Cryosurgery as a Treatment for Prostate Carcinoma Results and Complications

ABSTRACT
BACKGROUND. There has been a resurgence of interest in cryosurgical ablation of the prostate for the treatment of carcinoma. This is due to recent advances in cryosurgical technology, which have resulted in relatively lower morbidity. The objective of this study was to evaluate the effectiveness of ultrasound-guided cryosurgical ablation of prostate carcinoma.
METHODS. Eighty-three patients who had biopsy-proven prostate carcinoma underwent cryosurgical ablation of their entire prostate gland. The initial group of 12 patients had their procedures performed under ultrasound guidance only. The other 71 patients had cryosurgery performed with temperature monitoring in combination with ultrasound guidance. Twelve patients who had positive biopsies underwent a second cryosurgical procedure. All patients had prostate specific antigen (PSA) levels measured at 3, 6, 12, 18, 24, and 30 months after cryosurgery. Ultrasound-guided sextant biopsies were performed at 3-6, 12-18, and 24 months.
RESULTS. The median PSA dropped by 95%, from a preoperative value of 4.3 ng/mL to 0.2 ng/mL 30 months after cryosurgery. The authors experienced a high failure rate (positive biopsies) of 83% for the initial group of 12 patients who did not have temperature monitoring during the cryosurgical procedure. This was in contrast to a success rate of 90% (negative biopsies) for the next 71 patients, who did have temperature monitoring (P < 0.05, chi-square test). Twelve patients underwent a second cryosurgery, and the success rate for this group was 91% (11 of 12 patients). The combined success rate for both the first cryosurgery and the second was 94% (62 of 77 patients). Complications included urethral sloughing, urinary incontinence, impotence, bladder neck contracture, and bladder contracture. The majority of patients recovered rapidly from their cryosurgical procedures and were able to resume normal activities 3-4 weeks afterward.
CONCLUSIONS. These preliminary results demonstrate that cryosurgical ablation of the prostate is a viable treatment option for prostate carcinoma. In the authors' experience, ultrasound alone may not be adequate for monitoring the entire cryosurgical procedure. The authors found that temperature monitoring shortened their learning curve, enabled them to freeze prostate tissue more aggressively, and may have contributed to their overall success.
KEYWORDS: prostate carcinoma, cryosurgery, cryoablation, cancer treatment, prostate neoplasm, temperature monitoring.

Between April 1993 and September 1995, 83 patients underwent prostate cryosurgery. The mean age of the patients was 69 years (range, 53-84 years). Because the vast majority of these patients reside in the San Gabriel Valley of southern California, we are continuing to acquire direct follow-up data on 98% of the patients.

All patients who underwent prostate cryosurgery signed informed consent forms approved by the Institutional Review Board (IRB) for human subjects. The IRB-approved consent forms state that the urethral warming device was investigational and that the temperature monitoring system (including the thermocouples) was experimental and not approved by the Food and Drug Administration of the U.S. Department of Health and Human Services (FDA).

All patients had prostate carcinoma diagnosed and staged by transrectal ultrasound-guided biopsies in which the sextant approach was used.^11-14 Neurovascular bundles and seminal vesicles were also biopsied in patients with prostate specific antigen (PSA) > 15 ng/mL or in patients who were suspected to have those areas involved with cancer by ultrasound¹⁴ or digital rectal exam. As part of the initial staging workup, all patients had a chest X-ray and bone scan. Many of the patients underwent pelvic and endorectal magnetic resonance imaging. Laparoscopic pelvic lymph node dissection (LPND) was recommended for patients with a PSA > 15 ng/mL or with a total Gleason tumor grade > 7.

Because of the inability of 5 cryoprobes to freeze a prostate gland with volume > 45 cc, 47 of the 83 patients were treated with androgen ablation therapy prior to the cryosurgery to shrink the gland. Forty-three patients who had a gland 50-80 cc were treated with leuprolide acetate depot, 7.5 mg intramuscularly every 4 weeks, for an average of 4.5 months (range, 1-15 months). Four patients who had a gland > 80 cc were treated with a combination of leuprolide acetate depot, 7.5 mg intramuscularly every 4 weeks, and flutamide, 250 mg orally 3 times daily for and average of 5.3 months (range, 3-12 months). Two patients were also treated for hot flashes with megestrol acetate, 40 mg orally 3 times daily, for 1 and 4 months.

Transrectal ultrasound was used to recheck the size of the gland after 3 months of therapy. Androgen ablation therapy could be continued for up to 12 months, depending on the response of the gland. All androgen ablation was halted just before or at the time of cryosurgery.

