahn et al.,28 1995 Wieder et al.,29 1995 Shinohara et al.,26 1996 Present study, 2002 2

55 62 87 210 83 102 93

(23) (62) (87) (130) (61) (92) (75)

Nadir PSA, n (%) <0.4

<5

Mean

Median

7/20 (35) NR NR NR NR NR 63/75 (84)

11/20 (55) NR NR NR 27/47 (57) 76/92 (83) 63/75 (84)

NR 0.59 0.65 0.35 NR NR 0.23

NR 0.1 0.95 NR NR NR 0.0

NR ⫽ not reported.

28 of 34 patients (82.4%), and 6 patients (17.6%) remained potent after the procedure. Universal and often transient impotence immediately after the procedure was expected because of the damage that occurs to the neurovascular bundles.23 Although the follow-up time of this series is limited, there is merit in analysis of our PSA nadirs. Shinohara et al.24 showed that a PSA nadir ⱕ0.4 ng/mL is an excellent predictor of long-term biochemical survival. Conversely, a PSA nadir ⬎0.4 ng/mL is associated with a high probability of residual disease and biochemical failure. Of the 75 patients with sufficient follow-up time, 63 (84%) demonstrated a PSA nadir of ⬍0.4 ng/mL. The median and mean 3-month PSA values of the entire group were 0 and 0.23 ng/mL, respectively. In the favorable group, 20 of 22 patients (91%) achieved a PSA nadir ⬍0.4 ng/mL, and 33 of 41 patients (80%) of the patients in the unfavorable group achieved the same. There were no patients with PSA nadir values between 0.4 and 0.5 ng/mL. DISCUSSION As with a number of previous researchers12,22,23,25,26 this series demonstrates that cryosurgery of the prostate is an effective and safe primary therapy for localized prostate cancer. In addition, it is possible to perform targeted cryoablation of the prostate in a community hospital setting with outcomes comparable to outcomes achieved with procedures conducted in academic hospital settings. A purpose of this article is to provide a detailed overview of the state-of-the-art surgical procedure. However, this knowledge of procedure must be complemented by hands-on experience. As with any procedure, appropriate training is imperative. The training I received consisted of didactic instructions, with subsequent proctoring by an experienced cryosurgeon for my first several cases. The preliminary results of this research are promising. From a therapeutic efficacy standpoint, UROLOGY 60 (Supplement 2A), August 2002

PSA levels of ⱕ0.4 ng/mL were achieved in 84% of the patients at 3 months. In addition, when subjects were divided into favorable and unfavorable groups (based on pretreatment PSA, Gleason score, and T-stage), nadir PSA levels were 91% and 80%, respectively. Although opinions vary, a number of medical professionals contend that a PSA nadir of ⱕ0.4 ng/mL is an excellent predictor of long-term biochemical survival. As can be seen in Table II, the percentages of 3-month, nadir PSA levels compared favorably with and even exceeded those in a number of studies conducted in the early and mid 1990s. The results of this study also compared favorably with studies conducted in the 1990s from a morbidity point of view.2,26 As can be seen in Table III,27–30 the procedures were well tolerated. No rectourethral fistula occurred, and there was only a 1.5% occurrence of severe incontinence and a 5.5% occurrence of urinary retention after suprapubic catheter removal. Clearly, what the comparison of these preliminary results with the studies of the early 1990s signifies is the evolution of the prostate cryosurgery procedure. A demonstration of the effects of that evolution can be seen in the present study—in the higher percentages of nadir PSA levels and lower percentages of complications, which according to thought leaders could ultimately portend long-term biochemical survival and better quality of life for individuals with prostate cancer. Among the developments and improvements in the prostate cryosurgery procedure that have contributed to the evolution of the prostate cryosurgery procedure are: (1) the use of ultrasound to determine the appearance of the ice ball31 as well as to guide cryoprobe placement,2 (2) the urethral warming catheter to protect the urethra from lethal temperatures,32,33 (3) the placement of thermosensors to enhance the temperature information provided by transrectal ultrasound,16 (4) the use of 6 to 8 cryoprobes in place of the traditional 5 37

TABLE III. Comparison of complications in 1990s prostate cryosurgeries and the present study Complications Patients, total (no. tested)

Study Onik et al., 1993 Miller et al.,7 1994 Coogan and McKiel,27 1995 Bahn et al.,28 1995 Cox and Crawford,10 1995 Wieder et al.,29 1995 Shinohara et al.,26 1996 Long et al.,30 1998 Badalament et al.,13 1999 Present study, 2002 2

55 62 87 210 63 83 102 145 290 93

Rectal Fistula

Incontinence

Sloughing

Retention

ED

2.9 0 0 2.4 3 0 0.8 1.3 0.4 0

NR 2.7 3 8.7 27 2.5 4 3 4.3 5.5

4.4 1.3 9 NR 19 3.8 NR 8.9 10 6.7

NR 1.3 5 NR 29 3.8 NR 3.4 NR 6.7

NR NR NR NR NR NR NR NR NR 82.4

(23) (62) (87) (130) (63) (61) (92) (27) (208) (75)

ED ⫽ erectile dysfunction; NR ⫽ not reported.

probes,14 and (5) the use of the double-freeze technique to ensure a successful freeze.16 Together, the developments and improvements in the procedure and the current technological contributions have revolutionized prostate cryosurgery, such that it is now considered a safe and effective technique for targeted destruction of localized prostate cancer. As outlined by Saliken et al.,34 the requirements for proficiency in the prostate cryosurgery procedure are intense. Requirements achieved by urologists who have mastered the technique of the procedure include: (1) imaging, interventional, and surgical skills; (2) competence with a cystoscope; (3) an understanding of ice ball thermodynamics and cryobiology; and (4) cryosurgery-specific experience. These requirements have been recognized by major cryogenic vendors, who are responding by linking sales with dedicated teaching and by developing software to assist urologists with preoperative planning and accurate probe placement. CONCLUSION This article presented an account of the prostate cryosurgery procedure as performed at 2 community hospitals. The preliminary results are consistent with those of procedures performed in academic medical centers, which show the procedure to be an effective and safe primary therapy for localized prostate cancer. Long-term results and randomized trials are the next step in determining whether these preliminary results could mean longer disease-free intervals and increased patient survival compared with results of the current therapeutic methods of radical prostatectomy and radiotherapy. ACKNOWLEDGMENT. I thank J. Clif Vestal, MD, and Douglas O. Chinn, MD, for their patience and support while instructing me in the techniques of the prostate cryosurgery proce38

dure, and Elaine H. Wacholtz, PhD, for assisting with the literature review and preparation of this article.

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