All procedures were performed with the AccuProbe System (Cryomedical Sciences, Inc. [CMSI], Rockville, MD). The Aloka 650 ultrasound scanner (Aloka, Walling Ford, CT), with a biplane probe (transaxial sector 5 MHz and linear 7.5 MHz), was used to guide the cryogenic probe placement and to monitor the freezing process for all patients. All procedures were performed by a two-physician team composed of an urologist (D.C., M.C. or J.C.) and a radiologist (W.W.) experienced in ultrasound.

Initially, we used the fixed-guide technique described by Onik et al.^5,6 However, we changed to the free hand placement method described by Lee et al.¹⁵ because it allows the freedom of configuring the placement of the

needles and cryogenic probes to the shape of the gland. We used the same mapping technique as Lee et al.¹⁵ for probe placement (Fig. 1).

 

From April to May 1993, our first 12 patients underwent prostate cryosurgery according to the method originally described by Onik et al.^5,6 Ultrasound alone was used to monitor the freezing process. The leading edge of the ice ball was originally thought to be fatal to tissue and was delineated on ultrasound as a thin white line (hyperechoic) surrounding an area of acoustic shadowing.^5,6 The termination point for the freezing process occurred when the entire prostate gland was encompassed by the area of shadowing and the white line of the ice ball encroached on the muscularis (dark band) around the rectal wall. The cryogenic probes were pulled back by 1-2 cm to ensure that the ice ball encompassed the full length of the prostate gland.

Figure 1. A planning map for cryoablation is shown. (a) A transverse view, near the mid-gland of the prostate, is shown. Cryogenic probes depicted by are numbered 1-5. Attempts were made to keep the distances between the probes less than 1.8 cm. Probes 1 and 4 are placed in a way that allows distance y to exceed distance x. Thermocouple positions are depicted as open circles. Anterior thermocouple (An) is placed in the anterior fibromuscular stroma. Apex thermocouple (Ap) is imbedded 1 cm within the substance of the prostate in between Probes 4 and 5. The neurovascular thermocouples (R and L) are placed in the posterolateral margins of the mid-gland. (b) A longitudinal view through the midline of the gland is shown. Denonvilliers' thermocouple (D) is placed in between the rectum and the posterior portion of the prostate gland. Probe 5 is placed closer to the prostatic urethra than to the rectum. UW: urethral warming catheter.

From June 1993 to September 1993, we modified the original technique of Onik et al.^5,6 by using thermocouples as part of our procedure on 29 patients. Initially, we placed a thermocouple in Denonvilliers' fascia as an extra safety device to prevent freezing the rectal wall, which would result in urethrorectal fistula. Later, we started placing thermocouples in the region of the neurovascular bundle. Since October 1993, we have consistently placed 5 thermocouples in the following areas (Fig. 1): (1) anterior portion at mid-gland, (2) apex, (3) Denonvilliers' fascia, (4) right neurovascular bundle, and (5) left neurovascular bundle.

Initially, the thermocouples were connected to individual hand-held meters to measure the temperatures. This became quite cumbersome when we used five thermocouples simultaneously. We subsequently developed a computerized data acquisition system that could continuously monitor and record five temperatures simultaneously (Fig. 2). This system graphically displays the temperature on a real-time basis by sampling the five thermocouple temperatures once every second. Temperature records are stored in a data file that can be retrieved for later review.

We currently use a combination of transrectal ultrasound and thermocouple temperature monitoring to determine the end point of the cryosurgical procedure. The target fatal temperature that we try to achieve in all 5 thermocouple positions is below -40 °C.¹⁶ Sometimes we cannot achieve the fatal target temperature in certain areas. In such a situation, we hold the freeze longer and utilize another freeze thaw cycle.¹⁷ We stop the freezing process prior to achieving our target temperature if the ultrasound image indicates that we may be in danger of freezing the rectal mucosa. Our current technique is to perform a double freeze, a freeze plus a pullback, or a double freeze and then a pullback as determined by gland length, with a target temperature of -40 °C for each freeze cycle.

We originally used a urethral warming catheter supplied by CMSI to prevent freezing of the prostatic urethra. In April 1994, the FDA removed the warming catheter system from the market. We then used an alternative warming catheter system.^18,19 In May 1995, we were able to locate a manufacturer that was able to supply a warming catheter that closely resembled the original design. We also designed our own fluid warmer, which could maintain the water temperature at 44-45 °C.

All patients were evaluated 3-5 days after surgery. They were then evaluated at 2- to 4-week intervals for approximately ^2-4 months. If they had any complications, they were examined at more frequent intervals and over a longer time period.

PSA levels were drawn at 3, 6, 12, 18, 24, and 30 months after the procedure. Sextant biopsies were performed at 3, 12, and 24 months after surgery. The 3-month biopsies were later changed to 6-month biopsies to allow for further healing after the surgery.